阿尔茨海默病性别差异机制研究进展

doi:10.3969/j.issn.1003-9198.2025.04.020

摘要/Abstract

摘要： AD是一种神经退行性疾病,在流行病学、临床症状、神经影像、标志物等方面均显示存在性别差异,然而造成这种差异的潜在机制尚不明确。目前,已有研究表明染色体、性激素、载脂蛋白E、炎症免疫及血管疾病等相关因素可能参与了AD易感性的性别差异机制,但尚需更多研究证据支持,以便靶向新的干预靶点,推动AD的精准诊疗。

关键词: 阿尔茨海默病, 性别差异, 性染色体, 性激素, 载脂蛋白E, 免疫炎症, 血管疾病

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that exhibits gender differences in epidemiology, clinical symptoms, neuroimaging and biomarkers. The underlying mechanisms contributing to these differences remain unclear. Current research suggests that sex chromosomes, sex hormones, apolipoprotein E, inflammatory and immune factors, and vascular disease-related factors may be involved in the gender-specific mechanisms of AD susceptibility. However, more research evidence is needed to support these findings and to identify new intervention targets, thereby promoting precision diagnosis and treatment for AD.

Key words: Alzheimer’s disease, gender differences, sex chromosomes, sex hormones, apolipoprotein E, immune inflammation, vascular disease

中图分类号:

R 749.16

林小琦, 赵新静, 吴亚双, 赵薇, 陈琛, 高天语, 周国钰. 阿尔茨海默病性别差异机制研究进展[J]. 实用老年医学, 2025, 39(4): 420-425.

LIN Xiaoqi, ZHAO Xinjing, WU Yashuang, ZHAO Wei, CHEN Chen, GAO Tianyu, ZHOU Guoyu. Advances of the mechanisms of gender differences in Alzheimer’s disease[J]. Practical Geriatrics, 2025, 39(4): 420-425.

