Gender differences in the moderating capacity of reserve and resilience factors on the association of Alzheimer’s disease brain pathology and cognitive function

Background In the context of ageing and Alzheimer’s disease (AD), factors linked to reserve and resilience may confer protection against impact of underlying neuropathology on cognitive function. Such factors are differentially manifested in men and women, yet limited studies have explored potential divergence in their capacity to moderate cognitive outcomes, particularly within at‐risk preclinical populations. Here we evaluate gender dichotomies in the effect modification of independent brain and cognitive reserve factors on associations of AD‐related neuropathology and cognition. Method Gender‐stratified analysis of CHARIOT:PRO SubStudy data (2,451 preclinical older adults: 60‐85 years, screened at Imperial College London and University of Edinburgh) was performed using a‐priori confounder‐adjusted linear regression models. The effect modifying role of brain (intracranial volume) and cognitive (educational attainment, estimated premorbid‐intelligence: epIQ, physical activity) reserve proxies on the associations of AD neuropathology (brain amyloid load: via PET/CSF Aβ42; and hippocampal volumes: structural MRI) with multidomain cognitive performance (assessed via learning effect [i.e. difference in initial administration and baseline scores – median 3.5 months] on the Repeatable Battery Assessment of Neuropsychological Status‐RBANS) were independently examined in men and women. Result Learning effects were negatively modulated by amyloid positivity and male gender. Larger hippocampal volumes predicted better global cognition in men, and better immediate memory for both men and women (All P‐values