White matter hyperintensities, plasma biomarkers, and cognitive decline in Alzheimer’s disease: Insights from early- and late-onset subgroups and APOE e4 carriers

White matter hyperintensities (WMHs) are a prominent neuroimaging feature in Alzheimer’s disease (AD), but their relationship with plasma biomarkers, cognitive decline, and genetic factors like APOE ε4 remains poorly understood. This study investigates WMH volumes, their association with plasma biomarkers, and cognitive performance in AD, with a focus on differences between early-onset (EOAD) and late-onset (LOAD) subgroups and the influence of APOE ε4 carrier status. In this cross-sectional study, 144 AD patients (66 EOAD, 78 LOAD) and 156 cognitively unimpaired controls (CU) underwent 3T MRI, plasma biomarker analysis (Aβ42/40, p-tau181, p-tau217, NfL, GFAP), and cognitive assessments (MoCA). WMH volumes were quantified using automated segmentation and normalized to intracranial volume. APOE ε4 status was determined from plasma samples. Statistical analyses included regression and mediation models, adjusting for age, sex, and vascular risk factors. AD patients exhibited higher WMH volumes, particularly periventricular WMHs (PWMH), compared to CU (p < 0.05). LOAD showed greater WMH burden and hippocampal atrophy than EOAD (p < 0.05). PWMH volumes correlated with lower Aβ42/40 and elevated p-tau, GFAP, and NfL (p < 0.05), with stronger associations in LOAD and APOE ε4 carriers. Mediation analysis revealed that PWMH volume partially explained the association between APOE ε4 and lower MoCA scores (ß = 0.039, p = 0.038). WMHs, especially PWMH, are linked to adverse plasma biomarker profiles and cognitive decline in AD, with pronounced effects in LOAD and APOE ε4 carriers. These findings highlight WMHs as a potential neuroimaging marker for disease progression and underscore the interplay between vascular pathology, genetic factors, and neurodegeneration in AD.

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