Dissociable influences of maternal vs paternal Alzheimer’s risk on neurocognitive and cardiovascular health in men and women

Abstract

AbstractBackgroundParental history of sporadic Alzheimer’s disease (AD) is considered a prime risk factor since at least the late 1980s. Routinely used clinical samples of at‐risk individuals (8‐16 subjects) may conceal weaker population‐based effects, especially those of paternal inheritance. We performed a phenome‐wide examination of the dissociable influences of maternal vs. paternal AD risk on male vs. female probands in the largest single‐site family‐based at‐risk AD cohort: PREVENT‐AD.MethodWe built sex‐specific PLS‐regression models in which the APOE genotypes (e.g., ɛ3/3, ɛ3/4, ɛ3/2) were estimated based on ∼1,000 patient visits, each covering ∼260 risk indicators, to derive three APOE‐driven intermediate phenotypes (IPs). We examined how much the three IPs vary with regard to sex and maternal vs. paternal AD lineage across the phenome. We assessed the sex‐specific and lineage‐specific variation of the IPs over a 4‐year follow‐up period. Lastly, we examined how matri‐ vs. patrilinear AD risk captured by the IPs were expressed in AD‐vulnerable brain structures.ResultAcross IPs, we linked patrilinear AD risk to verbal‐numerical cognition and cardiovascular health in males. In contrast, we linked matrilinear AD risk to memory performance in both sexes. Over time, the mean difference in cognitive performance decreases with regard to sex but increases with regard to AD lineage. Cis‐ and trans‐generational sex effects in neocortex subregions (e.g., mPFC, PCu) were captured by the first and second IPs, respectively. The third IP mainly captured trans‐generational sex effects in hippocampus subregions (e.g., CA1, CA4).ConclusionWe uncovered IPs of AD susceptibility differently expressed in male and female probands and affected by the diagnosed parent’s sex. Maternal inheritance highlighted memory performance in both sexes, whereas paternal inheritance was particularly linked to cardiovascular health in males. The inheritance of the IPs was reflected in the brain structure at both superficial and deeper layers of the cortex. As the first study of its kind, our cross‐generational analysis of matri‐ vs. patrilinear AD risk bridges the epidemiological and clinical literature by leveraging the power of ∼1,000 patient visits. Our completely data‐driven framework ultimately dissociated phenotypes of maternal and paternal AD risk single‐handedly expressed in male and female probands.