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Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials

Open AccessPublished:June 30, 2021DOI:https://doi.org/10.1016/j.jagp.2021.06.016

      Highlights

      • What is the primary question addressed by this study? To determine evidence-based suggestions for future trial designs targeting apathy in neurocognitive disorders by evaluating recent advances in four key areas of progress: assessment, mechanisms/biomarkers, treatment/intervention efficacy, pre-dementia states.
      • What is the main finding of this study? Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a carefully considered and well-formed approach to the development of intervention strategies.
      • What is the meaning of the finding? A better understanding of the subdomains and biological mechanisms of apathy are needed to advance apathy as a treatment target for clinical trials.

      Abstract

      Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

      Key Words

      INTRODUCTION

      Apathy is a common neuropsychiatric symptom (NPS) characterized by a loss of motivation, emotional reactivity and initiative.
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      Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study.
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      De novo genesis of neuropsychiatric symptoms in mild cognitive impairment (MCI).
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      Prevalence, neurobiology, and treatments for apathy in prodromal dementia.
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      whether detected in cognitively normal (CN) older adults
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      or in those with MCI.
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      Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer's disease in non-depressed subjects.
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      Apathy has been associated with an approximately 2-fold increased risk of dementia in MCI, which was 1) independent of current depression, 2) greater in the short term, and 3) less strong with higher age and greater cognitive impairment.
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      Furthermore, apathy has been linked to a three-fold increased risk of mortality.
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      Patterns and persistence of behavioural and psychological symptoms in those with cognitive impairment: the importance of apathy.
      ,
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      Apathy: risk factor for mortality in nursing home patients.
      Finally, apathy negatively impacts both patients and caregivers, having been associated with greater functional impairment
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      With better understanding of the mechanistic underpinnings of apathy,
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      combined with ongoing efforts to refine its diagnostic criteria,
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      apathy is increasingly becoming a target for clinical trials.
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      Considering new treatment paradigms for neuropsychiatric symptoms of Alzheimer's disease.
      ,
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      Pharmacological interventions for apathy in Alzheimer's disease.
      Recent efforts by key opinion leaders and regulatory officials have led to diagnostic criteria for apathy specifically in neurocognitive disorders, defining it as an indication for treatment.
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      Given the increased interest in and recognition of apathy as an important target for research and intervention,
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      Apathy associated with neurocognitive disorders: recent progress and future directions.
      this paper 1) offers a critical evaluation of recent advances in key areas of research focusing on apathy as a treatment target; 2) provides suggestions for future trial designs; and 3) identifies areas of research warranting future attention.

      APATHY IN PRE-DEMENTIA STATES

      Much of the evidence base for apathy in NCD has been driven by research in AD dementia.
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      Apathy also is a common preclinical and prodromal symptom, and an area of growing interest in advance of dementia
      • Lanctôt KL
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      Apathy associated with neurocognitive disorders: recent progress and future directions.
      but there are issues regarding the definition of apathy and variation in apathy symptoms across the spectrum of cognitive impairment.
      Consistent with other NPS, apathy is associated with poorer outcome in pre-dementia populations. Cross-sectionally, apathy in non-demented groups is associated with executive dysfunction,
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      poorer quality of life,
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      olfactory disturbance,
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      subjective impairments in physical functioning,
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      Apathy is associated with greater decline in subjective, but not in objective measures of physical functioning in older people without dementia.
      impairment in instrumental activities of daily living,
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      and greater family caregiver burden.
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      Longitudinally, apathy in non-demented individuals is associated with functional decline,
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      slowed gait and frailty,
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      Symptoms of apathy independently predict incident frailty and disability in community-dwelling older adults.
      and incident cognitive decline and dementia.
      • Vicini Chilovi B
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      • Zanetti M
      • et al.
      Differential impact of apathy and depression in the development of dementia in mild cognitive impairment patients.
      ,
      • Duara R
      • Loewenstein DA
      • Greig MT
      • et al.
      Pre-MCI and MCI: neuropsychological, clinical, and imaging features and progression rates.
      ,
      • Geda YE
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      Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study.
      Thus apathy is increasingly identified as an important dementia risk marker, whose relevance is highlighted by the inclusion of NPS in the 2011 National Institute on Aging–Alzheimer's Association (NIA-AA) consensus recommendations for diagnosis of all-cause dementia.
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      The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
      To explore the importance of NPS and dementia risk, the NPS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment of the Alzheimer's Association (ISTAART-AA) developed research diagnostic criteria for mild behavioral impairment (MBI).
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      Apathy is 1 of the 5 MBI domains. Importantly, the ISTAART-AA MBI criteria specify explicitly that symptoms emerge in later life and persist for ≥6-months in persons without dementia to qualify as MBI. These criteria minimize false positives from the inclusion of reactive symptomatology or medical comorbidity. Also clarified in the ISTAART-AA MBI criteria are the relationship between MCI (which, along with SCD, represents the neurocognitive axis of neurodegenerative disease) and MBI (representing the neurobehavioral axis), allowing for neurocognitive and neurobehavioral syndromes to emerge in parallel or sequentially, with all groups reflecting at-risk states for further cognitive decline and dementia.
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      Mild behavioral impairment and subjective cognitive decline predict cognitive and functional decline.
      Prevalence rates of MBI-apathy using a retrospective operationalization matrix have been reported as 20.4% in population-based
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      and 42.2% in clinical samples,
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      Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden.
      and 17%–24% using an MBI-specific assessment tool.
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      Profile of mild behavioral impairment and factor structure of the mild behavioral impairment checklist in cognitively normal older adults.
      In a large study of CN participants, MBI was associated with poorer attention and working memory scores which declined over 1 year.
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      Mild behavioral impairment as a marker of cognitive decline in cognitively normal older adults.
      Thus, MBI apathy represents a potential target in disease modifying dementia prevention trials.
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      Dementia clinical trial implications of Mild Behavioral Impairment.
      In addition to associations with cognitive impairment and incident cognitive decline and dementia,
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      Mild behavioral impairment and subjective cognitive decline predict cognitive and functional decline.
      ,
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      Risk of conversion to dementia in a mild behavioral impairment group compared to a psychiatric group and to a mild cognitive impairment group.
      MBI has links to known dementia markers. These markers include amyloid-β,
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      Mild behavioral impairment is associated with β-amyloid but not tau or neurodegeneration in cognitively intact elderly individuals.
      ,
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      Plasma β-amyloid in mild behavioural impairment-neuropsychiatric symptoms on the Alzheimer's continuum.
      tau,
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      Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.
      neurodegeneration,
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      Mild behavioral impairment is associated with atrophy of entorhinal cortex and hippocampus in a memory clinic cohort.
      functional dysconnectivity,
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      Mild behavioral impairment in Parkinson's disease is associated with altered corticostriatal connectivity.
      and AD genetic loci.
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      ,
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      Summary: With the high prevalence of apathy as a preclinical symptom, and the robust evidence for apathy as a prodromal feature, enrolling participants with emergent apathy is both feasible and scientifically sound. Ensuring participation of study partners, who provide the descriptions of apathy, may help overcome difficulties in ensuring those with behavioral apathy or decreased initiative do attend study visits. Emergent apathy in older adults without dementia is a potential treatment target for both pharmacological and non-pharmacological interventions. Treating this clinically significant later life symptom/syndrome will reduce suffering and inform clinicians and researchers on the role of treating late life apathy in dementia risk mitigation.

      Assessment

      Apathy, considered as a symptom or a syndrome, is a concept still lacking a unified and generally accepted definition. Historic, but somewhat confusing terms, used to either describe apathy or as synonyms of apathy include abulia, indifference, avolition, lack of motivation, flattened affect, social withdrawal, or procrastination. However, update diagnostic criteria have sought to rectify such confusion.
      • Robert P
      • Lanctot KL
      • Aguera-Ortiz L
      • et al.
      Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group.
      ,
      • Miller D
      • Robert P
      • Ereshefsky L
      • et al.
      Diagnostic criteria for apathy in neurocognitive disorders.
      While apathy is common in dementia and has been linked to poorer prognosis,
      • Groeneweg-Koolhoven I
      • Comijs HC
      • Naarding P
      • et al.
      Apathy in older persons with depression: course and predictors: the NESDO study.
      its assessment is challenging. Discrepancies in reported prevalence estimates and frequencies have been attributed to a lack of standardized diagnostic criteria and assessment methods.
      • Brodaty H
      • Burns K
      Nonpharmacological management of apathy in dementia: a systematic review.
      A particular challenge to apathy diagnostics is its overlap with depression in dementia.

      Differentiating Apathy From Depression: Implications For Assessment and Treatment Options

      Symptoms of both apathy and depression are associated with many neurological conditions including Parkinson's disease, stroke and all-cause dementia, and psychiatric conditions such as schizophrenia and major depression. Apathy is often misdiagnosed as depression, is common in people with late-life depression and is unresponsive to antidepressants.
      While syndromic apathy and depression in dementia share a number of symptoms (lack of interest, lack of initiative, low motivation, decreased libido, decreased concentration and lower energy), there is increasing evidence to indicate that they are distinct, but overlapping entities (see
      • Mortby ME
      • Maercker A
      • Forstmeier S
      Apathy: a separate syndrome from depression in dementia? A critical review.
      for a detailed review). Clinical differences (Table 1) can assist the differentiation of apathy and depression in dementia,
      • Brodaty H
      • Connors MH
      Pseudodementia, pseudo- pseudodementia and pseudodepression.
      and a key distinguishing feature is that while depression predominantly affects mood, apathy predominantly affects volition.
      • Brodaty H
      • Connors MH
      Pseudodementia, pseudo- pseudodementia and pseudodepression.
      Similarly, treatments of depression such as SSRIs are linked with the onset of a dose-dependent, sometimes reversible, apathy.
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      • Padala KP
      • Monga V
      • et al.
      Reversal of SSRI-associated apathy syndrome by discontinuation of therapy.
      Further evidence, as detailed below, also supports distinct neuroanatomical pathology, with apathy having been linked to pathology in the left orbitofrontal cortex,
      • Holthoff VA
      • Beuthien-Baumann B
      • Kalbe E
      • et al.
      Regional cerebral metabolism in early Alzheimer's disease with clinically significant apathy or depression.
      right anterior cingulate grey matter,
      • Lavretsky H
      • Ballmaier M
      • Pham D
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      Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study.
      and right fronto-subcortical circuit,
      • Brodaty H
      • Sachdev P
      • Withall A
      • et al.
      Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke – the Sydney Stroke Study.
      while depression appears to be linked to pathology in left dorsolateral prefrontal cortex
      • Holthoff VA
      • Beuthien-Baumann B
      • Kalbe E
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      Regional cerebral metabolism in early Alzheimer's disease with clinically significant apathy or depression.
      and orbitofrontal grey matter.
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      Neuroanatomical characteristics of geriatric apathy and depression: a magnetic resonance imaging study.
      It is therefore important to distinguish the two conditions in treatment trials and to specify the context in which apathy occurs, to differentiate apathy from depression, and/or to capture apathy symptomatology within a full depressive disorder. This is particularly important in clinical practice as clinicians often are faced with treating patients exhibiting both dimensions.
      Table 1Clinical Features Differentiating Apathy from Depression
      ApathyDepression
      Symptomatology
      AffectLack emotionSad, tearful
      Thought contentDoes not careNo point to life, pessimistic, hopeless, worthless
      BehaviorPassive, compliantMay avoid socialisation or treatment
      SuicidalityNot suicidalMaybe suicidal/“rather be dead“
      AnxietyNot usually anxiousMaybe anxious
      RuminationUsually absentMay be present
      Vegetative symptomsUsually absent although weight loss can occur if lacks initiative to organize mealsCan occur – poor sleep, loss of appetite, weight loss
      Longitudinal courseIncreases over time if part of a neurodegenerative condition (e.g. dementia)May resolve or fluctuate; generally diminishes in late stages of a neurodegenerative disease
      Treatment Features
      Response to activitiesMay be amenable to structured activitiesMay resist structured activities; active avoidance
      Counter-transferenceNo sadness transmits to clinicianClinician feels sadness and despair
      Response to antidepressant medicationsNot responsiveMay respond
      Note. Table of differences in clinical presentation of apathy adapted from Brodaty and Connors.
      • Brodaty H
      • Connors MH
      Pseudodementia, pseudo- pseudodementia and pseudodepression.

