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Sexual dimorphism in predisposition to Alzheimer's disease.

ABSTRACT: Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and rate of symptom progression, but the mechanisms underlying this sexual divergence are unknown. Although some have suggested this difference in risk is a reflection of the known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities toward the disease. Although a number of potential risk factors have been hypothesized to mediate these differences, none have been definitively verified. In this review, we first summarize the epidemiologic studies of prevalence and incidence of AD among the sexes. Next, we discuss the most likely risk factors to date that interact with biological sex, including (1) genetic factors, (2) sex hormones (3) deviations in brain structure, (4) inflammation and microglia, and (5) and psychosocial stress responses. Overall, though differences in life span are likely to account for part of the divide between the sexes in AD prevalence, the abundance of preclinical and clinical evidence presented here suggests an increase in intrinsic AD risk for women. Therefore, future studies focusing on the underlying biological mechanisms for this phenomenon are needed to better understand AD pathogenesis in both sexes, with the eventual goal of sex-specific prevention and treatment strategies.

SUBMITTER: Fisher DW

PROVIDER: S-EPMC6368179 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Sexual dimorphism in predisposition to Alzheimer's disease.

Fisher Daniel W DW Bennett David A DA Dong Hongxin H

Neurobiology of aging 20180417

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and rate of symptom progression, but the mechanisms underlying this sexual divergence are unknown. Although some have suggested this difference in risk is a reflection of the known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities toward the disease. Although a number of potential risk fa ...[more]

PMID: 29754747

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Project description:BackgroundLate-onset Alzheimer's disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined.MethodsIn-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted.ResultsThe relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia.ConclusionThis study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development.

Project description:BackgroundTau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content.MethodWe systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain.ResultsMale P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice.ConclusionOur findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

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Sexual dimorphism in predisposition to Alzheimer's disease.

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Sexual dimorphism in predisposition to Alzheimer's disease.

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