Influence of White Matter Hyperintensities on Baseline and Longitudinal Amyloid-β in Cognitively Normal Individuals

Abstract

Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales = 36) = 73.80 years, SD = 6.73; mean education years = 17.1, SD = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p = 0.008) and two-year change in Aβ1-42 (p = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Additional support for this less prominent pathway comes from a study of CU participants 243 in which lower baseline CSF Aβ42 together with higher WMH were associated with worse memory but not executive function. Small vessel disease early in AD progression combined with abnormal Aβ may therefore promote an AD-typical disease pathway characterized by memory impairment.…”

“…The authors suggested that this latter Aβ‐mediated pathway reflects exacerbation of AD‐related pathology via reduced Aβ clearance and/or induction of neuroinflammatory responses, as described in Sections 3.2.2 and 3.2.3 . Additional support for this less prominent pathway comes from a study of CU participants 243 in which lower baseline CSF Aβ42 together with higher WMH were associated with worse memory but not executive function. Small vessel disease early in AD progression combined with abnormal Aβ may therefore promote an AD‐typical disease pathway characterized by memory impairment.…”

White matter hyperintensity longitudinal morphometric analysis in association with Alzheimer disease

“…In observational studies, increases in WMH are associated with both cumulative and longitudinal Aβ burden, even in healthy controls 5 . In contrast, WMH presence is less associated with cerebrospinal fluid t‐tau or p‐tau.…”

“…4 In observational studies, increases in WMH are associated with both cumulative and longitudinal Aβ burden, even in healthy controls. 5 In contrast, WMH presence is less associated with cerebrospinal fluid t-tau or p-tau. In the ATN framework, amyloid accumulation occurs earlier in the disease suggesting that WMH changes might occur earlier in the AD process.…”

Current and Future Trends in Biomarkers for the Early Detection of Alzheimer’s Disease in Asia: Expert Opinion

“…In a survey conducted by 16 dementia specialists from nine Asia Pacific countries, the co-existence of AD and CVD accounted for 10–20% of all dementia cases in Asia [ 5 ]. This high burden of AD and CVD in the Asian dementia population can also further accelerate underlying amyloid and tau pathology, contributing to poor cognitive outcomes [ 6 ]. The apolipoprotein E ( APOE ) ɛ4 allele is the most common genetic variant associated with AD, and its frequency is seemingly dependent on racial and regional differences.…”