      Diagnostic Criteria

      The conceptualization and measurement of apathy are critical factors in the design of pharmacological and non-pharmacological clinical trials. Apathy should be defined in clinical trials using widely accepted diagnostic criteria. Table 2 provides a summary of the diagnostic criteria and recent revisions aimed at improving care and clinical trial investigation, and aimed to enhance their applicability to diverse clinical populations.
      Table 2Evolution of the Diagnostic Criteria for Apathy
      2008 Diagnostic Criteria for Apathy in Alzheimer's disease and other Neuropsychiatric Disorders
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      • Leentjens AF
      • et al.
      Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders.
      For a diagnosis of Apathy the patient should fulfil the criteria A, B, C and D.
      Criterion A.Loss of or diminished motivation in comparison to the patient's previous level of functioning and which is not consistent with his age or culture. These changes in motivation may be reported by the patient himself or by the observations of others
      Criterion B.Presence of at least one symptom in at least two of the three following domains for a period of at least four weeks and present most of the time.
      Domain B1 - Behaviour

      Loss of, or diminished, goal-directed behaviour as evidenced by at least one of the following:
      Initiation symptom: loss of self-initiated behaviour (for example: starting conversation, doing basic tasks of day-to-day living, seeking social activities, communicating choices)
      Responsiveness symptom: loss of environment-stimulated behaviour (for example: responding to conversation, participating in social activities)
      Domain B2 - Cognition

      Loss of, or diminished, goal-directed cognitive activity as evidenced by at least one of the following:
      Initiation symptom: loss of spontaneous ideas and curiosity for routine and new events (i.e, challenging tasks, recent news, social opportunities, personal/family and social affairs).
      Responsiveness symptom: loss of environment-stimulated ideas and curiosity for routine and new events (i.e., in the person's residence, neighbourhood or community)
      Domain B3 - Emotion

      Loss of, or diminished, emotion as evidenced by at least one of the following:
      Initiation symptom: loss of spontaneous emotion, observed or self-reported (for example, subjective feeling of weak or absent emotions, or observation by others of a blunted affect).
      Responsiveness symptom: loss of emotional responsiveness to positive or negative stimuli or events (for example, observer-reports of unchanging affect, or of little emotional reaction to exciting events, personal loss, serious illness, emotional-laden news).
      Criterion C.These symptoms (A - B) cause clinically significant impairment in personal, social, occupational, or other important areas of functioning.
      Criterion D.The symptoms (A - B) are not exclusively explained or due to physical disabilities (e.g. blindness and loss of hearing), to motor disabilities, to diminished level of consciousness or to the direct physiological effects of a substance (e.g. drug of abuse, a medication).
      2018 Proposed New Diagnostic Criteria for Apathy
      • Robert P
      • Lanctot KL
      • Aguera-Ortiz L
      • et al.
      Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group.
      Criterion A.A quantitative reduction of goal-directed activity either in behavioral, cognitive, emotional or social dimensions in comparison to the patient's previous level of functioning in these areas. These changes may be reported by the patient himself/herself or by observation of others.
      Criterion B.The presence of at least 2 of the 3 following dimensions for a period of at least four weeks and present most of the time
      B1. Behaviour & Cognition

      Loss of, or diminished, goal-directed behaviour or cognitive activity as evidenced by at least one of the following:
      General level of activity: the patient has a reduced level of activity either at home or work, makes less effort to initiate or accomplish tasks spontaneously, or needs to be prompted to perform them.
      Persistence of activity: He/she is less persistent in maintaining an activity or conversation, finding solutions to problems or thinking of alternative ways to accomplish them if they become difficult.
      Making choices: He/she has less interest or takes longer to make choices when different alternatives exist (e.g., selecting TV programs, preparing meals, choosing from a menu, etc.)
      Interest in external issue: He/she has less interest in or reacts less to news, either good or bad, or has less interest in doing new things.
      Personal wellbeing: He/she is less interested in his/her own health and wellbeing or personal image (general appearance, grooming, clothes, etc.)
      B2. Emotion

      Loss of, or diminished, emotion as evidenced by at least one of the following:
      Spontaneous emotions: the patient shows less spontaneous (self-generated) emotions regarding their own affairs, or appears less interested in events that should matter to him/her or to people that he/she knows well.
      Emotional reactions to environment: He/she expresses less emotional reaction in response to positive or negative events in his/her environment that affect him/her or people he/she knows well (e.g., when things go well or bad, responding to jokes, or events on a TV program or a movie, or when disturbed or prompted to do thing she/she would prefer not to do).
      Impact on others: He/she is less concerned about the impact of his/her actions or feelings on the people around him/her.
      Empathy: He/she shows less empathy to the emotions or feelings of others (e.g., becoming happy or sad when someone is happy or sad, or being moved when others need help).
      Verbal or physical expressions: He/she shows less verbal or physical reactions that reveal his/her emotional states.
      B3. Social Interaction

      Loss of, or diminished engagement in social interaction as evidenced by at least one of the following:
      Spontaneous social initiative: the patient takes less initiative in spontaneously proposing social or leisure activities to family or others.
      Environmentally stimulated social interaction: He/she participates less, or is less comfortable or more indifferent to social or leisure activities suggested by people around him/her.
      Relationship with family members: He/she shows less interest in family members (e.g., to know what is happening to them, to meet them or make arrangements to contact them).
      Verbal interaction: He/she is less likely to initiate a conversation, or he/she withdraws soon from it.
      Homebound: He /She prefer to stays at home more frequently or longer than usual and shows less interest in getting out to meet people.
      Criterion C.These symptoms (A - B) cause clinically significant impairment in personal, social, occupational, or other important areas of functioning.
      Criterion D.The symptoms (A - B) are not exclusively explained or due to physical disabilities (e.g. blindness and loss of hearing), to motor disabilities, to a diminished level of consciousness, to the direct physiological effects of a substance (e.g. drug of abuse, medication), or to major changes in the patient's environment.
      2021 Consensus Diagnostic Criteria for Apathy in Neurocognitive Disorders
      • Miller D
      • Robert P
      • Ereshefsky L
      • et al.
      Diagnostic criteria for apathy in neurocognitive disorders.
      Criterion A.

      Primary diagnoses
      The patient meets criteria for a syndrome of cognitive impairment or dementia (as defined by either ICD or DSM-5 criteria; e.g.: AD, vascular dementia, FTD, DLB, PDD, a pre-dementia cognitive impairment syndrome such as MCI, prodromal AD, or other cognitive disorder).
      Criterion B.

      Symptoms and duration
      The patient exhibits at least one symptom in at least two of the following 3 dimensions (B1 to B3). These symptoms have been persistent or frequently recurrent for a minimum of 4 wks and represent a change from the patient's usual behavior. These changes may be reported by the patient themselves or by observation of others.
      Dimension B1

      Diminished initiative: Less spontaneous and/or active than usual self: Less likely to initiate usual activities such as hobbies, chores, self-care, conversation, work-related or social activities
      Dimension B2

      Diminished interest: Less enthusiastic about usual activities:

      - Less interested in, or less curious about events in their environment

      - Less interested in activities and plans made by others

      - Less interested in friends and family

      - Reduced participation in activities even when stimulated

      - Less persistence in maintaining or completing tasks or activities
      Dimension B3

      Diminished emotional expression/responsiveness:

      - Less spontaneous emotions

      - Less affectionate compared to their usual self

      - Expresses less emotion in response to positive or negative events

      - Less concerned about the impact of their actions on other people

      - Less empathy
      Criterion C.

      Exclusionary criteria
      These symptoms are not exclusively explained by psychiatric illnesses, intellectual disability, physical disabilities, motor disabilities, change in level of consciousness, or the direct physiological effects of a substance.
      Criterion D.

      Severity
      These symptoms cause clinically significant impairment in personal, social, occupational, and/or other important areas of functioning. This impairment must be a change from their usual behaviour.
      Abbreviations: AD: Alzheimer's disease; DLB: dementia with Lewy bodies; DSM: Diagnostic and Statistical Manual of Mental Disorders; FTD: frontotemporal lobar degeneration; ICD: International Classification of Diseases; MCI: mild cognitive impairment; PDD: Parkinson's disease dementia.
      Building on initial attempts to define
      • Marin RS
      Apathy: a neuropsychiatric syndrome.
      and operationalize
      • Starkstein SE
      • Petracca G
      • Chemerinski E
      • et al.
      Syndromic validity of apathy in Alzheimer's disease.
      diagnostic criteria for apathy, an international consensus proposed initial diagnostic criteria for the syndrome apathy
      • Robert P
      • Onyike CU
      • Leentjens AF
      • et al.
      Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders.
      to be applied in clinical practice independently of its etiology. Those criteria were validated in different diseases, and showed good reliability, validity and acceptability.
      • Mulin E
      • Leone E
      • Dujardin K
      • et al.
      Diagnostic criteria for apathy in clinical practice.
      The two most recent revisions apply to apathy in the context of brain disorders
      • Robert P
      • Lanctot KL
      • Aguera-Ortiz L
      • et al.
      Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group.
      or specifically for neurocognitive disorders.
      • Miller D
      • Robert P
      • Ereshefsky L
      • et al.
      Diagnostic criteria for apathy in neurocognitive disorders.
      These aimed to achieve better adaptation for use in clinical trials and to increase the validity of apathy as a clinical construct by providing a clinical and scientific framework. While the revisions to the diagnostic criteria proposed in 2018
      • Robert P
      • Lanctot KL
      • Aguera-Ortiz L
      • et al.
      Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group.
      preserved the overall diagnostic structure, they included the following key changes: Criterion A: 1) replacement of the term “motivation” with “goal directed behavior” as this could be measured more objectively; 2) removal of the phrase “which is not consistent with his age or culture” as this was deemed unnecessary when the reduction is compared to the patient's prior level of functioning; 3) addition of the apathy domains of behavior, cognition, emotion and social in the definition. Criterion B: 1) combination of the behavior and cognition domains into a single domain due to challenges with differentiating emotion form behavioral deficits as the cause of the observed behavior decrease; the emotion domain remained unchanged; addition of social interaction as it is proposed to represent a distinct element of apathy;
      • Ang YS
      • Lockwood P
      • Apps MA
      • et al.
      Distinct subtypes of apathy revealed by the apathy motivation index.
      2) addition of differences between environment-stimulated and self-initiated deficits; 3) addition of examples of symptoms for each area of impairment. Criterion C: unchanged. Criterion D: modification to include significant environmental changes as a potential reason for exclusion, as well as conditions which can mimic apathy, those which are transient and/or are the result of medication. A further advancement, the 2021 Consensus Diagnostic Criteria for Apathy in Neurocognitive Disorders, were developed in collaboration with regulatory authorities and other stakeholders and apply specifically to those with a syndrome of cognitive impairment or dementia.
      • Miller D
      • Robert P
      • Ereshefsky L
      • et al.
      Diagnostic criteria for apathy in neurocognitive disorders.
      A particular goal was to facilitate use of the criteria among those with either mild or advanced cognitive deficits or physical impairment. The criteria utilize the 3-dimension construct of apathy: diminished initiative/activity, interest/enthusiasm, and emotional expression/responsiveness. Examples are provided for each dimension, including social interactions. While further work is needed to fully validate the criteria, they provide a clear framework for the apathy syndrome among those with cognitive deficits and can aid development of optimal clinical trials.

