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

Objective: 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 (A13) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. Methods: 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 A13, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. Results: We found that, in WMH (+) older adults greater A13 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 A13 burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter den-sity. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. Conclusion: These observations support a hippocampal excito-toxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from AO positivity to neurode-generation, and subsequent AD. (Am J Geriatr Psychiatry 2023; 31:112-123)