Pregnancy and breastfeeding are associated with less later‐life cognitive decline in a longitudinal, prospective cohort

Abstract INTRODUCTION The brains of female mammals evolved to undergo structural and functional changes during pregnancy and lactation, equipping them for motherhood. However, long‐term cognitive health implications of these adaptations in women are poorly understood. METHODS In the Women's Health Initiative (WHI) Memory Study (WHIMS; n  = 7427) and WHI Study of Cognitive Aging (WHISCA; n  = 2304), postmenopausal women completed reproductive history interviews, annual global cognitive assessment from mean age 70 for up to 13 years, and multi‐domain cognitive testing for up to 8 years. RESULTS Each additional month pregnant was associated with higher scores of global cognition. Each additional month of breastfeeding corresponded to higher scores of global cognition, verbal memory, and visual memory. We observed equivalent results for binary formulations of gravidity and breastfeeding. DISCUSSION Low rates of fertility and breastfeeding may have implications for postmenopausal cognitive health at the population level. Next steps include examining mechanisms linking women's reproductive history with postmenopausal cognitive health. Highlights Motherhood may leave an enduring mark on women's brains, shaping cognitive health. Over 7000 women were assessed annually from approximately age 70 for up to 13 years. Ever being pregnant and cumulative time pregnant were linked with better cognition. Ever having breastfed and more time breastfeeding were linked with better cognition. These results imply that declining fertility may affect cognitive aging in future generations.

Lifetime risk of incident dementia and incident mild cognitive impairment in older adults

Abstract INTRODUCTION We estimated the lifetime risk of incident dementia and mild cognitive impairment (MCI) from ages 55–105 and examined differences by sex and race. METHODS Data were drawn from five harmonized longitudinal cohort studies at the Rush Alzheimer's Disease Center, including 4611 participants for dementia and 3915 for MCI. Diagnoses were based on annual clinical evaluations. Lifetime risk was estimated using nonparametric cumulative incidence curves by age conditional on being alive and event‐free at the index age, accounting for competing mortality and delayed study entry, stratified by sex and race. RESULTS Lifetime risk from age 55 was 43% (95% confidence interval [CI]: 38%–47%) for dementia and 62% (95% CI: 57%–67%) for MCI. Female participants had higher risks than male participants, and racial differences were modest. DISCUSSION These findings extend lifetime risk estimation beyond age 90 among diverse older adults and provide MCI estimates, emphasizing equity‐focused prevention and public health strategies to reduce cognitive impairment. Highlights Lifetime risk (cumulative incidence) of dementia and mild cognitive impairment (MCI) was estimated from ages 55 to 105 using nonparametric cumulative incidence models accounting for competing risk of death and left truncation. The estimated lifetime risk was 43% for incident dementia and 62% for MCI, with risk rising steeply after age 75 and appearing to level off at the oldest ages. Women and Black participants showed higher lifetime risks, partly reflecting mortality and selective survival dynamics. Exploratory analyses suggested elevated risks among Latino participants and those with a history of stroke. These findings extend lifetime risk estimation beyond age 90 and highlight the need for equitable, culturally informed dementia prevention and monitoring strategies.

Accelerating real‐world prediction and research in Alzheimer's: The M3AD study

Abstract Chronic diseases, including Alzheimer's disease (AD) and related dementia (ADRD), do not exist solely as isolated entities. Instead, they weave concomitant trajectories of multiple diseases, conditions, behaviors, and risks, mutually influencing each other's course and natural history, in ways yet unexplored. Electronic health records (EHRs) provide us with a unique opportunity to look at related and unrelated clinical trajectories over time, thus potentially providing insight into unrecognized prodromes, while incorporating the complexities of patients' lives. We harmonize and federate a three‐city EHR metaplatform of nearly 10 million patients (∼60,000 with AD/ADRD), which we further embed within census tracts, to contextualize these health trajectories. Our multidisciplinary approach ambitions a unique dynamic platform to inform strategies to tailor risk prediction, complex clinical management, and real‐world evaluation of future treatments of AD/ADRD. We present the rationale for and design of the Multimorbidity Three‐City Alzheimer's Disease EHR (M3AD) Study and real‐world data metaplatform, progress and demonstration of feasibility, its expected singular and complementary contributions to the field. Highlights Our success in living longer lives often brings chronic conditions and multimorbidity. Alzheimer's research should comprise life trajectories’ complexity in multimorbidity. New real‐world analytical approaches allow integrated prediction of Alzheimer's disease. We are building a three‐city electronic health record (EHR) metaplatform for prediction, prevention, and impact We further embed EHR within census tracts to contextualize Alzheimer's trajectories

Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's disease

Abstract INTRODUCTION Neuroimaging genetics has advanced our understanding of Alzheimer's disease (AD); however, frameworks using functional genomics are needed to elucidate mechanisms connecting loci to neurological outcomes. To address this need, we explored relationships between AD‐associated variants and disease via their impact on gene expression and neuroanatomical phenotypes. METHODS We mapped established AD genes to neuroimaging traits using the NeuroimaGene Atlas and predicted transcript‐driven neurological features of AD by comparing gene‐derived neuroimaging features with clinical neuroimaging data. Genetic covariance analyses were performed to characterize shared genetic architecture between AD endophenotypes and neuroimaging features, and to identify neuroimaging features associated with a family history of dementia. RESULTS Our analyses implicate PSMC3 as a contributor to AD pathophysiology and identify AD endophenotypes, including dementia family history, linked to frontal cortex thickness and volume, as well as changes in cerebrospinal fluid volume. DISCUSSION Our findings prioritize AD genes whose regulation is associated with vulnerable brain regions, offering a potential mechanistic framework for downstream functional validation.

Correction to "The National Alzheimer's Coordinating Center (NACC) 1999‐2025: Personal history and recollections"

Social disadvantage outweighs knowledge in dementia risk

Abstract INTRODUCTION Public health efforts promote dementia knowledge to reduce risk, but it is unclear whether knowledge predicts lower risk compared to social determinants like education and socioeconomic status (SES). METHODS We analyzed cross‐sectional data from 1730 adults to examine how age, sex, education, SES, family history of dementia, and Alzheimer's disease (AD) knowledge predicted behavioral and health‐related dementia risk. We used linear regressions and machine learning to compare the explanatory and predictive value of each factor. RESULTS Lower SES and education were the strongest predictors of increased behavioral risk. Health‐related risk was associated only with SES. AD knowledge accuracy and confidence were not significantly associated with either index. Machine learning confirmed these patterns, with SES and education emerging as key features. DISCUSSION Low SES and education were more strongly linked to dementia risk than AD knowledge. Findings underscore the need for equity‐focused strategies beyond public awareness campaigns to improve knowledge.

Alzheimer's disease and related dementias among transfeminine adults: A cohort study

Abstract INTRODUCTION We investigated whether Alzheimer's disease and related dementias (ADRD) are more common among transfeminine (TF) adults than among demographically similar cisgender people enrolled in the same health system. METHODS We analyzed electronic health records of 856 TF adults aged 65+ and matched cisgender men (CM) and cisgender women (CW) and compared ADRD prevalence across groups by calculating enrollment‐adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS The aOR of ADRD among TF adults were 1.39 (95% CI: 0.99–1.97) relative to CM and 1.29 (95% CI: 0.92–1.82) relative to CW referents. For TF adults with evidence of receiving gender‐affirming hormone therapy (GAHT) receipt, the associations were slightly stronger: 1.75 (1.13–2.69) and 1.70 (1.11–2.60). Results restricted to minoritized ethnoracial groups appeared smaller, but imprecise. DISCUSSION These findings suggest that ADRD diagnosis and management may represent a priority in the healthcare of older TF people, particularly those with a history of GAHT.