      Rating Scale Aspects

      Apart from defining the apathy syndrome, it is equally important to measure its severity to assess the efficacy of interventions. NPS are usually measured with rating scales. Several apathy rating scales have been published, both as independent measurement instruments and as part of general scales measuring a range of NPS (see Supplementary Material 1 for summary). Table 3 shows the main characteristics of interest for treatment studies of the most frequently used apathy rating scales.
      Table 3Principal Characteristics of Interest for Treatment Studies of the Most Frequently Used Rating Scales for the Measurement of Apathy
      Apathy Evaluation Scale
      • Marin RS
      • Biedrzycki RC
      • Firinciogullari S
      Reliability and validity of the apathy evaluation scale.
      Neuropsychiatric Inventory: Apathy item
      • Cummings JL
      • Mega M
      • Gray K
      • et al.
      The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia.
      Dementia Apathy Interview and Rating
      • Strauss ME
      • Sperry SD
      An informant-based assessment of apathy in Alzheimer disease.
      Apathy Scale
      • Starkstein SE
      • Mayberg HS
      • Preziosi TJ
      • et al.
      Reliability, validity, and clinical correlates of apathy in Parkinson's disease.
      Apathy Inventory
      • Robert PH
      • Clairet S
      • Benoit M
      • et al.
      The apathy inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment.
      Lille Apathy Rating Scale
      • Sockeel P
      • Dujardin K
      • Devos D
      • et al.
      The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease.
      Type of scaleApathy in generalGeneral neuropsychiatric assessment including apathyApathy in dementiaApathy in generalApathy in generalApathy in Parkinson's disease
      Apathy domainsYes. 3 domainsNoNoNoYes. 3 domainsYes. 9 domains
      Sensitivity to changeYesYesUnknownYesUnknownUnknown
      Time-frame of assessment4 wks4 wks4 wks4 wksNot established4 wks
      Information source and type of raterPatient-rated, informant-rated and clinician-rated versions with semi-structured interviewClinician-rated through interview with informant. One version (NPI-C) also includes patient's examinationClinician-rated through structured interview with informantClinician-rated through patient or informant interviewClinician-rated through interview with patient. One version through interview with informantClinician-rated through structured interview with patient. One version with structured interview with informant
      Specific validation in nursing home patientsYes (AES-10)Yes (NPI-NH version)NoYes (AS-10-NH version)NoNo
      Accumulated experience shows that apathy scales should take into consideration:
      • 1
        Psychometric properties. The scale must have good enough psychometric properties in terms of quality of its construction, reliability, validity, and sensitivity to change (see below). Floor and ceiling effects are particularly important in measuring apathy since apathy is often quite severe in advanced dementia resulting in maximal scores or ceiling effects.
      • 2
        Type of scale. Apathy rating scales range from general scales to disease- or symptom-specific scales. The Neuropsychiatric Inventory (NPI) apathy item and the Apathy Evaluation Scale (AES) are the most widely used. These were designed to measure apathy independently of the base disorder and thus offer broad utility but disease-specific scales may have better properties such as greater sensitivity to change and specificity of symptoms. The question about the convenience of developing and using specific scales for individual major diseases or syndromes that cause apathy remains, as do questions about the difference between measuring apathy as symptom or as a syndrome.
      • 3
        Apathy domains. Apathy is not a single construct; several domains have been proposed depending on different conceptualizations. Marin's model of apathy
        • Marin RS
        Differential diagnosis and classification of apathy.
        defined the following domains: emotional response, cognitive activity directed to a specific purpose or goal, and behavior directed to a specific purpose or goal. Levy and Dubois's model
        • Levy R
        • Dubois B
        Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits.
        defined the domains of emotional blunting, cognitive inertia, and deficit of thinking and self-generated behaviors. Current diagnostic criteria have diminished initiative, diminished interest and diminished emotional expression and/or responsiveness,
        • Miller D
        • Robert P
        • Ereshefsky L
        • et al.
        Diagnostic criteria for apathy in neurocognitive disorders.
        with social interaction considered under each. Ideally, apathy rating scales should take into account apathy dimensions and be able to measure them independently since they may be associated with different neurobiological changes, and may respond differently to interventions.
      • 4
        Sensitivity to change. A rating scale for clinical trials must be sensitive to treatment- induced symptom change but to date we have a limited evidence-base to determine the precise sensitivity to change of currently used apathy rating scales and what effect size represents clinically significant change.
      • 5
        Time-frame of assessment. The different rating instruments for apathy measure symptoms within different specific periods, typically ranging between 1 week to 1 month. While this can be acceptable for a cross-sectional assessment of apathy severity, scales intended for use in clinical trials should consider the time necessary to observe clinically significant changes after the introduction of the tested intervention.
      • 6
        Information source and type of rater. Current apathy rating scales obtain information directly from the patient, caregiver (professional or informal)/study partner, clinician evaluation, or a combination of these. There is a consensus that in cognitively impaired individuals self-administered rating scales should not be used, especially in clinical trials, due to bias imposed by the symptom itself and difficulty of patients to rate changes in themselves; frequently, patients lack insight into their deficits (anosognosia). Instruments based on caregiver input and direct patient observation/assessment are preferable.
      • 7
        Setting. Apathy is commonly linked to disorders affecting older persons, some who may be institutionalized. While the process of institutionalization can lead to apathy, the institutional environment, which can be highly organized and directive, also poses peculiarities and differential aspects that can affect many behaviors, including apathy.
      Regarding NPS measurement in preclinical and prodromal populations, and incorporating the framework set out in the ISTAART-AA criteria, the MBI checklist (MBI-C) has been developed specifically as a case ascertainment instrument for MBI.
      • Ismail Z
      • Agüera-Ortiz L
      • Brodaty H
      • et al.
      The Mild behavioral impairment checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations.
      ,
      • Aguera-Ortiz LF
      • Lopez-Alvarez J
      • Del Nido-Varo L
      • et al.
      Mild behavioural impairment as an antecedent of dementia: presentation of the diagnostic criteria and the Spanish version of the MBI-C scale for its evaluation.
      The MBI-C is available in multiple translations at www.MBItest.org, and has potential utility in dementia prevention trials. The MBI-C is a general psychopathology scale, designed to detect NPS in pre-dementia populations. Apathy is reflected in the MBI-C with 6 questions: 2 each with respect to cognitive, behavioral and emotional apathy,
      • Ismail Z
      • Agüera-Ortiz L
      • Brodaty H
      • et al.
      The Mild behavioral impairment checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations.
      developed a priori to map onto the 3 domains for the apathy clinical criteria. With more robust queries for apathy symptoms and focusing on apathy as a syndrome in pre-dementia populations, the MBI-C may provide an avenue to explore further the prevalence and prognostic utility of apathy in older adults with normal cognition, SCD and MCI. The MBI-C has been validated in CN, SCD and MCI for in-person, telephone and online administration.
      • Creese B
      • Griffiths A
      • Brooker H
      • et al.
      Profile of mild behavioral impairment and factor structure of the mild behavioral impairment checklist in cognitively normal older adults.
      ,
      • Mallo SC
      • Ismail Z
      • Pereiro AX
      • et al.
      Assessing mild behavioral impairment with the mild behavioral impairment checklist in people with subjective cognitive decline.
      ,
      • Mallo SC
      • Ismail Z
      • Pereiro AX
      • et al.
      Assessing Mild Behavioral Impairment with the Mild Behavioral Impairment-Checklist in People with Mild Cognitive Impairment.
      Research into apathy amongst cognitively unimpaired older adults (i.e., NIA-AA Stage 2 disease) with AD is still emerging. However, it has been limited by the challenges of confirming AD pathology in cognitively normal older adults, and by appropriate neuropsychiatric symptom measurement to determine case positivity for apathy. A recent study of amyloid+ cognitively unimpaired older adults (i.e., Stage 2 disease) found a relationship between global MBI-C score and tau uptake in early Braak regions associated with AD. While affective dysregulation and impulse dyscontrol predicted tau, apathy score demonstrated only a trend level of association (P = 0.09) in this sample.
      • Johansson M
      • Stomrud E
      • Insel PS
      • et al.
      Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.
      It is not yet clear if the presence/absence of apathy symptoms, or scores above a specific threshold would provide more accurate prevalence estimates in this population. Further, many studies only report mean scores for the sample, rather than prevalence.
      • Lussier FZ
      • Pascoal TA
      • Chamoun M
      • et al.
      Mild behavioral impairment is associated with β-amyloid but not tau or neurodegeneration in cognitively intact elderly individuals.
      ,
      • Johansson M
      • Smith R
      • Stomrud E
      • et al.
      Mild behavioral impairment is predictive of tau deposition in the earliest stages of Alzheimer's disease.
      • Johansson M
      • Stomrud E
      • Insel PS
      • et al.
      Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.
      Further research is required.
      Apathy has also been linked to important geriatric risk markers including hearing impairment and frailty. A study of older adults referred for audiometry found a link between MBI-C score and hearing impairment. Specifically, patients with hearing impairment had greater global MBI-C burden, and these findings were significantly higher for the apathy and impulse dyscontrol domains, emphasizing the clinical relevance of apathy in advance of dementia.
      • Gosselin PA
      • Ismail Z
      • Faris PD
      • et al.
      Effect of hearing ability and mild behavioral impairment on Moca and memory index scores.
      Similarly, MBI has been linked to frailty in a sample of elderly primary care patients with CN or MCI. In that recent study, the MBI-C composite score was associated with frailty, and those with apathy, affective dysregulation, and social inappropriateness were more likely to meet frailty criteria.
      • Fan S
      • Liang X
      • Yun T
      • et al.
      Mild behavioral impairment is related to frailty in non-dementia older adults: a cross-sectional study.
      Summary: The selection of the measurement tools of apathy in AD or other NCD is central to the design of pharmacological or non-pharmacological clinical trials for the treatment of apathy. Researchers should choose a tool with robust psychometric properties that is not exclusively based on information given by the patient, includes the usual apathy domains, is sensitive to change within the time-frame necessary to see treatment effects, that is preferably disease-specific and appropriate for the place (home or institution) where the patient lives. Unfortunately, none of the currently used scales meets these requirements and there is no widely accepted gold-standard assessment instrument. Detection of emergent apathy with the MBI-C is relevant given that syndromic apathy domains are measured, and scalable, as the rating scale is free and validated for multiple modes of administration.
      Assessment methods based on Information and Communication Technologies (ICT) offer a novel and more ecological way of evaluating aspects and dimensions of apathy.
      • Konig A
      • Aalten P
      • Verhey F
      • et al.
      A review of current information and communication technologies: can they be used to assess apathy?.
      ,
      • Zeghari R
      • Manera V
      • Fabre R
      • et al.
      The "Interest Game": a ludic application to improve apathy assessment in patients with neurocognitive disorders.
      Actigraphy and methods used to monitor motor activity and rest-activity rhythms have also been shown to be useful, although do not address all apathy domains. Several actigraphy studies report the association of apathy in AD with diminished motor activity.
      • David R
      • Mulin E
      • Friedman L
      • et al.
      Decreased daytime motor activity associated with apathy in Alzheimer disease: an actigraphic study.
      • Kuhlmei A
      • Walther B
      • Becker T
      • et al.
      Actigraphic daytime activity is reduced in patients with cognitive impairment and apathy.
      • Mulin E
      • Zeitzer JM
      • Friedman L
      • et al.
      Relationship between apathy and sleep disturbance in mild and moderate Alzheimer's disease: an actigraphic study.
      Other methodologies, like voice analysis, video analysis, or “serious games” are also being researched, with promising evidence emerging that has shown the utility of “serious games/interest games” to differentiate apathetic from non-apathetic individuals,
      • Zeghari R
      • Manera V
      • Fabre R
      • et al.
      The "Interest Game": a ludic application to improve apathy assessment in patients with neurocognitive disorders.
      and machine learning speech analysis to be a reliable biomarker to detect/assess apathy and its subdomains.
      • König A
      • Linz N
      • Zeghari R
      • et al.
      Detecting apathy in older adults with cognitive disorders using automatic speech analysis.
      Although the NPI-Apathy item is the most frequently used tool, it is too simple for the task and does not accomplish many of the aforementioned requirements. Better assessment scales alternatives are the AES and the Dementia Apathy Interview and Rating, but both have limitations. Until further research brings new advancements in the area, we recommend using more than one assessment scale in the trial design and, when possible, including a measurement method different from rating scales, such as actigraphy. While the combined use of rating scales and actigraphy has to date never been done in treatment trials, its combined implementation is needed to determine efficacy. As a next step, the ability of scales to measure different dimensions of apathy in the diagnostic criteria need to be established.

