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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.

The influence of environmental factors on the development of autoimmune disease is being broadly investigated to better understand the multifactorial nature of autoimmune pathogenesis and to identify potential areas of intervention. Areas of particular interest include the influence of lifestyle, nutrition, and vitamin deficiencies on autoimmunity and chronic inflammation. In this review, we discuss how particular lifestyles and dietary patterns may contribute to or modulate autoimmunity. We explored this concept through a spectrum of several autoimmune diseases including Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and Alopecia Areata (AA) affecting the central nervous system, whole body, and the hair follicles, respectively. A clear commonality between the autoimmune conditions of interest here is low Vitamin D, a well-researched hormone in the context of autoimmunity with pleiotropic immunomodulatory and anti-inflammatory effects. While low levels are often correlated with disease activity and progression in MS and AA, the relationship is less clear in SLE. Despite strong associations with autoimmunity, we lack conclusive evidence which elucidates its role in contributing to pathogenesis or simply as a result of chronic inflammation. In a similar vein, other vitamins impacting the development and course of these diseases are explored in this review, and overall diet and lifestyle. Recent work exploring the effects of dietary interventions on MS showed that a balanced diet was linked to improvement in clinical parameters, comorbid conditions, and overall quality of life for patients. In patients with MS, SLE and AA, certain diets and supplements are linked to lower incidence and improved symptoms. Conversely, obesity during adolescence was linked with higher incidence of MS while in SLE it was associated with organ damage. Autoimmunity is thought to emerge from the complex interplay between environmental factors and genetic background. Although the scope of this review focuses on environmental factors, it is imperative to elaborate the interaction between genetic susceptibility and environment due to the multifactorial origin of these disease. Here, we offer a comprehensive review about the influence of recent environmental and lifestyle factors on these autoimmune diseases and potential translation into therapeutic interventions.

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.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS. Published version Study Funding: Supported in part by NIH grants R01 NS102267 and R01 NS112907 (D.P.) and a career transition fellowship from the Consortium of Multiple Sclerosis Centers and the National Multiple Sclerosis Society (M.R.L.). The Article Processing Charge was funded by the authors.