Sex and life experience shape locus coeruleus pretangle tau pathology

Abstract INTRODUCTION Alzheimer's disease features early a pathology in the locus coeruleus (LC), yet how sex and life experience shape LC vulnerability remains poorly understood. METHODS We expressed pseudophosphorylated human tau (htauE14) in LC neurons of TH‐Cre rats and exposed both sexes to early‐ or late‐life enrichment or stress. Behavioral, histological, protein, and hippocampal single‐nucleus RNA sequencing (snRNA‐seq) analyses were performed. RESULTS LC‐targeted htauE14 impaired learning and increased anxiety‐like behavior. Early enrichment reduced htauE14 spread and LC microglia activation, elevated hippocampal brain‐derived neurotrophic factor (BDNF), and improved olfactory learning in males. Late enrichment alleviated anxiety and enhanced spatial memory, whereas late stress exacerbated LC degeneration. Hippocampal snRNA‐seq revealed sex‐ and cell type–specific transcriptional responses, with htauE14 preferentially engaging metabolic and synaptic pathways in females, effects amplified by early stress but stabilized by early enrichment. Late‐life experiences primarily recruited homeostatic regulatory programs. DISCUSSION Sex and developmental history critically shape early LC tau‐related vulnerability.

New approaches to treating chronic obstructive pulmonary disease with Colla corii asini

Abstract Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death and disability worldwide. Its complex etiology involves factors such as smoking, air pollution, genetic susceptibility, and social environment. With the accelerating global aging population and urbanization, the incidence and burden of COPD continue to rise. Current treatment strategies for COPD are relatively conservative, primarily focusing on bronchodilators, inhaled corticosteroids, and long‐term oxygen therapy. Although these approaches can alleviate symptoms and slow disease progression to some extent, they fail to effectively target the underlying mechanisms of the disease, leaving an unmet clinical need for more‐effective therapies. This highlights the urgency of developing innovative drugs that are both safe and efficacious to address the challenges in COPD treatment. As a traditional Chinese medicine with a long history, Colla corii asini has garnered significant attention for its diverse pharmacological effects and favorable safety profile. Research has shown that Colla corii asini possesses multiple biological activities, including hematopoiesis, nourishing the lungs, enhancing immunity, anti‐infection, antiaging, antitumor, and antifatigue effects. Moreover, it has demonstrated potential in regulating oxidative stress, immune imbalance, and inflammatory responses. Recent evidence suggests that Colla corii asini may play a protective role in lung function through multitarget and multipathway mechanisms. Based on previous research findings, this paper explores the potential therapeutic value of Colla corii asini in COPD treatment by addressing the current clinical management challenges and identifying potential therapeutic targets. It also integrates the pharmacological effects of Colla corii asini into a broader treatment context, providing new perspectives for comprehensive COPD management and laying the theoretical foundation for its modernization and innovative application.

Persisting Transglutaminase 6 Antibodies in Neurological Gluten‐Related Disorders

Objective Gluten‐related autoimmunity can cause neurological disease, although the best way to diagnose and monitor such patients is unclear. Serological testing for antibodies against transglutaminase 6 (TG6) has been proposed; however, this is not widely available in clinical practice. Using longitudinal data from patients attending a specialist neurological center with routine TG6 testing, this observational study explores how antibody history relates to brain atrophy, cognition, and quality of life. Methods Serological records of patients with gluten‐related neurological disease were collected alongside clinical brain magnetic resonance imaging. Patients were recruited to undertake questionnaires that assessed/included chronic symptom severity, the hospital anxiety and depression scale, the SF‐12, and the Biagi scale for gluten‐free diet adherence. Volunteers were offered the cerebellar cognitive affective syndrome scale for cognitive testing. Primary analyses focused on patients with ≥5 years of serology (n = 462), and related TG6 history to available clinical outcomes (primary analysis range 89–104). Results Patients with a previous positive immunoglobulin A (IgA) TG6 result reported greater depression, symptom severity, and poorer physical functioning. IgA TG6 antibody exposure was correlated with regional brain atrophy (age‐corrected). Greater self‐reported gluten‐free diet adherence significantly predicted a recent negative IgA TG6 test. Subgroup analyses replicated multiple findings in patients with and without celiac disease. Interpretation TG6 testing can identify patients at risk of accelerated brain atrophy, poorer physical functioning, and worsened mental health. IgA TG6 should be used as a diagnostic and monitoring test for patients with relevant neurological presentations, while achieving negative serology with a strict gluten‐free diet should be the goal. ANN NEUROL 2026;99:274–282