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Background and ObjectivesLifetime risk of Alzheimer disease (AD) dementia is twofold higher in women compared with men, and low estrogen levels in postmenopause have been suggested as a possible contributor. We examined 3ER(GPER1,ER2, andER1) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. Although the study focus was on women, in a comparison, we separately examinedERmolecular variants in men.MethodsParticipants were followed for an average of 10 years in one of the 2 longitudinal clinical pathologic studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathologic assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangle count) and 8 non-AD pathology indices.ERmolecular genomic variants included genotyping and examiningERDNA methylation and RNA expression in brain regions including the dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology.ResultsThe mean age of women (N = 1711) at baseline was 78.0 (SD = 7.7) years. In women,GPER1molecular variants had the most consistent associations with AD traits.GPER1DNA methylation was associated with cognitive decline, tau tangle density, and global AD pathology score.GPER1RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations ofER2andER1sequence variants and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangle density in women. In men (N = 651, average age at baseline: 77.4 [SD = 7.3]), there were less robust associations betweenERmolecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen betweenERmolecular genomic variations and non-AD pathologies in either of the sexes.DiscussionERDNA methylation and RNA expression, and to some extentERpolymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lesser extent in men.

Background and ObjectivesCognitive resilience is a well-recognized concept, but knowledge gaps about its underlying mechanisms have made it difficult to develop instruments that identify older adults with high or low resilience. We tested whether aggregating cortical peptides associated with cognitive resilience into an index can identify adults with higher or lower cognitive resilience.MethodsWe used data from 1,192 older decedents, including annual clinical testing, indices of 10 Alzheimer disease (AD) and related dementia (ADRD) pathologies, and 226 proteotypic peptides measured in the dorsal lateral prefrontal cortex. We used linear mixed-effects models to identify peptides that were related to cognitive resilience (i.e., cognitive decline not explained by ADRD pathologies [false discovery rate ResultsWe constructed a resilience index from 52 of 226 peptides related to cognitive resilience. A higher index was associated with slower cognitive decline (estimate 0.05, SE 0.003, p < 0.001) and slower motor decline (estimate 0.005, SE 0.001, p < 0.001). Most resilience peptides (70%) were specific to cognitive decline, but 30% also provided resilience for motor decline. A higher index was also related to a lower burden of AD pathologies (odds ratio [OR] 0.41, SE 0.01, p < 0.001) and modified the association of AD pathology with cognition in that a higher index modified the negative effects of AD pathology on AD dementia proximate to death (OR 0.70, SE 0.14, p = 0.010). Up to 90% of cognitive resilience peptides were related to AD pathologic phenotypes.DiscussionCortical proteins may provide some degree of cognitive resilience. These multifunctional proteins also seem to provide resilience to other AD clinical phenotypes and have independent associations with ADRD pathologies. Resilience proteins may be high-value therapeutic targets for drug discovery of interventions that maintain brain health in aging adults via multiple pathways.

Background and Objectives:Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat AD/ADRD. Previous studieFFs using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors.Methods:Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs Day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies.Results:The 53 human donors died at a mean age of 91, all were non-Latino White and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer’s dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the prior report for brain AK4 expression.Discussion:By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes like cognitive reserve in a dish.