参考文献

[1] FERRARI C, SORBI S. The complexity of Alzheimer’s disease: an evolving puzzle[J].Physiol Rev, 2021, 101(3):1047-1081.
[2] FERRETTI M T, IULITA M F, CAVEDO E, et al. Sex differences in Alzheimer disease-the gateway to precision medicine[J].Nat Rev Neurol, 2018, 14:457-469.
[3] CHANDA K, MUKHOPADHYAY D. LncRNA xist, X-chromosome instability and Alzheimer’s disease[J].Curr Alzheimer Res, 2020, 17(6):499-507.
[4] ARMON C, WOLFSON S, MARGALIT R, et al. Estimating the X chromosome-mediated risk for developing Alzheimer’s disease[J].J Neurol, 2022, 269(5):2479-2485.
[5] DAVIS E J, SOLSBERG C W, WHITE C C, et al. Sex-specific association of the X chromosome with cognitive change and tau pathology in aging and Alzheimer disease[J].JAMA Neurol, 2021, 78(10):1249-1254.
[6] BAJIC V P, ESSACK M, ZIVKOVIC L, et al. The X files: “The Mystery of X Chromosome Instability in Alzheimer’s Disease”[J].Front Genet, 2019, 10:1368.
[7] YANG X, XU B, MULVEY B, et al. Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1[J].Nat Neurosci, 2019, 22(3):362-373.
[8] DAVIS E J, BROESTL L, ABDULAI-SAIKU S, et al. A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease[J].Sci Transl Med, 2020, 12(558):eaaz5677.
[9] SAHAB-NEGAH S, HAJALI V, MORADI H R, et al. The impact of estradiol on neurogenesis and cognitive functions in Alzheimer’s disease[J].Cell Mol Neurobiol, 2020, 40(3):283-299.
[10]UDDIN M S, RAHMAN M M, JAKARIA M, et al. Estrogen signaling in Alzheimer’s disease: molecular insights and therapeutic targets for Alzheimer’s dementia[J].Mol Neurobiol, 2020, 57(6):2654-2670.
[11]MAIOLI S, LEANDER K, NILSSON P, et al. Estrogen receptors and the aging brain[J].Essays Biochem, 2021, 65(6):913-925.
[12]RAHMAN A, JACKSON H, HRISTOV H, et al. Sex and gender driven modifiers of Alzheimer’s: the role for estrogenic control across age, race, medical, and lifestyle risks[J].Front Aging Neurosci, 2019, 11:315.
[13]XU Q, JI M, HUANG S, et al. Association between serum estradiol levels and cognitive function in older women: a cross-sectional analysis[J].Front Aging Neurosci, 2024, 16:1356791.
[14]GIRARD R, MÉTÉREAU E, THOMAS J, et al. Hormone therapy at early post-menopause increases cognitive control-related prefrontal activity[J].Sci Rep, 2017, 7:44917.
[15]SHUMAKER S A, LEGAULT C, KULLER L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study[J].JAMA, 2004, 291(24):2947-2958.
[16]ROCCA W A, FAUBION S S. Estrogen and dementia[J].Maturitas, 2022, 165:120-121.
[17]CAI Z, LI H. An updated review: androgens and cognitive impairment in older men[J].Front Endocrinol: Lausanne, 2020, 11:586909.
[18]KUZNETSOV K O, KHAIDAROVA R R, KHABIBULLINA R H, et al. Testosterone and Alzheimer’s disease[J].Probl Endokrinol: Mosk, 2022, 68(5):97-107.
[19]SUN M, COLE A P, HANNA N, et al. Cognitive impairment in men with prostate cancer treated with androgen deprivation therapy: a systematic review and meta-analysis[J].J Urol, 2018, 199(6):1417-1425.
[20]BIANCHI V E. Impact of testosterone on Alzheimer’s disease[J].World J Mens Health, 2022, 40(2):243-256.
[21]SUNDERMANN E E, PANIZZON M S, CHEN X, et al. Sex differences in Alzheimer’s-related Tau biomarkers and a mediating effect of testosterone[J].Biol Sex Differ, 2020, 11(1):33.
[22]NAGY B, SZEKERES-BARTHÓ J, KOVÁCS G L, et al. Key to life: physiological role and clinical implications of progesterone[J].Int J Mol Sci, 2021, 22(20):11039.
[23]BASSANI T B, BARTOLOMEO C S, OLIVEIRA R B, et al. Progestogen-mediated neuroprotection in central nervous system disorders[J].Neuroendocrinology, 2023, 113(1):14-35.
[24]JIN J, LU L, HUA K, et al. Correlations between SHBG, sex hormones, inflammation, and neurocognitive decline in Alzheimer’s disease: a retrospective study[J].Curr Alzheimer Res, 2024, 21(7):491-502.
[25]KANG J H, WEUVE J, GRODSTEIN F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women[J].Neurology, 2004, 63(1):101-107.
[26]OYOLA M G, HANDA R J. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity[J].Stress, 2017, 20(5):476-494.
