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PubMed2026

Impact of sex differences on microglial function in Alzheimer's disease.

Aging is the strongest risk factor for Alzheimer's disease (AD), a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology (hyperphosphorylated tau and neurofibrillary tangles [NFTs]), and associated neuroinflammatory processes. Age-related cellular and molecular stressors, including mitochondrial dysfunction, genomic instability, and chronic low-grade inflammation, progressively increase vulnerability to neurodegeneration. In parallel, sex is increasingly recognized as a biological variable that shapes AD risk, clinical course, and neuropathological burden. Women account for roughly two-thirds of AD cases, a disparity not fully explained by longevity. Multiple factors likely contribute, including hormonal transitions across the lifespan (particularly menopausal estrogen decline), sex chromosome-linked immune regulation, sex-dependent interactions between genetic risk factors (e.g., APOE4 and TREM2) and brain aging, and differences in vascular risk, cognitive reserve, and sociocultural exposures that influence disease expression and detection. Microglia, the brain's resident immune cells, are sexually dimorphic, and respond to Aβ and tau pathology, modulating inflammatory signaling, synaptic remodeling, and neurovascular dysfunction implicated in AD. Emerging human and experimental evidence indicate that microglial activation states, immunometabolism, and functional responses differ between males and females and may contribute to sex-specific AD trajectories. Here, we synthesize current evidence supporting microglial sexual dimorphism across aging and AD, highlight possible candidates (hormonal signaling, immuno-aging, disease-associated microglial states, and immunometabolic remodeling), and discuss key knowledge gaps toward sex-informed precision approaches for prevention and treatment.

Humans↗

PubMed2026

Life-course stress exposure and cognitive decline in middle-aged and older Chinese adults: The role of sex differences and educational protection.

BACKGROUND: Stressful life events (SLEs) across the life course have been associated with cognitive decline, but evidence on their cumulative impact and potential modifiers remains limited. We aimed to examine the associations between SLE exposure in childhood, adulthood, or both life stages and cognitive trajectories, and to investigate whether these associations vary by sex and education. METHODS: We used data from the China Health and Retirement Longitudinal Study, a nationally representative cohort of adults aged ≥45 years. Participants with complete data on SLEs, cognition, and covariates were included (n = 5922). SLEs were retrospectively assessed for childhood and adulthood. Cognitive function was measured using a composite score (range 0-21) across three waves (2011-2015). Linear mixed-effects models examined longitudinal associations, adjusting for sociodemographic factors, health behaviors, and chronic conditions, with interaction analyses for sex and education. RESULTS: Compared with participants reporting no SLEs, cumulative exposure showed the strongest association with cognitive decline (β = -0.52, 95% CI -0.69 to -0.35), followed by childhood-only (β = -0.34, -0.48 to -0.20) and adulthood-only exposure (β = -0.22, -0.37 to -0.07). Sex significantly moderated the associations for childhood and cumulative exposure, with women exhibiting greater cognitive vulnerability. Higher educational attainment attenuated the associations between single-period stress and cognitive decline, with only partial protection observed against cumulative adversity. CONCLUSION: Cumulative life-course stress is associated with accelerated cognitive decline in Chinese middle-aged and older adults. Women appear more vulnerable to stress-related cognitive effects, whereas higher education confers partial resilience, highlighting the need for sex-sensitive and education-informed prevention strategies.

Humans↗

PubMed2026

Molecular analysis of individuals with suspected 46,XY differences of sex development in a homogenous and understudied population.

Differences of sex development (DSD) are a group of rare congenital conditions defined by atypical chromosomal, gonadal, and/or hormonal sex. Despite advances in massively parallel sequencing (MPS), more than half of DSD cases have an unknown genetic aetiology. We recruited and analysed 21 individuals with 46,XY DSD from the Greater Middle East population using chromosomal microarray and whole exome sequencing. Participants had DSD ranging from micropenis to anorchia (absence of testes) with extra-genital features reported in four individuals (19%). Using a combination of microarray and WES, a genetic diagnosis (variants curated as likely pathogenic or pathogenic) was identified in 12/21 (57%) individuals. Microarray analysis showed two DSD participants with extra genital features had chromosomal abnormalities (48,XXXY and mosaic Y chromosomal rearrangement). Microarray also indicated a high degree of consanguinity, with extensive long contiguous stretches of homozygosity (LCSH) (>3% of the genome) in 6/21 (28.6%) individuals, all of whom received a genetic diagnosis. WES analysis revealed variants in the NR5A1 (three individuals), SRD5A2 (three individuals), TALDO1 (one individual) and AR (two individuals) genes. This includes the novel frameshift variant, c.1309del (p.Leu437Cysfs*59), in NR5A1. This study contributes to the characterisation of clinical features and molecular findings in individuals with DSD in this understudied and homogenous population and highlights the challenges with DSD diagnosis in the region. The genetic diagnoses identified may contribute to improved patient care and management.