      MECHANISMS AND BIOMARKERS

      The mechanisms and biomarkers underpinning apathy as a treatment target in pre-dementia and dementia populations remain poorly understood. Different underlying disease processes and disruption of different neurocircuit pathways can result in the same phenotypic expression of apathy.
      Neuroimaging correlates of apathy consistently show involvement of the medial frontal cortex and subcortical structures, including the anterior cingulate cortex, medial orbitofrontal cortex and ventral striatum.
      • Le Heron C
      • Apps MAJ
      • Husain M
      The anatomy of apathy: a neurocognitive framework for amotivated behaviour.
      ,
      • Kos C
      • van Tol MJ
      • Marsman JB
      • et al.
      Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders.
      Given the regular involvement of these structures in the development of apathy across a variety of neuropathologic disease processes, disruptions of functional neurobiological systems may be more important than specific molecular pathologies.
      • Le Heron C
      • Holroyd CB
      • Salamone J
      • et al.
      Brain mechanisms underlying apathy.
      The role of mechanisms and biomarkers are important when considering apathy as a treatment target in pre-dementia and dementia populations. Research on pre-dementia populations shows that subjects with MCI or prodromal-AD demonstrate a different pattern of hypometabolism on F18-fluorodeoxyglucose positron emission tomography (FDG-PET) (parietal-temporal cortex and posterior cingulate cortex) than seen in the dementia stage of AD (medial frontal regions). In 65 MCI ADNI subjects (11 apathetic; 54 apathy-free)
      • Delrieu J
      • Desmidt T
      • Camus V
      • et al.
      Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study.
      the apathetic group showed decreased metabolism in the posterior cingulate cortex. Gatchel et al.
      • Gatchel JR
      • Donovan NJ
      • Locascio JJ
      • et al.
      Regional 18F-fluorodeoxyglucose hypometabolism is associated with higher apathy scores over time in early Alzheimer's Disease.
      analyzed the relationship of regional brain glucose metabolism with F18-FDG-PET to apathy in a larger ADNI cohort, finding both cross-sectional and longitudinal correlations between high apathy scores and posterior cingulate hypometabolism. Baseline supramarginal gyrus (lateral parietal) hypometabolism was also found to be directly correlated with the rate of change in apathy. Interestingly, in these MCI populations, unlike those in AD dementia studies, there was no association between apathy and glucose hypometabolism in medial frontal regions.
      • Marshall GA
      • Monserratt L
      • Harwood D
      • et al.
      Positron emission tomography metabolic correlates of apathy in Alzheimer disease.
      ,
      • Sultzer DL
      • Leskin LP
      • Jacobs ZM
      • et al.
      Cognitive, behavioral, and emotional domains of apathy in Alzheimer's disease: clinical and neurobiological features.
      Lower inferior temporal cortical thickness in amnestic MCI patients with apathy is reported.
      • Donovan NJ
      • Wadsworth LP
      • Lorius N
      • et al.
      Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum.
      ,
      • Guercio B
      • Donovan NJ
      • Ward A
      • et al.
      Apathy is associated with lower inferior temporal cortical thickness in mild cognitive impairment and normal elderly.
      Guercio and colleagues
      • Guercio B
      • Donovan NJ
      • Ward A
      • et al.
      Apathy is associated with lower inferior temporal cortical thickness in mild cognitive impairment and normal elderly.
      linked greater apathy to lower inferior temporal cortical thickness and greater anterior cingulate cortical thickness, while Donovan et al.
      • Donovan NJ
      • Wadsworth LP
      • Lorius N
      • et al.
      Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum.
      reported reduced baseline inferior temporal cortical thickness to predict increased apathy over time. CSF biomarkers did not relate to apathy severity.
      In AD dementia populations apathy is most consistently implicated with frontal-subcortical reward circuits,
      • Rosenberg PB
      • Nowrangi MA
      • Lyketsos CG
      Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits?.
      ,
      • Levy R
      • Dubois B
      Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits.
      ,
      • Levenson RW
      • Sturm VE
      • Haase CM
      Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology.
      with anterior cingulate cortex dysfunction most frequently associated with apathy.
      • Starkstein SE
      • Brockman S
      The neuroimaging basis of apathy: empirical findings and conceptual challenges.
      Multiple cross-sectional studies in mild to moderate AD dementia examined the association between apathy and neuroimaging measures, including hypoperfusion on SPECT, hypometabolism on FDG-PET, atrophy (cortical thinning/decreased volume) on structural MRI, and loss of white matter integrity (decreased fractional anisotropy) seen with diffusion tensor imaging. The most common region implicated has been the anterior cingulate cortex unilaterally or bilaterally.
      • Marshall GA
      • Monserratt L
      • Harwood D
      • et al.
      Positron emission tomography metabolic correlates of apathy in Alzheimer disease.
      ,
      • Apostolova LG
      • Akopyan GG
      • Partiali N
      • et al.
      Structural correlates of apathy in Alzheimer's disease.
      • Bruen PD
      • McGeown WJ
      • Shanks MF
      • et al.
      Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.
      • Lanctot KL
      • Moosa S
      • Herrmann N
      • et al.
      A SPECT study of apathy in Alzheimer's disease.
      • Ota M
      • Sato N
      • Nakata Y
      • et al.
      Relationship between apathy and diffusion tensor imaging metrics of the brain in Alzheimer's disease.
      • Tunnard C
      • Whitehead D
      • Hurt C
      • et al.
      Apathy and cortical atrophy in Alzheimer's disease.
      • Büyükgök D
      • Bayraktaroğlu Z
      • Buker HS
      • et al.
      Resting-state fMRI analysis in apathetic Alzheimer's disease.
      • Chan NK
      • Gerretsen P
      • Chakravarty MM
      • et al.
      Structural brain differences between cognitively impaired patients with and without apathy.
      Other frontal regions implicated include the orbitofrontal cortex
      • Holthoff VA
      • Beuthien-Baumann B
      • Kalbe E
      • et al.
      Regional cerebral metabolism in early Alzheimer's disease with clinically significant apathy or depression.
      ,
      • Marshall GA
      • Monserratt L
      • Harwood D
      • et al.
      Positron emission tomography metabolic correlates of apathy in Alzheimer disease.
      ,
      • Lanctot KL
      • Moosa S
      • Herrmann N
      • et al.
      A SPECT study of apathy in Alzheimer's disease.
      ,
      • Tunnard C
      • Whitehead D
      • Hurt C
      • et al.
      Apathy and cortical atrophy in Alzheimer's disease.
      ,
      • Chan NK
      • Gerretsen P
      • Chakravarty MM
      • et al.
      Structural brain differences between cognitively impaired patients with and without apathy.
      • Benoit M
      • Clairet S
      • Koulibaly PM
      • et al.
      Brain perfusion correlates of the apathy inventory dimensions of Alzheimer's disease.
      • Ballarini T
      • Iaccarino L
      • Magnani G
      • et al.
      Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.
      • Stanton BR
      • Leigh PN
      • Howard RJ
      • et al.
      Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders.
      and dorsolateral and medial frontal cortices.
      • Apostolova LG
      • Akopyan GG
      • Partiali N
      • et al.
      Structural correlates of apathy in Alzheimer's disease.
      ,
      • Bruen PD
      • McGeown WJ
      • Shanks MF
      • et al.
      Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.
      ,
      • Benoit M
      • Clairet S
      • Koulibaly PM
      • et al.
      Brain perfusion correlates of the apathy inventory dimensions of Alzheimer's disease.
      ,
      • Ballarini T
      • Iaccarino L
      • Magnani G
      • et al.
      Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.
      A few studies have implicated the insula,
      • Stanton BR
      • Leigh PN
      • Howard RJ
      • et al.
      Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders.
      ,
      • Moon Y
      • Moon WJ
      • Kim H
      • et al.
      Regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in Alzheimer's disease patients.
      parietal lobe,
      • Ota M
      • Sato N
      • Nakata Y
      • et al.
      Relationship between apathy and diffusion tensor imaging metrics of the brain in Alzheimer's disease.
      thalamus,
      • Marshall GA
      • Monserratt L
      • Harwood D
      • et al.
      Positron emission tomography metabolic correlates of apathy in Alzheimer disease.
      ,
      • Ota M
      • Sato N
      • Nakata Y
      • et al.
      Relationship between apathy and diffusion tensor imaging metrics of the brain in Alzheimer's disease.
      and basal ganglia.
      • Bruen PD
      • McGeown WJ
      • Shanks MF
      • et al.
      Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.
      Some studies have looked at the cross-sectional relationship between apathy and connectivity using resting-state functional MRI or FDG-PET in AD dementia. These show an association between apathy and decreased default mode network connectivity, increased salience network (ventral attention network) connectivity, and either decreased or increased fronto-parietal control network (central executive network) connectivity.
      • Ballarini T
      • Iaccarino L
      • Magnani G
      • et al.
      Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.
      ,
      • Munro CE
      • Donovan NJ
      • Guercio BJ
      • et al.
      Neuropsychiatric symptoms and functional connectivity in mild cognitive impairment.
      ,
      • Joo SH
      • Lee CU
      • Lim HK
      Apathy and intrinsic functional connectivity networks in amnestic mild cognitive impairment.
      Regional hypoperfusion and hypometabolism: Associated neuroimaging findings of AD dementia include patterns of hypoperfusion and hypometabolism in several frontal regions. A study of AD dementia patients measuring perfusion with 99mTc-labeled bicisate (ECD) single PET showed negative correlations of apathy symptoms - specifically lack of initiative, lack of interest and emotional blunting - with brain perfusion of the right anterior cingulate cortex, the right middle frontal orbital gyrus and the left superior dorsolateral prefrontal cortex, when controlling for depression.
      • Benoit M
      • Clairet S
      • Koulibaly PM
      • et al.
      Brain perfusion correlates of the apathy inventory dimensions of Alzheimer's disease.
      Using F18 FDG-PET, Marshall and colleagues
      • Marshall GA
      • Monserratt L
      • Harwood D
      • et al.
      Positron emission tomography metabolic correlates of apathy in Alzheimer disease.
      demonstrated a definite association of apathy in AD dementia with hypometabolism in the bilateral anterior cingulate cortex and the medial orbitofrontal cortex, and a possible association of apathy with hypometabolism of the medial thalamus when controlling for age, education, cognitive symptom duration, depressed mood and delusional thought. Moreover, the individual cognitive, behavioral and emotional domains of apathy in AD dementia may be associated with distinct patterns of regional hypometabolism in medial thalamus, anterior cingulate, insula and temporal cortex.
      • Sultzer DL
      • Leskin LP
      • Jacobs ZM
      • et al.
      Cognitive, behavioral, and emotional domains of apathy in Alzheimer's disease: clinical and neurobiological features.
      Regional atrophy: Studies examining apathy-related regional cortical atrophy in AD dementia consistently demonstrate atrophy of the medial frontal regions, including cortical thinning of the bilateral anterior cingulate cortex, left medial frontal cortex, bilateral frontal cortex, head of the left caudate nucleus and bilateral putamen.
      • Apostolova LG
      • Akopyan GG
      • Partiali N
      • et al.
      Structural correlates of apathy in Alzheimer's disease.
      ,
      • Bruen PD
      • McGeown WJ
      • Shanks MF
      • et al.
      Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.
      Tunnard et al.
      • Tunnard C
      • Whitehead D
      • Hurt C
      • et al.
      Apathy and cortical atrophy in Alzheimer's disease.
      partially verified these findings, demonstrating cortical thinning of the left caudal anterior cingulate cortex, the left lateral orbitofrontal cortex, and left superior and ventrolateral portions of the frontal regions.
      More recently, Agüera-Ortiz and colleagues
      • Aguera-Ortiz L
      • Hernandez-Tamames JA
      • Martinez-Martin P
      • et al.
      Structural correlates of apathy in Alzheimer's disease: a multimodal MRI study.
      found differing apathy-related brain damage in more advanced stages of AD dementia and between the three apathy domains using the APAthy in DEMentia Nursing Home scale.
      • Aguera-Ortiz L
      • Gil-Ruiz N
      • Cruz-Orduna I
      • et al.
      A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH.
      In particular, they found that apathy severity was associated with bilateral damage to the corpus collosum and internal capsule; higher emotional blunting was linked to a smaller and more anteriorly located region of the right internal capsule and corpus collosum; and higher thinking deficits were linked to more ischemic damage in the right periventricular frontal region.
      • Aguera-Ortiz L
      • Hernandez-Tamames JA
      • Martinez-Martin P
      • et al.
      Structural correlates of apathy in Alzheimer's disease: a multimodal MRI study.
      Cortical tau depositions: Neuropathologic and in vivo tau deposition studies of apathy in AD dementia align with regional hypometabolism findings. Neuropathologic correlation of AD dementia patients with chronic apathy found high density deposition of neurofibrillary tangles in the anterior cingulate cortex (signifying tau burden), but not associated with neuritic plaques (signifying amyloid burden).
