Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Measurement Precision Across Cognitive Domains in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Data Set

ObjectiveTo demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.MethodParticipants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores.ResultsAcross all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial.ConclusionModern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved)