In Pre-Clinical AD Small Vessel Disease is Associated With Altered Hippocampal Connectivity and Atrophy

Published:September 24, 2022DOI:


      • What is the primary question addressed by this study?We investigated whether the presence of small vessel disease (SVD) (measured as significant WMH burden) altered the associations between brain amyloid-beta (Aβ) and hippocampal functional connectivity during associative encoding in cognitively normal older adults.
      • What is the main finding of this study?In older adults with significant WMH burden (WMH+), greater Aβ burden was associated with a more localized pattern of hippocampal-medial temporal lobe (MTL) hyperconnectivity, but not in individuals with minimum WMH burden (WMH-). This local hippocampal-MTL hyperconnectivity is associated with local MTL atrophy.
      • What is the meaning of the finding?These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in pre-clinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD.



      Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aβ) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume.


      This study included 61 cognitively normal older adults (age range: 65–93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aβ, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity.


      We found that, in WMH (+) older adults greater Aβ burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aβ burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy.


      These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aβ positivity to neurodegeneration, and subsequent AD.



      AD (Alzheimer's disease), AIR (automated image registration), (beta-Amyloid-beta), SVD (cerebral small vessel disease), EPI (echo-planar imaging), TE (echo time), FOV (field of view), fMRI (functional magnetic resonance imaging), gPPI (generalized psychophysiological interactions), MPRAGE (magnetization-prepared rapid gradient echo sequence), MTL (medial temporal lobe), MCI (mild cognitive impairment), MMSE (Mini–Mental State Examination), MNI (Montreal Neurological Institute), PiB (Pittsburgh Compound-B), TR (repetition time), SUVR (standardized uptake value ratio), T1w (T1-weighted), WML (white matter lesion), WMH (white matter hyperintensities)
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