The moderation and mediation roles of white matter insults in relationship of APOE ε4 genotype with Alzheimer’s disease and related phenotypes: two longitudinal studies

• APOE ε3/ε4 and ε4/ε4 genotypes were associated with higher levels and accelerated progression of WMH; • WMH partially mediate the associations of APOE ε4 with impaired cognitive function, neurodegeneration, Aβ deposition, and incident AD; • The presence of WMH could amplify the role of APOE ε4 in cognitive function, neurodegeneration, and Aβ deposition; • NfH and SMOC2 are involved in neuroinflammatory and axonal injury–related pathways, which may underlie the mediating and moderating roles of WMH. The Apolipoprotein E ε4 (APOE ε4) allele and white matter hyperintensities (WMH) have been implicated in the pathogenesis of Alzheimer’s disease (AD). To investigate the dual roles of WMH in statistically moderating and mediating the relationship of APOE ε4 with AD and related phenotypes, as well as the potential biological correlates. Data were derived from 34,783 non-demented participants in the UK Biobank (UKB; mean age = 55 years; follow-up = 4.3 years) and 863 in the Alzheimer’s disease Neuroimaging Initiative (ADNI; mean age = 71.9 years; follow-up = 3.8 years). Multivariable models evaluated associations of APOE ε4 status, WMH, and their interaction with cognition, neurodegeneration, core pathologies, and AD risk. Mediation analyses were performed to quantify the extent to which WMH statistically explained ε4-outcome associations. Cerebrospinal fluid proteomic and bioinformatic analyses were used to explore biological clues in a subsample of ADNI (n = 708). APOE ε4 carriers exhibited larger WMH volumes (p < 0.001, UKB) and faster WMH change rates (p = 0.019, ADNI). In UKB, WMH statistically mediated a small proportion of associations between APOE ε4 and poorer numeric memory performance, smaller hippocampal volume, increased incident AD and all-cause dementia (ACD). In ADNI, WMH showed statistical mediation signals in the associations of APOE ε4 with faster rates of cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration. Notably, WMH interacted with APOE ε4 to exacerbate cognitive decline, hippocampal atrophy, and Aβ deposition. Proteomic analyses suggested that neuroinflammatory and axonal injury pathways may be associated with the observed mediating and moderating patterns. WMH mediates and enhanced the associations of APOE ε4 with AD-related phenotypes. These findings warrant further studies to clarify the underlying mechanisms and clinical implications.