In this study, we aimed to examine the effect of WMH on memory and executive function (EF) across different clinical and biomarker categories of AD.

Increasing evidence supports the idea that Alzheimer’s disease (AD) is a heterogenous disease with multiple factors contributing to its pathophysiology. The 2018 NIA-AA research framework proposed a biological definition for AD, which uses imaging and cerebrospinal fluid biomarkers of amyloid-β [A], pathological tau [T], and neurodegeneration [(N)] to classify individuals along the AD continuum. Vascular diseases commonly co-exist with AD and prior studies suggest that greater white matter hyperintensities (WMH), a surrogate marker for vascular disease, is associated with decline in global cognition or specific cognitive domains.

We selected 216 cognitively normal (CN) participants and 407 participants with mild cognitive impairment (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) at baseline. Based on the 2018 research framework, participants were classified using AT(N) biomarkers into one of 3 categories: biomarker negative (A-T-N-), amyloid negative but biomarker positive (A-T±N+ or A-T+N±) or amyloid positive (A+T±N±). Linear regressions were then used to examine the association between WMH and cognitive function.

Higher WMH burden was associated with worse EF in both CN and MCI subgroups while a significant association between WMH and memory was only found in the MCI subgroup. Furthermore, WMH was associated with EF in the group with A-T±N+ or A-T+N± biomarker category, but not for A-T-N- (normal biomarker) and A+T±N± (AD pathology). The association between higher WMH and worse memory was independent of amyloid levels in individuals with MCI with evidence of AD pathology.

Vascular disease, as indexed by WMH, independent of AD pathology affects cognitive function in both CN and MCI subgroups. Future studies using the AT(N) research framework should consider white matter lesions as a key biomarker contributing to the clinical presentation of AD.