Humans↗

PubMed2026

Sex-specific differences in liver DNA methylation patterns and epigenetic aging in mice.

Biological sex has been shown to influence aging outcomes, contributing to distinct trajectories in disease susceptibility and lifespan. DNA methylation patterns provide a quantitative measure of biological aging. This study investigated whether aged male and female mice display distinct liver DNA methylation patterns and differences in epigenetic aging. Liver samples were collected from 17 aged c57BL/6 mice (6 males, 11 females). Genomic DNA was extracted and bisulfite-converted before targeted enrichment of 2,045 murine age-associated CpG loci. Biological age (DNAge) was estimated using a previously developed DNA methylation-based predictor generated through elastic net regression. The difference (ΔDNAge) between DNAge and chronological age was computed. Sex-specific differences were assessed by comparing site-specific methylation ratios, ΔDNAge values, and through principal component analysis (PCA) and multiple linear regression. Twelve CpG sites across six genes (Fam84b, Zswim6, Hsf4, Mn1, Qprt, and Rapgefl1) showed significant sex-associated differences in methylation. Fam84b demonstrated the largest and most consistent sex-associated effect, with all three associated CpG sites showing higher methylation in males (regression coefficients: -0.204, -0.281, and -0.294). Zswim6 exhibited consistent lower methylation ratios in females, whereas the other genes showed higher methylation in females. There were no sex differences in biological age or ΔDNAge (P = 0.596). Although the epigenetic clock did not reveal differences between sexes in aging, aged mice did exhibit sex-specific liver methylation patterns different from those reported in younger mice, suggesting that sex-dependent epigenetic changes may emerge later in life and may reflect sexual dimorphism in liver function with age.NEW & NOTEWORTHY Males and females are known to age differently and develop certain diseases at different rates. Here, we examined the livers of aged male and female mice to see if they show different DNA methylation patterns. We found that aged male and female mice had distinct DNA methylation patterns at specific genes. Interestingly, most of these methylation differences were not present in younger mice, suggesting that sex differences in the genome may change with age.

Animals↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2026

Genital surgery in children with differences of sex development (DSD): Strengths and concerns across diverging regulations in four European countries.

Differences of Sex Development (DSD) is a collective term for a heterogeneous group of rare congenital conditions characterized by atypical genetic, gonadal, or genital sexual development. The treatment of children with DSD, particularly the indications for and timing of surgical interventions, has been the subject of debate for decades. In recent years, social developments emphasizing children's rights to self-determination and bodily integrity, along with increasing societal acceptance of atypical sex characteristics, have encouraged a more cautious approach toward early genital surgery in children with DSD. In 2019, the European Parliament adopted a resolution urging Member States to enact legislation prohibiting elective genital surgical interventions on intersex infants and children. Since then, several countries have indeed implemented restrictive measures, including legal bans on early surgical procedures. In this paper, we share the experiences and insights gained in recent years as pediatric urologists working in four neighboring countries in multidisciplinary university centers specializing in DSD care and research. We focus on current approaches to the care of children with DSD, the evolution of relevant national policies over time, and the nature and impact of recently introduced restrictive regulations on early surgical interventions. By presenting perspectives from pediatric urologists across these four countries, we aim to contribute to ongoing discussions on the alignment and refinement of surgical treatment practices for children with DSD.

Humans↗

PubMed2016

Epigenetic mechanisms in sexual differentiation of the brain and behaviour.

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

Animals↗

PubMed2025

Distinct Behavioral Profiles and Neuronal Correlates of Heroin Vulnerability Versus Resiliency in a Multi-Symptomatic Model of Heroin Use Disorder in Rats.

OBJECTIVE: The behavioral and diagnostic heterogeneity within the opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting the translational relevance of the mechanistic research that is conducted in experimental animals. The authors hypothesized that a nonlinear clustering of OUD-like behavioral traits would capture population heterogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles. METHODS: Over 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors. A nonlinear stochastic block model clustering analysis was used to assign rats to OUD vulnerable, intermediate, and resilient clusters. Additional behavioral tests and circuit analyses using c-fos protein activation were conducted on the vulnerable and resilient subpopulations. RESULTS: OUD vulnerable rats exhibited greater heroin taking and seeking behaviors relative to those in the intermediate and resilient clusters. Akin to human OUD diagnosis, further vulnerable rat subclustering revealed subpopulations with different combinations of behavioral traits, including sex differences. Lastly, heroin cue-induced neuronal patterns of circuit activation differed between resilient and vulnerable phenotypes. Behavioral sex differences were recapitulated in patterns of circuitry activation, including preferential engagement of extended amygdala stress circuitry in males and cortico-striatal drug cue-seeking circuitry in females. CONCLUSION: Using a nonlinear clustering approach in rats, the analysis captured behavioral diagnostic heterogeneity reflective of human OUD diagnosis. OUD vulnerability and resiliency were associated with distinct neuronal activation patterns, posing this approach as a translational tool in assessing neurobiological mechanisms underpinning OUD.

