Mediation of the Association Between APOE ε4 Genotype, Cognition, and Dementia by Neuropathology Imaging Markers in the Rotterdam Study.

BACKGROUND AND OBJECTIVES Insight into APOE-related pathways is important to unravel pathophysiology and identify therapeutic targets against late-life cognitive decline. We aimed to estimate mediators of APOE ε4 on cognition and dementia through different disease markers on structural in vivo brain imaging. METHODS All participants from the population-based Rotterdam Study who underwent brain MRI between 2005 and 2009 were included. Cognition was assessed cross-sectionally during center visits, and participants were followed up for incident dementia until January 1, 2020. Imaging markers included hippocampal volume (HV), volume of white matter hyperintensities (WMHs), Alzheimer disease-specific regional cortical thickness, and presence of ≥2 cerebral microbleeds. We performed causal mediation analyses to decompose the total effect of APOE ε4 carriership on cognition and dementia into natural direct and indirect effects and corresponding percentage mediated. We adjusted models for potential confounders. RESULTS Among 5,510 participants (mean age at time of MRI scan: 65.0 [±10.9] years, 55.0% women), 349 developed dementia, of whom 148 were ε4 carriers. Carriers of ε4 had slightly lower Z-scores for global cognition (β = -0.02 [-0.07 to 0.02], age-related cognitive decline = 4.4 months), with 7% (β = -0.00 [0.00-0.00]) of this association mediated by HV and 4% (β = -0.00 [-0.01 to 0.00]) by cortical thickness. In total, an estimated 25% of the effect of ε4 on cognition was mediated by microbleeds (p value = 0.24, [β = -0.00 {-0.01 to 0.00}]) and 12% by WMHs (p value = 0.44, [β = -0.00 {-0.01 to 0.00}]). In multiple mediator analyses, WMHs and microbleeds together accounted for 27% of the mediated effect of APOE ε4 on cognition (p value = 0.48). Carriers of ε4 had higher risk of incident dementia (HR 2.35 [95% CI 2.06-2.65]). For dementia, there was little to no evidence of mediation by either HV (3%, p value = 0.09, OR = 1.01 [1.00-1.03]) or regional cortical thickness (0%, p value = 0.79, OR = 1.00 [0.99-1.02]). In total, 1% of the effect of ε4 on dementia was mediated by WMHs (p value 0.29, OR = 1.00 [1.00-1.02]) and 5% by microbleeds (p value = 0.06), OR = 1.03 (1.00-1.07). In multiple mediator analyses, all 4 imaging markers together explained 6% of the mediated effect on incident dementia (p value = 0.04). DISCUSSION In this population-based cohort study, we found that an estimated one-fourth of the effect of APOE ε4 on cognition is mediated by structural brain imaging markers, driven mainly by cerebral microbleeds. For dementia, mediation by these markers was limited.