      • Marshall GA
      • Fairbanks LA
      • Tekin S
      • et al.
      Neuropathologic correlates of apathy in Alzheimer's disease.
      Another in vivo study of tau using flortaucipir PET showed associations between greater apathy and right anterior cingulate and dorsolateral prefrontal cortex tau burden in MCI and AD dementia, particularly in those with greater amyloid burden.
      • Marshall GA
      • Gatchel JR
      • Donovan NJ
      • et al.
      Regional Tau correlates of instrumental activities of daily living and apathy in mild cognitive impairment and Alzheimer's disease dementia.
      Cortical beta-amyloid: The relationship of amyloid pathology to apathy is still being elucidated. Several primarily cross-sectional studies have focused on pathological markers of AD dementia assessed in vivo with CSF or PET imaging or post-mortem. One study failed to show an association between CSF ß-amyloid (Aß) 1-42, total tau, and phosphorylated-tau and apathy at baseline or over time across CN older adults, MCI, and mild AD dementia,
      • Donovan NJ
      • Wadsworth LP
      • Lorius N
      • et al.
      Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum.
      while another showed an association between apathy and CSF total tau and phosphorylated-tau, but not Aß 1-42.
      • Skogseth R
      • Mulugeta E
      • Jones E
      • et al.
      Neuropsychiatric correlates of cerebrospinal fluid biomarkers in Alzheimer's disease.
      However, Krell-Roesch et al.
      • Krell-Roesch J
      • Vassilaki M
      • Mielke MM
      • et al.
      Cortical β-amyloid burden, neuropsychiatric symptoms, and cognitive status: the Mayo Clinic Study of Aging.
      reported 7.1 times higher odds of having apathy in MCI with amyloid deposition than MCI subjects without amyloid deposition. Similarly, Goukasian et al.
      • Goukasian N
      • Hwang KS
      • Romero T
      • et al.
      Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study.
      found amyloid positive MCI subjects to be more likely to develop apathy compared to amyloid negative MCI subjects.
      A cross-sectional study of MCI showed a direct correlation between apathy and cortical amyloid burden, as measured by the Pittsburgh Compound B (PiB) tracer, irrespective of age.
      • Marshall GA
      • Donovan NJ
      • Lorius N
      • et al.
      Apathy is associated with increased amyloid burden in mild cognitive impairment.
      In the same study, FDG-PET showed no relationship between apathy and regional hypometabolism. Mori and colleagues
      • Mori T
      • Shimada H
      • Shinotoh H
      • et al.
      Apathy correlates with prefrontal amyloid beta deposition in Alzheimer's disease.
      studied a PiB-positive AD cross-sectional cohort and found apathy scores correlated with PiB deposition in the bilateral frontal cortex and right anterior cingulate cortex.
      Neurotransmitters: Post-mortem, imaging and pharmacologic studies of apathy in AD dementia support the involvement of the cholinergic, dopaminergic (DA), serotonergic, GABA-nergic and noradrenergic neurotransmitter systems, all of which are affected by the AD dementia disease process.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      ,
      • Lanctot KL
      • Herrmann N
      • Mazzotta P
      Role of serotonin in the behavioral and psychological symptoms of dementia.
      ,
      • Lanctot KL
      • Herrmann N
      • Rothenburg L
      • et al.
      Behavioral correlates of GABAergic disruption in Alzheimer's disease.
      Deficits in the cholinergic system are a well-known and a characteristic finding of AD dementia. A meta-analysis examining the efficacy of pharmacologic interventions for apathy in AD dementia reported a possible slight improvement in apathy for those who received cholinesterase inhibitors, suggesting that cholinergic deficits are an important target for apathy treatment.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      PET studies of AD dementia patients have shown a trend for correlation between decreased nicotinic cholinergic receptor binding in the anterior cingulate cortex and apathy.
      • Sultzer DL
      • Melrose RJ
      • Riskin-Jones H
      • et al.
      Cholinergic receptor binding in alzheimer disease and healthy aging: assessment in vivo with positron emission tomography imaging.
      A subsequent analysis revealed similar findings: severity of apathy was associated with lower cholinergic receptor binding in bilateral middle cingulate and lateral orbitofrontal cortices.
      • Sultzer DL
      • Melrose RJ
      • Narvaez TA
      • et al.
      Apathy and regional cholinergic receptor binding in Alzheimer's disease: 2-FA PET imaging.
      Relationships were strongest for the behavioral domain of apathy and findings were not driven by anxiety or depression.
      • Sultzer DL
      • Melrose RJ
      • Narvaez TA
      • et al.
      Apathy and regional cholinergic receptor binding in Alzheimer's disease: 2-FA PET imaging.
      Extensive serotonergic denervation in multiple locations including the raphe nuclei
      • Chen CP
      • Eastwood SL
      • Hope T
      • et al.
      Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer's disease prospectively assessed for behavioral changes.
      and temporal cortex
      • Chen CP
      • Alder JT
      • Bowen DM
      • et al.
      Presynaptic serotonergic markers in community-acquired cases of Alzheimer's disease: correlations with depression and neuroleptic medication.
      ,
      • Mann DM
      • Yates PO
      Neurotransmitter deficits in Alzheimer's disease and in other dementing disorders.
      has also been documented in post-mortem pathologic examinations of brain specimens with AD dementia. Alterations in 5HT-1A receptors and serotonin re-uptake (5HTT) sites within the hippocampus have been linked to agitation and depression in AD dementia, however the relationship is less clear with apathy.
      • Lai MK
      • Tsang SW
      • Esiri MM
      • et al.
      Differential involvement of hippocampal serotonin1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer's disease.
      The serotonergic system is known to inhibit cholinergic output and thus the cholinergic to serotonergic ratio of neurotransmission likely plays an important role in associated NPS.
      • Garcia-Alloza M
      • Gil-Bea FJ
      • Diez-Ariza M
      • et al.
      Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease.
      Supporting this hypothesis are findings that selective serotonin re-uptake inhibitors (SSRIs) can induce an apathy syndrome in those with depression without AD dementia
      • Barnhart WJ
      • Makela EH
      • Latocha MJ
      SSRI-induced apathy syndrome: a clinical review.
      which can be reversed with discontinuation of the SSRI.
      • Padala PR
      • Padala KP
      • Monga V
      • et al.
      Reversal of SSRI-associated apathy syndrome by discontinuation of therapy.
      Thus far, study design and selective reporting make the effect of SSRIs on apathy in the pre-dementia and AD dementia populations difficult to interpret.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      Individuals with AD dementia have disruptions in DA neurotransmission between the basal ganglia, anterior cingulate and frontal cortex,
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      ,
      • Lanctot KL
      • Moosa S
      • Herrmann N
      • et al.
      A SPECT study of apathy in Alzheimer's disease.
      leading to impairment in the brain reward system. Apathy should be considered at least in part a hypodopaminergic syndrome based on the high prevalence of apathy (27%) seen early in the course of Parkinson's disease.
      • Chagraoui A
      • Boukhzar L
      • Thibaut F
      • et al.
      The pathophysiological mechanisms of motivational deficits in Parkinson's disease. Progress in neuro-psychopharmacology.
      • Aarsland D
      • Bronnick K
      • Alves G
      • et al.
      The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson's disease.
      • Liu J
      • Cooper CA
      • Weintraub D
      • et al.
      Pharmacological treatment of apathy in Lewy body disorders: A systematic review.
      David and colleagues
      • David R
      • Koulibaly M
      • Benoit M
      • et al.
      Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases A SPECT study with partial volume effect correction.
      reported on 14 AD dementia and 8 Dementia with Lewy Bodies (DLB) patients who were assessed clinically for apathy and for dopamine transporter (DAT) striatal uptake using
      • Lanctot KL
      • Herrmann N
      • Mazzotta P
      Role of serotonin in the behavioral and psychological symptoms of dementia.
      I-FP-CIT (DaTSCAN) SPECT. Lower DAT uptake correlated with greater apathy. More specifically, lower bilateral putamen DAT uptake correlated with lack of initiative.
      • David R
      • Koulibaly M
      • Benoit M
      • et al.
      Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases A SPECT study with partial volume effect correction.
      However, another study showed no association with dopamine (D2/D3) receptor availability.
      • Reeves S
      • Brown R
      • Howard R
      • et al.
      Increased striatal dopamine (D2/D3) receptor availability and delusions in Alzheimer disease.
      Nonetheless, dopaminergic deficits as a treatment target in apathy are supported by recent positive meta-analysis findings of three methylphenidate treatment studies of apathy in AD dementia.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      ,
      • Herrmann N
      • Rothenburg LS
      • Black SE
      • et al.
      Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge.
      • Padala PR
      • Padala KP
      • Lensing SY
      • et al.
      Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer's Disease: a double-blind, randomized, placebo-controlled trial.
      • Rosenberg PB
      • Lanctot KL
      • Drye LT
      • et al.
      Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.
      Noradrenergic and GABA-nergic systems are also potential treatment targets for apathy, but less is known about their involvement in AD-associated apathy. Noradrenergic and GABA-nergic neuronal loss is well described in AD dementia,
      • Ellison DW
      • Beal MF
      • Mazurek MF
      • et al.
      A postmortem study of amino acid neurotransmitters in Alzheimer's disease.
      • Lowe SL
      • Francis PT
      • Procter AW
      • et al.
      Gamma-aminobutyric acid concentration in brain tissue at 2 stages of Alzheimer's disease.
      • Rossor MN
      • Garrett NJ
      • Johnson AL
      • et al.
      A post-mortem study of the cholinergic and GABA systems in senile dementia.
      and these neurons are hypothesized to be co-transmitters with the serotonergic system.
      • Rossor MN
      • Garrett NJ
      • Johnson AL
      • et al.
      A post-mortem study of the cholinergic and GABA systems in senile dementia.
      Higher GABA plasma levels appear to be correlated with apathy.
      • Lanctot KL
      • Herrmann N
      • Rothenburg L
      • et al.
      Behavioral correlates of GABAergic disruption in Alzheimer's disease.
      Fluid biomarkers: Two cross-sectional studies have looked at the relationship between serum biomarkers and apathy across MCI and AD dementia. One study showed an association with reduced brain-derived neurotrophic factor (BDNF),
      • Alvarez A
      • Aleixandre M
      • Linares C
      • et al.
      Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease.
      while another study showed an association with increased tumor necrosis factor alpha (TNF-alpha), but no association with BDNF.
      • Guimaraes HC
      • Caramelli P
      • Fialho PPA
      • et al.
      Serum levels of soluble TNF-alpha receptors but not BDNF are associated with apathy symptoms in mild Alzheimer's disease and amnestic mild cognitive impairment.
      Summary: Most studies examining the mechanisms and biomarkers of apathy in AD have been cross-sectional, focused on proxies of neurodegeneration, and looked at individuals with dementia. Those studies have primarily yielded a medial frontal localization in the anterior cingulate and orbitofrontal cortices. The few studies that examined people at earlier stages of AD (MCI or CN older adults at risk for AD dementia) and/or followed individuals longitudinally have shown associations with parietal and inferior temporal regions usually implicated more generally in early stages of AD. The few studies that investigated pathologic markers of AD and apathy have shown associations with amyloid at earlier stages of AD and with tau at later stages. While apathy is suspected to be a disorder of monoaminergic neurotransmission, almost no studies have looked at its relationship using neurochemical imaging (e.g. norepinephrine receptors or transporters) or serum biomarkers including markers of monoaminergic neurotransmission.
      Thus, taking these many studies into consideration, there appears to be a more consistent localization of apathy to frontal regions with biomarkers of neurodegeneration and tau later in the AD disease process. On the other hand, earlier in the disease process, there appears to be more of an association of apathy with regions implicated in early stages of AD and global amyloid burden, similarly implicated in early stages, which may not correspond to a true localization but rather a reflection of apathy also being an early symptom of AD. We therefore conclude that the use of biomarkers in clinical trials targeting apathy in AD requires more observational studies with longitudinal follow-up, earlier stages of AD, and pathologic and neurochemical markers of AD. Meanwhile, at the stage of dementia, structural MRI or FDG PET imaging, with anterior cingulate and medial orbitofrontal cortices serving as regions of interest, may provide reasonable biomarkers for clinical outcomes. For trials in preclinical AD or prodromal AD (MCI), the evidence for using a biomarker outcome is weaker but one could consider biomarkers that are generally consistent with early stages of AD dementia such as inferior temporal and parietal atrophy on MRI or globally elevated cortical amyloid on PET.

