Sex and gender differences in cognitive resilience to aging and Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5695 - 5719

Published: July 5, 2024

Abstract Sex and gender—biological social constructs—significantly impact the prevalence of protective risk factors, influencing burden Alzheimer's disease (AD; amyloid beta tau) other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding interplay these factors is central to understanding resilience resistance mechanisms explaining maintained function reduced pathology accumulation in aging AD. In this narrative review, ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach provide foundations recommendations for future research into sex‐ gender‐specific drivers resilience, including sex/gender‐oriented review genetics, AD non‐AD pathologies, brain structure function, animal research. We urge field adopt sex/gender‐aware advance our intricate biological determinants consider sex/gender‐specific throughout stages. Highlights differences decline vary by age status. Initial evidence supports sex‐specific distinctions pathology. Findings suggest sex on cognition. There change transition clinical Gender warrant study: modifiable, immune, inflammatory, vascular.

Language: Английский

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Aging activates escape of the silent X chromosome in the female mouse hippocampus

Science Advances, Journal Year: 2025, Volume and Issue: 11(10)

Published: March 5, 2025

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive (Xi) active (Xa), in contrast males with only Xa. Thus, reactivation of silent Xi genes may contribute differences. We use allele-specific, single-nucleus RNA sequencing show that aging remodels transcription the Xa across hippocampal cell types. Aging preferentially changed gene expression on X's relative autosomes. Select underwent activation, new escape cells including dentate gyrus, critical learning memory. Expression escapee Plp1, a myelin component, was increased hippocampus female mice parahippocampus women. AAV-mediated Plp1 elevation gyrus male improved cognition. Understanding how confer advantage could lead novel targets counter brain disease both sexes.

Language: Английский

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Role of the X Chromosome in Alzheimer Disease Genetics

JAMA Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 9, 2024

Importance The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion genes expressed brain, making particularly appealing as potential source unexplored genetic variation AD. Objectives To perform first large-scale chromosome–wide association study (XWAS) Design, Setting, Participants This was meta-analysis studies case-control, family-based, population-based, longitudinal AD-related cohorts from US Alzheimer’s Disease Genetics Consortium, Sequencing Project, UK Biobank, Finnish health registry, Million Veterans Program. Risk AD evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 March 2024. Genetic data available high-density single-nucleotide variant microarrays whole-genome sequencing summary statistics for multitissue expression protein quantitative trait loci published included, enabling follow-up colocalization A total 1 629 863 eligible participants selected referred volunteer samples, 477 596 whom excluded analysis exclusion criteria. number who declined to participate original not available. Main Outcome Measures AD, reported odds ratios (ORs) with 95% CIs. Associations considered at ( P < × 10 −5 ) genome-wide 5 −8 significance. Primary analyses are nonstratified, while secondary evaluate sex-stratified effects. Results Analyses included 152 284 non-Hispanic White, European ancestry (664 403 [57.7%] female 487 881 [42.3%] male), including 138 558 individuals Six independent passed significance, 4 showing support links signal nearby brain nonbrain tissues. One these conservative its lead centered on an intron SLC9A7 (OR, 1.03; CI, 1.02-1.04) prioritizing both CHST7 genes. Of 6 loci, displayed evidence escape inactivation regard risk. Conclusion Relevance XWAS identified novel locus. regulates pH homeostasis Golgi secretory compartments is anticipated have downstream effects amyloid β accumulation. Overall, this advances our knowledge genetics may provide biological drug targets. results further initial insights into elucidating role sex-based differences

Language: Английский

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Davunetide sex-dependently boosts memory in prodromal Alzheimer’s disease

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 2, 2024

Language: Английский

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Biological sex matters in brain aging

Neuron, Journal Year: 2025, Volume and Issue: 113(1), P. 2 - 6

Published: Jan. 1, 2025

Language: Английский

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Sex-related differences in genetically determined Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 4, 2025

We reviewed the literature on sex differences in genetically determined Alzheimer’s disease (AD), focusing autosomal dominant AD (ADAD), Down syndrome-associated (DSAD), and APOE4 homozygosity, particularly regarding penetrance, symptom onset clinical progression, trajectories for markers of amyloidosis (A), tau pathology (T) neurodegeneration (N). Data suggests that onset, AT(N) biomarker are typically subtle populations. Noteworthy exceptions, such as increased later stages females while similar cognitive outcomes, suggest a potential differential reserve warrants further investigation. Additionally, interaction between APOE genotype reveals complex multifaceted effects DSAD, with implications ADAD remain underexplored. The smaller observed compared to sporadic offer insights into different underlying mechanisms Future research should prioritize sex-specific investigations AD, refining methodologies. This includes prioritizing longitudinal designs, adjustment key confounders, adherence guidelines.

