Location matters: The link between regional white matter hyperintensity burden and subjective cognitive decline in those at risk of Alzheimer's disease

Background Subjective cognitive decline (SCD) is a potential early indicator of Alzheimer's disease (AD). While SCD has been linked to white matter hyperintensity (WMH) burden, it is unclear whether regional WMH lesion volume is differentially associated with domains of cognitive complaints. Objective Examine whether regional WMH burden is associated with domain-specific SCD (memory, executive function) in cognitively unimpaired older adults with a family history of AD. Methods Participants were 150 cognitively unimpaired older adults (65–89 years) with subjective memory complaints and a first-degree family history of AD. Cognitive complaints were assessed with the Cognitive Change Index (CCI-20). WMHs were quantified from T1-weighted and FLAIR MRI using an automated pipeline and categorized into sample-based tertiles for total, subcortical, and lobar regions. Hierarchical regressions examined associations between WMH burden and CCI-20 memory, executive, and total scores, while adjusting for demographics, total intracranial volume, MRI site, APOE ε4 status, and mood symptoms. Results Greater WMH burden in the left temporal lobe was associated with increased memory complaints and total SCD, whereas no WMH region was associated with executive function complaints. APOE ε4 status and depressive symptoms were associated with greater memory and total cognitive complaints across models. Apathy was uniquely related to memory complaints. Conclusions Among older adults with elevated risk of AD, memory-SCD was associated with greater region-specific left temporal cerebrovascular lesion volume. Findings highlight the clinical relevance of left temporal WMH burden and the importance of considering regional vascular pathology, genetic risk, and mood when characterizing early subjective cognitive changes.