      TREATMENT AND INTERVENTION EFFICACY

      Apathy treatment includes a variety of pharmacologic and non-pharmacologic therapies. Currently, no clear guidelines exist.

      Pharmacological

      While accumulating biological evidence points towards apathy as a treatment target, clinical trial data remain very limited and recent systematic reviews found that apathy is rarely considered a primary outcome measure or an inclusion criterion.
      • Theleritis C
      • Siarkos K
      • Katirtzoglou E
      • et al.
      Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease: a systematic review across modalities.
      ,
      • Berman K
      • Brodaty H
      • Withall A
      • et al.
      Pharmacologic treatmentof apathy in dementia.
      Both reviews found that cholinesterase inhibitors (ChEIs) may be the best available choice for the pharmacological treatment of apathy in dementia.
      • Theleritis C
      • Siarkos K
      • Katirtzoglou E
      • et al.
      Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease: a systematic review across modalities.
      ,
      • Berman K
      • Brodaty H
      • Withall A
      • et al.
      Pharmacologic treatmentof apathy in dementia.
      As reduced cholinergic tone has been linked to apathy,
      • Mega MS
      • Cummings JL
      • Salloway S
      • et al.
      The limbic system: an anatomic, phylogenetic, and clinical perspective.
      ChEIs might prove helpful.
      • Trinh NH
      • Hoblyn J
      • Mohanty S
      • et al.
      Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis.
      ,
      • Cummings JL
      • Mackell J
      • Kaufer D
      Behavioral effects of current Alzheimer's disease treatments: a descriptive review.
      While Ginkgo biloba was also found to be effective,
      • Scripnikov A
      • Khomenko A
      • Napryeyenko O
      Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial.
      ,
      • Bachinskaya N
      • Hoerr R
      • Ihl R
      Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb 761. Findings from a randomized controlled trial.
      there was weaker evidence of efficacy of memantine for apathy (compared to a higher efficacy when treating agitation and irritability).
      • Berman K
      • Brodaty H
      • Withall A
      • et al.
      Pharmacologic treatmentof apathy in dementia.
      ,
      • Cummings JL
      • Mackell J
      • Kaufer D
      Behavioral effects of current Alzheimer's disease treatments: a descriptive review.
      Stimulants alone, or in combination with ChEIs are also beneficial when treating apathy.
      • Herrmann N
      • Rothenburg LS
      • Black SE
      • et al.
      Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge.
      ,
      • Rosenberg PB
      • Lanctot KL
      • Drye LT
      • et al.
      Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.
      ,
      • Kaplitz SE
      Withdrawn, apathetic geriatric patients responsive to methylphenidate.
      ,
      • Lanctot KL
      • Chau SA
      • Herrmann N
      • et al.
      Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.
      In particular, the Apathy in Dementia Methylphenidate Trial (ADMET) - a multicenter, phase II, double-blind, placebo-controlled, 6-week, randomized trial (RCT)
      • Rosenberg PB
      • Lanctot KL
      • Drye LT
      • et al.
      Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.
      investigating the safety and efficacy of methylphenidate 10mg - showed significant between-group differences on the apathy domain of the NPI. While this was not reflected in changes on the AES, a secondary analysis of ADMET reported cognitive benefits.
      • Lanctot KL
      • Chau SA
      • Herrmann N
      • et al.
      Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial.
      A phase III clinical trial is currently underway (ADMET II).
      • Scherer RW
      • Drye L
      • Mintzer J
      • et al.
      The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial.
      A 12-week clinical trial involved male community-dwelling veterans living with mild AD dementia (DSM-IV criteria) receiving on average 19mg of methylphenidate (n=30) or a placebo (n=30).
      • Padala PR
      • Padala KP
      • Lensing SY
      • et al.
      Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer's Disease: a double-blind, randomized, placebo-controlled trial.
      Primary outcome was change in apathy scores on the clinician-rated version of the AES at treatment weeks 4, 8 and 12. Significant group mean differences in AES-Clinician version (AES-C) scores, after adjusting for baseline apathy, were found between the methylphenidate group and the placebo group and differences increased over time. Behavioral, cognitive and motivational domains of apathy improved at week 8, while the emotional domain improved at week 12.
      Conversely, atypical antipsychotics should not be used for long periods

      Administration FaD: Deaths with antipsychotics in elderly patients with behavioral disturbances, 2005

      and antidepressants (e.g., SSRIs, Chlor-phenyl-piperazine, L-Deprenyl) failed to improve patients’ apathy scores.
      • Berman K
      • Brodaty H
      • Withall A
      • et al.
      Pharmacologic treatmentof apathy in dementia.
      ,
      • Porsteinsson AP
      • Drye LT
      • Pollock BG
      • et al.
      Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial.
      • Siddique H
      • Hynan LS
      • Weiner MF
      Effect of a serotonin reuptake inhibitor on irritability, apathy, and psychotic symptoms in patients with Alzheimer's disease.
      • Lyketsos CG
      • DelCampo L
      • Steinberg M
      • et al.
      Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS.
      • Pollock BG
      • Mulsant BH
      • Rosen J
      • et al.
      Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients.
      • Nyth AL
      • Gottfries CG
      • Lyby K
      • et al.
      A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia.
      • Tariot PN
      • Cohen RM
      • Sunderland T
      • et al.
      L-deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition.
      • Freedman M
      • Rewilak D
      • Xerri T
      • et al.
      L-deprenyl in Alzheimer's disease: cognitive and behavioral effects.
      A recent meta-analysis of double-blind, randomized, placebo-controlled trials investigating apathy as a primary or secondary outcome in AD dementia, assessed1) the safety and efficacy of pharmacotherapies for the treatment of apathy in AD dementia and 2) the effect on apathy of pharmacotherapies for other primary outcomes in the treatment of AD dementia.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      Of 21 studies involving a total of 6384 participants, only four studies had a primary aim of improving apathy (three with methylphenidate
      • Herrmann N
      • Rothenburg LS
      • Black SE
      • et al.
      Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge.
      • Padala PR
      • Padala KP
      • Lensing SY
      • et al.
      Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer's Disease: a double-blind, randomized, placebo-controlled trial.
      • Rosenberg PB
      • Lanctot KL
      • Drye LT
      • et al.
      Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.
      and one with modafinil.
      • Frakey LL
      • Salloway S
      • Buelow M
      • et al.
      A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer's disease.
      ) Table 4 summarizes the findings of this meta-analysis of the efficacy of methylphenidate and modafinil. In summary, methylphenidate improved AES scores compared to placebo with greater effect in trials >12 weeks, but had no effect on NPI-apathy scores (possibly due to smaller sample sizes). This highlights the urgent need for well-defined clinical criteria and assessment tools that are consistent. Insufficient evidence was found based on one very small study of modafinil on apathy as assessed by the Frontal Systems Behavioral Scale apathy subscale.
      Table 4Efficacy of Methylphenidate and Modafinil Targeting Apathy
      OutcomesAnticipated Absolute Effects
      denotes the risk in the intervention group and its 95% confidence interval based on assumed risk in the comparison group and relative effect of the intervention (and its 95% confidence interval); GRADE Working Group Grades of Evidence:
      (95% CI)
      Relative Effect (95% CI)Number of Participants (studies)Quality of Evidence (GRADE)Comments
      Risk with PlaceboRisk with Methylphenidate
      MethylphenidateChange in apathy (AES score) assessed with: AES Scale from: 0 to 42 follow-up: range 2 wks – 12 wksThe mean change from baseline in apathy was -4.2 – 0.6MD 4.99 lower (9.55 lower to 0.43 lower)145

