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Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases. Editor's summary: Regulatory T cells (Tregs) are known to be dysfunctional in autoimmune diseases, but the cause of this dysfunction has not been fully elucidated. Here, Sumida et al. found that Tregs isolated from individuals with multiple sclerosis, an autoimmune disease of the central nervous system, had increased expression of the short isoform of PR domain zinc finger protein 1 (PRDM1-S), which destabilized expression of the essential Treg transcription factor FOXP3 and induced Treg dysfunction mediated through SGK1, a salt-sensing kinase. Upstream epigenetic analysis revealed a regulatory role for AP-1 and IRF transcription factors in this circuit. The authors detected similar up-regulation of PRDM1-S in other autoimmune diseases, suggesting that PRDM1-S overexpression may be a common feature of Treg dysfunction. —Courtney Malo [ABSTRACT FROM AUTHOR]

INTRODUCTION: The variability in apolipoprotein E (APOE) ε4‐attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. METHODS: We examined associations of compound genotypes (CompGs) comprising the ε4‐encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD‐affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. RESULTS: The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4‐bearing CompGs define lower‐ and higher‐AD‐risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear—with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between—patterns across ages. DISCUSSION: The ε4‐bearing CompGs have a potential to differentiate biological mechanisms of sex‐, age‐, and ancestry‐specific AD risks and serve as AD biomarkers. Highlights: Younger White women carrying the lower‐risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher‐risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks. [ABSTRACT FROM AUTHOR]

Background: Higher levels of frailty, quantified by a frailty index (FI), may be linked to fatigue severity as tasks become more physically and mentally demanding. Fatigue, a component of frailty research, has been ambiguous and inconsistent in its operationalization. Fatigability—the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities—offers a more sensitive and standardized approach, though the association between frailty and fatigability has not been assessed. Methods: Using cross‐sectional data from the Long Life Family Study at Visit 2 (2014–2017; N = 2524; mean age ± standard deviation (SD) 71.4 ± 11.2 years; 55% women; 99% White), we examined associations between an 83‐item FI after excluding fatigue items (ratio of number of health problems reported (numerator) out of the total assessed (denominator); higher ratio = greater frailty) and perceived physical and mental fatigability using the Pittsburgh Fatigability Scale (PFS) (range 0–50; higher scores = greater fatigability). Results: Participants had mean ± standard deviation FI (0.08 ± 0.06; observed range: 0.0–0.43), PFS Physical (13.7 ± 9.6; 39.5% more severe, ≥15), and PFS Mental (7.9 ± 8.9; 22.8% more severe, ≥13). The prevalence of more severe physical and mental fatigability was higher across FI quartiles. In mixed effects models accounting for family structure, a clinically meaningful 3%‐higher FI was associated with 1.9 points higher PFS Physical score (95% confidence interval (CI) 1.7–2.1) and 1.7 points higher PFS Mental score (95% CI 1.5–1.9) after adjusting for covariates. Conclusions: Frailty was associated with perceived physical and mental fatigability severity. Understanding this association may support the development of interventions to mitigate the risks associated with greater frailty and perceived fatigability. Including measurements of perceived fatigability, in lieu of fatigue, in frailty indices has the potential to alleviate the inconsistencies and ambiguity surrounding the operationalization of fatigue and provide a more precise and sensitive measurement of frailty. [ABSTRACT FROM AUTHOR]