Language: Английский

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Grief and Economic Stressors by Sex, Gender, and Education

Neurology, Journal Year: 2025, Volume and Issue: 104(8)

Published: March 31, 2025

The prevalence and impact of stressful life events (SLEs) on age-related Alzheimer disease (AD)-related pathways may depend social determinants including gender education. We investigated whether specific SLEs are associated with AD pathology neurodegeneration how these associations differ by This cross-sectional study included cognitively unimpaired participants, most a family history sporadic AD, from the ALzheimer's FAmilies (ALFA) cohort, based in Barcelona, Spain. Participants had available assessments occurrence type lifetime lumbar puncture and/or structural MRI. performed multiple regression analyses to examine SLE (1) pathologies (CSF phosphorylated tau 181 [p-tau181] β-amyloid [Aβ] 42/40) (2) markers neurogranin GM volumes voxel-wise) interaction stratification (women/men) In total, 1,290 participants (mean age = 59.4 years, range: 48-77 99% White 61% women) were (393 1,234 spectroscopic MRI assessments). Less educated women reported more grief-related economic-related SLEs. Furthermore, abuse reproductive Grief-related CSF outcomes while economic MRI-based outcomes, both an age-independent manner. Specifically, partner's death was lower Aβ42/40 (B -5.19; 95% CI -9.61 -0.76; p 0.022) higher p-tau181 0.18; 0.05-0.32; 0.007) 0.19; 0.007). driven less men women. Unemployment loss limbic frontal areas, women, respectively. Older adults at risk cognitive decline education be susceptible experience Men who have experienced widowhood unemployment financial difficulties benefit interventions.

Language: Английский

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Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease

Neurology, Journal Year: 2025, Volume and Issue: 104(9)

Published: April 9, 2025

Female sex and a parental history of Alzheimer disease (AD), especially maternal, confer increased risk AD. Associations between sex, or affected AD parent's biomarkers are less clear. We examined whether influences (1) β-amyloid (Aβ) tau burden/accumulation, (2) the association Aβ burden, (3) brain cognitive resilience to burden. The sample included 243 participants from Presymptomatic Evaluation Experimental Novel Treatments for cohort in Canada. All with [18F]-NAV4694 [18F]-AV1451 PET MRI were included. differences on regional burden/accumulation; 2-way interactions burden; 3-way time, deposition hippocampal volume (brain resilience) cognition (cognitive over time. Participants (69.4% female) aged 68.3 ± 5.1 years at their first scans. cognitively unimpaired baseline. Longitudinal data available 242 (follow-up, 6.72 2.38 years), including 238 (6.53 2.48 follow-up) follow-ups 115 (4.4 0.6 follow-ups, 71 developed mild impairment. Women showed greater (standardized β = 0.13 0.3) stronger global than men 0.79 0.1). Individuals an father those mother 0.65 Aβ-associated atrophy time 0.24 and, surprisingly, individuals paternal seemed more vulnerable Aβ-related spread tau, whereas women Aβ. Understanding sex-specific could allow clinical trial precision personalization. A major limitation reduced analyses.

Language: Английский

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The biological roots of the sex-frailty paradox

Experimental Gerontology, Journal Year: 2024, Volume and Issue: 198, P. 112619 - 112619

Published: Oct. 29, 2024

Aging is a dynamic process that requires continuous response and adaptation to internal external stimuli over the life course. This eventually results in people aging differently women than men. The "gender paradox" describes how experience greater longevity men, although linked with higher rates of disability poor health status. Recently, concept frailty has been incorporated into this paradox giving rise "sex-frailty which are frailer because they manifest worse status but, at same time, appear less susceptible death men age. However, very little known about biological roots sex-related difference frailty. Inflamm-aging, chronic low-grade inflammatory state associated age, plays key pathophysiological role several age-related diseases/conditions, including Alzheimer's disease (AD), for have lifetime risk Interestingly, inflamm-aging develops different rate compared features could play critical development AD women. According view, continuum between diseases probably lacks clear boundaries can be envisioned shared mechanisms progress pace may lead trajectories It therefore becomes urgent consider holistic approach study aging, declining it from gender medicine perspective also sex-frailty paradox.

Language: Английский

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Chronic traumatic encephalopathy: State-of-the-science update and narrative review

The Clinical Neuropsychologist, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 25

Published: Jan. 20, 2025

The long-recognized association of brain injury with increased risk dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure repetitive head impacts (RHI). We aim contextualize CTE within historical perspective among emerging data which highlights the scientific conceptual evolution CTE-related research parallel broader field disease dementia. provide narrative state-of-the-science update on neuropathology, clinical manifestations, biomarkers, different types patterns impact relevant for CTE, complicated influence co-pathology symptoms. Now almost 20 years since initial case report former American football player, continues evolving increasing clarity but also several ongoing controversies. Our understanding neuropathology outpaces that disease-specific correlates or development in-vivo biomarkers. Diagnostic criteria symptoms attributable are still being validated, leveraging increasingly available biomarkers other conditions like Alzheimer's may be helpful informing differential diagnosis. As diagnostic efforts advance, clinicians should care and/or referrals providers best suited treat an individual patient's symptoms, many have evidence-based behavioral treatment options etiologically agnostic. Several initiatives gradual accrual gold standard clinico-pathological will pay dividends advancing existing gaps CTE.

Language: Английский

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