Animals↗

PubMed2025

DHX37 variants in patients with 46,XY disorders or differences of sex development.

Here, using whole-exome sequencing of a cohort of 17 Japanese patients with 46,XY disorders or differences of sex development, we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in three patients. We also identified a patient with a likely pathogenic variant in SOX9 and a rare likely benign variant in DHX37. This Data Report highlights the genetic and phenotypic diversity of DXH37 variants.

Journal Article↗

PubMed2025

Suppression of LKB1-mutant lung adenocarcinoma by natural killer cells from females.

BACKGROUND: This study addressed the enigma of sex differences in smoking-related lung cancer, particularly focusing on the low LKB1 mutation frequency in female patients with lung adenocarcinoma. METHODS: Sex bias was studied with a genetically engineered mouse model and various tail-vein injection models. Immune cells were analyzed by antibody-depletion study, flow cytometry, and immunofluorescence. The relevance of our findings to human disease was validated by evaluating various lung adenocarcinoma datasets. All statistical tests are 2-sided. RESULTS: A statistically significant percentage of females are resistant to LKB1-mutant tumor formation in our models, reflecting this sex difference in humans. Natural killer (NK) cells were identified as a critical factor in this sex-biased response. This sex difference was observed primarily in LKB1-mutant lung adenocarcinoma, probably due to their low major histocompatibility complex class I level, making them the ideal target for NK cells through the missing-self recognition. Although females resistant to LKB1-mutant lung adenocarcinoma formation did not have enhancement of any specific NK subpopulation, our immunofluorescence analysis revealed high numbers of NKs in female lungs even with the presence of LKB1-mutant lung adenocarcinoma. Our gene set enrichment analysis of The Cancer Genome Atlas-lung adenocarcinoma dataset also showed that female LKB1-mutant lung adenocarcinoma patients have a stronger NK-mediated response after adjusting for other male-female differences using the LKB1 wild-type lung adenocarcinoma dataset. CONCLUSION: Females have a stronger NK-mediated response against LKB1-mutant lung adenocarcinoma, which was present in our mouse model and the human lung adenocarcinoma dataset. This study revealed a novel role of NK cells in suppressing LKB1-mutant lung adenocarcinoma in females, which should be assessed in the clinical setting in the future.

Killer Cells, Natural↗

PubMed2026

A single-cell meta-analysis evidences transposable element dysregulation in sex-based differences in Parkinson's disease.

Transposable elements (TEs) (mobile genetic elements comprising ∼45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood. Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 donors, generating a cell-type-resolved atlas of TE dysregulation in PD. We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes. Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons. Correlation and genomic proximity analyses also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination. Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.

Parkinson's disease↗

PubMed2026

Single-cell spatial transcriptomic atlas of the mouse adrenal gland reveals sexual dimorphism in steroidogenic enzyme and hormone receptor expression.

The adrenal cortex shows sexual dimorphism in structure and function. We analysed adrenal glands from 7-week-old male and female BALB/c mice using Visium HD with Cellpose 3 segmentation, comprising 236,077 cells across eleven populations, including four cortical zones. Using curated marker-gene-based zonal annotation, we focused on steroidogenic enzymes and hormone receptors, complementing our companion study based on the same primary dataset. The X-zone was nearly absent in males but prominent in females. Females showed higher Hsd3b1 expression across cortical zones and higher Cyp11b1 expression in outer cortical compartments. The strongest sex difference involved Srd5a2, with markedly higher expression in male zona fasciculata (inner: 77.1% vs. 28.9%), independently supported by RNAscope and immunohistochemistry. Mc2r and Mrap showed discordant spatial distributions, with limited co-expression, suggesting potential MC2R-independent MRAP roles. Agtr1a dominated angiotensin II receptor expression in zona glomerulosa without major sex differences, providing a zone-resolved reference for adrenal sexual dimorphism.

Adrenal cortex↗

PubMed2025

Reproducible autosomal gene expression changes with loss of typical X and Y complement across tumor types.