      (3 RCTs)
      LOW
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      ,
      denotes quality downgraded one level due to inconsistency (substantial heterogeneity was present
      AES: Limited data on clinically meaningful changes
      Change in apathy (NPI-apathy subscale score) assessed with: NPI-apathy subscale Scale from: 0 to 12 follow-up: 2 wks – 6 wksThe mean change from baseline in apathy -2.6 – -1.69MD 0.08 lower (3.85 lower – 3.69 higher)85

      (2 RCTs)
      LOW
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      ,
      denotes quality downgraded one level due to inconsistency (substantial heterogeneity was present
      1- to 2-point change suggested to be clinically significant in people with a clinically significant apathy
      • Rosenberg PB
      • Lanctot KL
      • Drye LT
      • et al.
      Safety and efficacy of methylphenidate for apathy in Alzheimer's disease: a randomized, placebo-controlled trial.
      Adverse events assessed with: Number of participants reporting ≥ 1 adverse event follow-up: 2 wks – 12 wksStudy populationRR 1.28

      (0.67 – 2.42)
      145

      (3 RCTs)
      LOW
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      ,
      denotes quality downgraded one level due to inconsistency (substantial heterogeneity was present
      534/1000684/1000

      (358 – 1,000)
      Change in NPS assessed with: NPI Scale from: 0 to 144 follow-up: 2 wksThe mean change from baseline in NPS was -2.08MD 0.16 higher (7.89 lower – 8.21 higher)25

      (1 RCT)
      LOW
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      4-point change suggested to be clinically significant
      Change in cognition assessed with: MMSE Scale from: 0 to 30 follow-up: 2 wks – 12 wksThe mean change from baseline in cognition was -1.08 – -0.3MD 1.79 higher (0.53 higher – 3.05 higher)145

      (3 RCTs)
      MODERATE
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      MMSE: 2- to 4-point change suggested to be clinically significant
      Change in functional performance assessed with: ADL scale Scale from: 0 to 6 follow-up: 12 wksThe mean change from baseline in functional performance was 0.4MD 0.50 higher (0.39 lower – 1.39 higher)60

      (1 RCT)
      MODERATE
      denotes quality downgraded one level due to imprecision (only one study, with a relatively small sample size)
      Limited data on clinically meaningful changes
      Change in functional performance assessed with: IADL scale Scale from: 0 to 8 for women, and 0 to 5 for men, to avoid potential for gender bias follow-up: 12 wksThe mean change from baseline in functional performance was -0.6MD 2.30 higher (0.74 higher – 3.86 higher)60

      (1 RCT)
      MODERATE
      denotes quality downgraded one level due to imprecision (only one study, with a relatively small sample size)
      Limited data on clinically meaningful changes
      Change in global disease severity assessed with: ADCS-CGIC or CGIC follow-up: 2 – 6 wksStudy populationRR 0.56

      (0.15 – 2.10)
      85

      (2 RCTs)
      MODERATE
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      116/100065/1000

      (17 – 244)
      Dropouts assessed with: Number of participants who dropped out prior to study completion. follow-up: 2 wks – 12 wksStudy populationRR 2.10

      (0.60 – 7.38)
      145

      (3 RCTs)
      LOW
      denotes quality downgraded two levels due to very serious imprecision (very wide 95% confidence interval).
      41/100086/1000

      (25 – 303)
      Risk with placeboRisk with Modafinil
      ModafinilChange in apathy assessed with: FrSBe-apathy subscale (T-score converted from raw score)

      Scale from: 14 to 70 (raw score) follow-up: mean 8 weeks
      The mean change from baseline in apathy was -6.82MD 0.27 higher (3.51 lower – 4.05 higher)22

      (1 RCT)
      LOW
      denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      Limited data on clinically meaningful changes on the FrSBe apathy score
      Note. Table of efficacy adapted from Ruthirakuhan et al.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      As in Ruthirakuhan et al.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      low asterisk denotes the risk in the intervention group and its 95% confidence interval based on assumed risk in the comparison group and relative effect of the intervention (and its 95% confidence interval); GRADE Working Group Grades of Evidence:
      a denotes quality downgraded one level due to imprecision (wide 95% confidence interval)
      b denotes quality downgraded one level due to inconsistency (substantial heterogeneity was present
      c denotes quality downgraded one level due to imprecision (only one study, with a relatively small sample size)
      d denotes quality downgraded two levels due to very serious imprecision (very wide 95% confidence interval).
      Ruthirakuhan and colleagues
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.
      concluded there was low or very low quality of evidence that ChEIs (6 studies), ChEI discontinuation (1 study), antipsychotics (2 studies), antipsychotic discontinuation (1 study), antidepressants (2 studies), mibampator (1 study), valproate (3 studies) and semagacestat (1 study) had any impact on apathy. Harrison et al.
      • Harrison F
      • Aerts L
      • Brodaty H
      Apathy in Dementia: systematic review of recent evidence on pharmacological treatments.
      recently reviewed 24 studies on pharmacological trials targeting apathy in various dementia types (10 in AD, 6 in Frontotemporal Lobar Degeneration/ Frontotemporal Dementia (FTLD/FTD), 4 in dementia or probable dementia and MCI, 1 in Parkinson's Disease Dementia, 1 in DLB, and 2 in unspecified dementia), finding inconclusive evidence for impact on apathy.
      Other pharmacological agents have also been used to target apathy. Callegari et al.
      • Callegari I
      • Mattei C
      • Benassi F
      • et al.
      Agomelatine improves apathy in frontotemporal dementia.
      evaluated the use of agomelatine for apathy in 24 participants with behavioral variant FTD with no history of depression. Agomelatine is a structural analogue of melatonin and has antagonistic effects on melatonergic receptors and the 5-HT2C serotonergic receptor.
      • Racagni G
      • Riva MA
      • Molteni R
      • et al.
      Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors. The world journal of biological psychiatry: the official journal of the World Federation of Societies of.
      It is approved for use in major depressive disorders and is used to treat disrupted circadian rhythms.
      • Laudon M
      • Frydman-Marom A
      Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders.
      The authors hypothesized that agomelatine could reduce apathy by restoring prefrontal dopaminergic and noradrenergic tone via 5-HT2C antagonism. To control for potential effects via the melatonergic system, melatonin was used as the control treatment for 10 weeks, followed by a 10-week crossover period. Agomelatine, but not melatonin, treatment was associated with significant decreases in AES, even when controlling for NPI-depression score and also in caregiver-rated NPI-apathy and NPI-distress scores. Switching from melatonin to agomelatine was associated with a decrease in AES score, while the reverse was associated with an increase in AES. In the largest RCT using bupropion (150mg per day) - a norepinephrine - dopamine reuptake inhibitor - to treat apathy in 54 non-depressed patients with dementia of the Alzheimer Type (mean MMSE=19.3), the drug failed to improve apathy as measured by the AES-C over a 12 week period when compared with the placebo.
      • Maier F
      • Spottke A
      • Bach JP
      • et al.
      Bupropion for the treatment of apathy in Alzheimer Disease: a randomized clinical trial.
      Interestingly, secondary analyses focusing on apathy subdomain factors of the AES scale showed significant worsening of the emotional apathy factor in the bupropion group after 12 weeks, whereas no significant differences were found between the groups for the other two factors.
      • Maier F
      • Spottke A
      • Bach JP
      • et al.
      Bupropion for the treatment of apathy in Alzheimer Disease: a randomized clinical trial.
      Furthermore, the multi-center, placebo-controlled, crossover trial with bupropion
      • Gelderblom H
      • Wustenberg T
      • McLean T
      • et al.
      Bupropion for the treatment of apathy in Huntington's disease: A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial.
      for the treatment of apathy diagnosed with the Structured Clinical Interview for Apathy-Dementia in Huntington's dementia failed to reveal significant differences in AES-informant scores between the groups.
      Summary: There are no established treatments for apathy to date. A key factors limiting informative conclusions and the formation of advice include the small study sample sizes and study designs being utilized. To improve the quality of evidence for pharmacological treatment, future studies need to address the current trial design limitations and challenges, by 1) utilizing and validating the recently revised diagnostic criteria of apathy as a treatment target outcome; 2) include neurobiological, neurochemical and neuroimaging endpoints to help identify pharmacological treatment target endpoints; 3) inclusion of cognitive and functional outcome measures to investigate the secondary benefits of targeting apathy; and 4) utilize longer study durations and adequately powered studies to investigate the impact of pharmacological treatment on clinically significant apathy as a primary outcome measure.
      • Ruthirakuhan MT
      • Herrmann N
      • Abraham EH
      • et al.
      Pharmacological interventions for apathy in Alzheimer's disease.