Although there are known sex differences in cancer incidence, severity, and treatment, the sex chromosomes are typically excluded from genomic analyses because of the unique technical challenges associated with assessing their copy number, sequence variation, and expression. Here we assess sex chromosome complement in three widely-used human genomics datasets from normal (non-cancerous) tissues, primary tumors, and cancer cell lines and study the effects on genome-wide gene expression. Expected sex chromosome complements based on reported patient sex were observed in non-cancerous tissues, but about half of tumors and cancer cell lines showed loss of typical sex chromosome gene expression across tissue types with three categories: loss of chromosome Y (LOY), loss of chromosome X (LOX) and reactivation of the inactive X chromosome (XaXa). Genes consistently differentially expressed in tumors with loss of chromosome X, loss of chromosome Y, or loss of X chromosome inactivation are associated with the hallmarks of cancer and include both sex-linked and autosomal genes from nearly all chromosomes, druggable genes, and genes with molecular functions relevant to cancer signaling, such as kinase activity. Strikingly, tumors that are X0, including tumors from female patients that have lost an X chromosome and tumors from male patients that have lost a Y chromosome, cluster together by gene expression profile. Patients with tumors that have LOX or LOY had poorer survival outcomes compared to those with tumors that had maintained their sex chromosome complement. Further, LOX and LOY eliminates nearly all of the differential gene expression between tumors from different patient sexes, affecting sex chromosomal and autosomal gene expression. Going forward, considering patient sex as well as the entire genome, including assessment of the sex chromosome complement, will provide additional insights into personalized tumor etiology, progression, treatment, and patient outcome.

Journal Article↗

PubMed2026

Characterizing 46,XY Differences of Sex Development: Novel Genetic Variants and Diagnostic Pitfalls in a Single-Center Cohort.

Explore the source record for details and available documents.

17β-hydroxysteroid dehydrogenase deficiency↗

PubMed2024

Multivariate genetic architecture reveals testosterone-driven sexual antagonism in contemporary humans.

Sex difference (SD) is ubiquitous in humans despite shared genetic architecture (SGA) between the sexes. A univariate approach, i.e., studying SD in single traits by estimating genetic correlation, does not provide a complete biological overview, because traits are not independent and are genetically correlated. The multivariate genetic architecture between the sexes can be summarized by estimating the additive genetic (co)variance across shared traits, which, apart from the cross-trait and cross-sex covariances, also includes the cross-sex-cross-trait covariances, e.g., between height in males and weight in females. Using such a multivariate approach, we investigated SD in the genetic architecture of 12 anthropometric, fat depositional, and sex-hormonal phenotypes. We uncovered sexual antagonism (SA) in the cross-sex-cross-trait covariances in humans, most prominently between testosterone and the anthropometric traits - a trend similar to phenotypic correlations. 27% of such cross-sex-cross-trait covariances were of opposite sign, contributing to asymmetry in the SGA. Intriguingly, using multivariate evolutionary simulations, we observed that the SGA acts as a genetic constraint to the evolution of SD in humans only when selection is sexually antagonistic and not concordant. Remarkably, we found that the lifetime reproductive success in both the sexes shows a positive genetic correlation with anthropometric traits, but not with testosterone. Moreover, we demonstrated that genetic variance is depleted along multivariate trait combinations in both the sexes but in different directions, suggesting absolute genetic constraint to evolution. Our results indicate that testosterone drives SA in contemporary humans and emphasize the necessity and significance of using a multivariate framework in studying SD.

Humans↗

PubMed2024

Variable resource allocation pattern, biased sex-ratio, and extent of sexual dimorphism in subdioecious Hippophae rhamnoides.

Evolutionary maintenance of dioecy is a complex phenomenon and varies by species and underlying pathways. Also, different sexes may exhibit variable resource allocation (RA) patterns among the vegetative and reproductive functions. Such differences are reflected in the extent of sexual dimorphism. Though rarely pursued, investigation on plant species harbouring intermediate sexual phenotypes may reveal useful information on the strategy pertaining to sex-ratios and evolutionary pathways. We studied H. rhamnoides ssp. turkestanica, a subdioecious species with polygamomonoecious (PGM) plants, in western Himalaya. The species naturally inhabits a wide range of habitats ranging from river deltas to hill slopes. These attributes of the species are conducive to test the influence of abiotic factors on sexual dimorphism, and RA strategy among different sexes. The study demonstrates sexual dimorphism in vegetative and reproductive traits. The sexual dimorphism index, aligned the traits like height, number of branches, flower production, and dry-weight of flowers with males while others including fresh-weight of leaves, number of thorns, fruit production were significantly associated with females. The difference in RA pattern is more pronounced in reproductive traits of the male and female plants, while in the PGM plants the traits overlap. In general, habitat conditions did not influence either the extent of sexual dimorphism or RA pattern. However, it seems to influence secondary sex-ratio as females show their significant association with soil moisture. Our findings on sexual dimorphism and RA pattern supports attributes of wind-pollination in the species. The observed extent of sexual dimorphism in the species reiterates limited genomic differences among the sexes and the ongoing evolution of dioecy via monoecy in the species. The dynamics of RA in the species appears to be independent of resource availability in the habitats as the species grows in a resource-limited and extreme environment.

Hippophae↗

PubMed2024

Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

Animals↗

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