      Non-Pharmacological

      Non-pharmacologic interventions, specifically individualized therapeutic activities,
      • Brodaty H
      • Burns K
      Nonpharmacological management of apathy in dementia: a systematic review.
      have shown promise in treating apathy. Goris and colleagues'
      • Goris ED
      • Ansel KN
      • Schutte DL
      Quantitative systematic review of the effects of non-pharmacological interventions on reducing apathy in persons with dementia.
      systematic review found that in institution-based settings music therapy, tailored personal contact, cognitive stimulation therapy, multi-sensory behavior therapy (including Snoezelen), group art therapy and therapeutic conversation all showed promise in reducing apathy, with the strongest evidence for music therapy (alone or in combination with other components). Most studies delivered at least 30-minute interventions for at least 10 sessions.
      • Goris ED
      • Ansel KN
      • Schutte DL
      Quantitative systematic review of the effects of non-pharmacological interventions on reducing apathy in persons with dementia.
      Exercise/activity interventions have also been shown to be effective.
      • Maci T
      • Pira FL
      • Quattrocchi G
      • et al.
      Physical and cognitive stimulation in Alzheimer Disease. the GAIA Project: a pilot study.
      ,
      • Telenius EW
      • Engedal K
      • Bergland A
      Effect of a high-intensity exercise program on physical function and mental health in nursing home residents with dementia: an assessor blinded randomized controlled trial.
      Challenges noted included heterogeneity between studies, methods used to engage the person with dementia in the activity, apparent target of therapeutic effect (i.e. behavioral, emotional or cognitive domain of apathy) and extent to which interventions were tailored to specific individuals.
      • Goris ED
      • Ansel KN
      • Schutte DL
      Quantitative systematic review of the effects of non-pharmacological interventions on reducing apathy in persons with dementia.
      Table 5 summarizes the efficacy of non-pharmacological interventions targeting apathy with several studies showing at least some benefit of non-pharmacological interventions for apathy. However, there were methodological challenges.
      • Theleritis C
      • Siarkos K
      • Politis AA
      • et al.
      A systematic review of non-pharmacological treatments for apathy in dementia.
      Apathy was a secondary outcome in more than half of the 37 studies included and tools used to assess apathy were often neither validated nor appropriate for the setting.
      • Theleritis C
      • Siarkos K
      • Politis AA
      • et al.
      A systematic review of non-pharmacological treatments for apathy in dementia.
      Table 5Efficacy of Non-Pharmacological Interventions Targeting Apathy
      Intervention:Effects:Number of Participants:Comparison Groups:Effect Sizes:
      Stimulation Retreat Model of CareIncreased external engagement; improved lack of interest and lack of initiative
      • Lawton MP
      • Van Haitsma K
      • Klapper J
      • et al.
      A stimulation-retreat special care unit for elders with dementing illness.
      , but not statistically significant.
      2 Units of 51 participants eachExperimental vs Control GroupNot reported.
      Simulated Presence - a personalized audiotape approachImproved withdrawn behavior; increased level of interest.
      • Camberg L
      • Woods P
      • Ooi WL
      • et al.
      Evaluation of Simulated Presence: a personalized approach to enhance well-being in persons with Alzheimer's disease.
      54Stimulated presence vs usual careImproved withdrawn behavior 69% (p < .001) of the time; was significantly better than usual care (55%; p < .001); improvement occurred nearly twice as often compared to placebo (34%; p < .001).
      Multi-Sensory StimulationImproved lack of interest and initiative.
      • Baker R
      • Bell S
      • Baker E
      • et al.
      A randomized controlled trial of the effects of multi-sensory stimulation (MSS) for people with dementia.
      ,
      • Baker R
      • Holloway J
      • Holtkamp CC
      • et al.
      Effects of multi-sensory stimulation for people with dementia.
      • Baker R
      • Bell S
      • Baker E
      • et al.
      A randomized controlled trial of the effects of multi-sensory stimulation (MSS) for people with dementia.
      : 50

      • Baker R
      • Holloway J
      • Holtkamp CC
      • et al.
      Effects of multi-sensory stimulation for people with dementia.
      : 136
      Multi-Sensory vs activity group
      • Baker R
      • Bell S
      • Baker E
      • et al.
      A randomized controlled trial of the effects of multi-sensory stimulation (MSS) for people with dementia.
      : MD in total score: -3.72, 95% CI -7.1 to -0.34; p = .032.

      • Baker R
      • Holloway J
      • Holtkamp CC
      • et al.
      Effects of multi-sensory stimulation for people with dementia.
      : -0.4 points in apathy (SD = 1.1, 95% CI -0.9 to 0.1; p < .05) in the severely impaired group.
      Kit‐Based Activity InterventionImproved lack of interest and initiative,
      • Politis AM
      • Vozzella S
      • Mayer LS
      • et al.
      A randomized, controlled, clinical trial of activity therapy for apathy in patients with dementia residing in long-term care.
      but not statistically significant.
      37Kit-based activity vs time and attention controlNot reported.
      Recreational activities derived from the NeedDriven DementiaCompromised Behavior ModelImproved emotional blunting.
      • Kolanowski AM
      • Litaker M
      • Buettner L
      Efficacy of theory-based activities for behavioral symptoms of dementia.
      301 of 6 possible order-of-condition presentationsMD in emotion sub-score = 10.71, SD = 7.2, 95% CI 8.5 – 13.0.
      Live Interactive MusicPositive engagement effects; improved lack of interest and initiative).
      • Holmes C
      • Knights A
      • Dean C
      • et al.
      Keep music live: music and the alleviation of apathy in dementia subjects.
      However, these improvements were not found in another recent review of 38 trials evaluating the efficacy of receptive music therapy for apathy as a secondary outcome.
      • Tsoi KKF
      • Chan JYC
      • Ng YM
      • et al.
      Receptive music therapy is more effective than interactive music therapy to relieve behavioral and psychological symptoms of dementia: a systematic review and meta-analysis.
      • Holmes C
      • Knights A
      • Dean C
      • et al.
      Keep music live: music and the alleviation of apathy in dementia subjects.
      : 32

      • Tsoi KKF
      • Chan JYC
      • Ng YM
      • et al.
      Receptive music therapy is more effective than interactive music therapy to relieve behavioral and psychological symptoms of dementia: a systematic review and meta-analysis.
      : 38

      trials involving 1418 participants
      • Holmes C
      • Knights A
      • Dean C
      • et al.
      Keep music live: music and the alleviation of apathy in dementia subjects.
      : Live interactive music, passive pre-recorded music or silence.

      • Tsoi KKF
      • Chan JYC
      • Ng YM
      • et al.
      Receptive music therapy is more effective than interactive music therapy to relieve behavioral and psychological symptoms of dementia: a systematic review and meta-analysis.
      : Diverse
      • Holmes C
      • Knights A
      • Dean C
      • et al.
      Keep music live: music and the alleviation of apathy in dementia subjects.
      : Not reported.

      • Tsoi KKF
      • Chan JYC
      • Ng YM
      • et al.
      Receptive music therapy is more effective than interactive music therapy to relieve behavioral and psychological symptoms of dementia: a systematic review and meta-analysis.
      : No significant difference: I2 = 97%, MD = -1.48, 95% CI -3.86 – 0.89.
      Multisensory Behavior Therapy - SnoezelenImproved lack of interest
      • Staal JA
      • Sacks A
      • Matheis R
      • et al.
      The effects of Snoezelen (multi-sensory behavior therapy) and psychiatric care on agitation, apathy, and activities of daily living in dementia patients on a short term geriatric psychiatric inpatient unit.
      and apathetic behaviour.
      • van Weert JC
      • van Dulmen AM
      • Spreeuwenberg PM
      • et al.
      Behavioral and mood effects of snoezelen integrated into 24-hour dementia care.
      • Staal JA
      • Sacks A
      • Matheis R
      • et al.
      The effects of Snoezelen (multi-sensory behavior therapy) and psychiatric care on agitation, apathy, and activities of daily living in dementia patients on a short term geriatric psychiatric inpatient unit.
      : 24

      • van Weert JC
      • van Dulmen AM
      • Spreeuwenberg PM
      • et al.
      Behavioral and mood effects of snoezelen integrated into 24-hour dementia care.
      :125
      • Staal JA
      • Sacks A
      • Matheis R
      • et al.
      The effects of Snoezelen (multi-sensory behavior therapy) and psychiatric care on agitation, apathy, and activities of daily living in dementia patients on a short term geriatric psychiatric inpatient unit.
      : Multi Sensory Behavior Therapy vs structured activity session

      • van Weert JC
      • van Dulmen AM
      • Spreeuwenberg PM
      • et al.
      Behavioral and mood effects of snoezelen integrated into 24-hour dementia care.
      : Experimental: 24-h Snoezel program vs control group: usual nursing home care
      • Staal JA
      • Sacks A
      • Matheis R
      • et al.
      The effects of Snoezelen (multi-sensory behavior therapy) and psychiatric care on agitation, apathy, and activities of daily living in dementia patients on a short term geriatric psychiatric inpatient unit.
      : MD (SD) in apathy group vs. control group: 22.2 (7.85) vs 32.13 (9.79).

      • van Weert JC
      • van Dulmen AM
      • Spreeuwenberg PM
      • et al.
      Behavioral and mood effects of snoezelen integrated into 24-hour dementia care.
      : Change score: 1.25, χ2 = 5.15; p < 0.05.
      Reminiscence Group TreatmentImmediate improvements on the behavior and cognition subscales of the MOSES in AD and particularly in vascular dementia patients.
      • Tadaka E
      • Kanagawa K
      Effects of reminiscence group in elderly people with Alzheimer disease and vascular dementia in a community setting.
      24Reminiscence group program vs routine daycare programNot reported.
      Tailored Activity ProgramImproved lack of interest and initiative.
      • Gitlin LN
      • Winter L
      • Burke J
      • et al.
      Tailored activities to manage neuropsychiatric behaviors in persons with dementia and reduce caregiver burden: a randomized pilot study.
      60 dyadsOccupational therapy intervention with customized activitiesCohen's d = .61 for activity engagement, p = 0.029.
      Music and Art Therapy and Psychomotor ActivityImproved engagement.
      • Ferrero-Arias J
      • Goni-Imizcoz M
      • Gonzalez-Bernal J
      • et al.
      The efficacy of nonpharmacological treatment for dementia-related apathy.
      146Initial intervention (music and art therapy and psychomotor activity) vs initial control (free activities in the day room)MD = 0.21, 95% CI 0.07 to 0.34, p < 0.005.
      Activities Tailored to Functional Level and Personality Style of InterestImproved passive behavior and engagement when in “personality style of interest” type of activities.
      • Kolanowski A
      • Litaker M
      • Buettner L
      • et al.
      A randomized clinical trial of theory-based activities for the behavioral symptoms of dementia in nursing home residents.
      128Activities adjusted to functional level (FL) vs personality style of interest (PSI), vs FL+PSI, vs active controlPSI: Least Square Means = 18.48, 95% CI 17.3 to 19.6, p < 0.005.

      Functional Level + PSI: Least Square Means = 18.74, 95% CI 17.5 to 19.9, p < 0.005.
      Brief Emotional Shaping InterventionImproved lack of interest and initiative to “yes” responses to engage in activity.
      • Di Domenico A
      • Palumbo R
      • Fairfield B
      • et al.
      Fighting apathy in Alzheimer's dementia: A brief emotional-based intervention.
      26 Alzheimer patients and 26 healthy controlsPositive conditioning vs neutral conditioningηp2 = .551 for activity condition and ηp2 = .194 for positive stimulus.
      Progressive Muscle Relaxation TreatmentImproved interest, volition and social relationships.
      • Ikemata S
      • Momose Y
      Effects of a progressive muscle relaxation intervention on dementia symptoms, activities of daily living, and immune function in group home residents with dementia in Japan.
      18 participants from 6 group home unitsProgressive muscle relaxation vs control group (normal routine)Not reported.
      Individualized Cognitive Rehabilitation InterventionLowered apathy-related functional disability and delay institutionalization.
      • Amieva H
      • Robert PH
      • Grandoulier AS
      • et al.
      Group and individual cognitive therapies in Alzheimer's disease: the ETNA3 randomized trial.
      40 sites including 653 outpatientsStandardized programs of cognitive training vs reminiscence therapy, vs individualized cognitive rehabilitation program vs usual careNot reported.