[27]PANDA S P, KESHARWANI A, SINGH G D, et al. Impose of KNDy/GnRH neural circuit in PCOS, ageing, cancer and Alzheimer’s disease: StAR actions in prevention of neuroendocrine dysfunction[J].Ageing Res Rev, 2023, 92:102086.
[28]PRÉVOT V, TENA-SEMPERE M, PITTELOUD N. New horizons: gonadotropin-releasing hormone and cognition[J].J Clin Endocrinol Metab, 2023, 108(11):2747-2758.
[29]MANFREDI-LOZANO M, LEYSEN V, ADAMO M, et al. GnRH replacement rescues cognition in Down syndrome[J].Science, 2022, 377(6610):eabq4515.
[30]MARBOUTI L, ZAHMATKESH M, RIAHI E, et al. GnRH protective effects against amyloid β-induced cognitive decline: a potential role of the 17β-estradiol[J].Mol Cell Endocrinol, 2020, 518:110985.
[31]ZHANG S, HU J, FAN W, et al. Aberrant cerebral activity in early postmenopausal women: A Resting-State Functional Magnetic Resonance Imaging Study[J].Front Cell Neurosci, 2018, 12:454.
[32]MAO L, WANG L, BENNETT S, et al. Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause[J].Front Physiol, 2022, 13:1043237.
[33]LI Y, LI S, XU S, et al. Association of androgens and gonadotropins with amnestic mild cognitive impairment and probable Alzheimer’s disease in Chinese elderly men[J].J Alzheimers Dis, 2020, 78(1):277-290.
[34]XIONG J, KANG S S, WANG Z, et al. FSH blockade improves cognition in mice with Alzheimer’s disease[J].Nature, 2022, 603(7901):470-476.
[35]KOUTSODENDRIS N, NELSON M R, RAO A, et al. Apolipoprotein E and Alzheimer’s disease: findings, hypotheses, and potential mechanisms[J].Annu Rev Pathol, 2022, 17:73-99.
[36]DENG S, SUN L, CHEN W, et al. Effect of APOEε4 on functional brain network in patients with subjective cognitive decline: a resting state functional MRI study[J].Int J Gen Med, 2021, 14:9761-9771.
[37]CHANG Y L, FENNEMA-NOTESTINE C, HOLLAND D, et al. APOE interacts with age to modify rate of decline in cognitive and brain changes in Alzheimer’s disease[J].Alzheimers Dement, 2014, 10(3):336-348.
[38]GAMACHE J, YUN Y, CHIBA-FALEK O. Sex-dependent effect of APOE on Alzheimer’s disease and other age-related neurodegenerative disorders[J].Dis Model Mech, 2020, 13(8):dmm045211.
[39]RIEDEL B C, THOMPSON P M, BRINTON R D. Age, APOE and sex: triad of risk of Alzheimer’s disease[J].J Steroid Biochem Mol Biol, 2016, 160:134-147.
[40]DUARTE-GUTERMAN P, ALBERT A Y, BARHA C K, et al. Sex influences the effects of APOE genotype and Alzheimer’s diagnosis on neuropathology and memory[J].Psychoneuroendocrinology, 2021, 129:105248.
[41]TANEJA V. Sex hormones determine immune response[J].Front Immunol, 2018, 9:1931.
[42]LOPEZ-LEE C, KODAMA L, GAN L. Sex differences in neurodegeneration: the role of the immune system in humans[J].Biol Psychiatry, 2022, 91(1):72-80.
[43]KAUR S, MALLESHWARI K, SHARMA A, et al. Brain resident microglia in Alzheimer’s disease: foe or friends[J].Inflammopharmacology, 2024, 32(5):2781-2800.
[44]LECCA D, JUNG Y J, SCERBA M T, et al. Role of chronic neuroinflammation in neuroplasticity and cognitive function: a hypothesis[J].Alzheimers Dement, 2022, 18(11):2327-2340.
[45]HAN J, FAN Y, ZHOU K, et al. Uncovering sex differences of rodent microglia[J].J Neuroinflammation, 2021, 18(1):74.
[46]CASALETTO K B, NICHOLS E, ASLANYAN V, et al. Sex-specific effects of microglial activation on Alzheimer’s disease proteinopathy in older adults[J].Brain, 2022, 145(10):3536-3545.
[47]KLOHS J. An integrated view on vascular dysfunction in Alzheimer’s disease[J].Neurodegener Dis, 2019, 19(3/4):109-127.
[48]CORTES-CANTELI M, IADECOLA C. Alzheimer’s disease and vascular aging: JACC Focus Seminar[J].J Am Coll Cardiol, 2020, 75(8):942-951.
[49]LOVE S, SCOTT MINERS J. Cerebrovascular disease in ageing and Alzheimer’s disease[J].Acta Neuropathol, 2016, 131(5):645-658.
[50]LI H, HUANG Z, GAO Z, et al. Sex difference in general cognition associated with coupling of whole-brain functional connectivity strength to cerebral blood flow changes during Alzheimer’s disease progression[J].Neuroscience, 2023, 509:187-200.
[51]BUSHNELL C D, CHATURVEDI S, GAGE K R, et al. Sex differences in stroke: challenges and opportunities[J].J Cereb Blood Flow Metab, 2018, 38(12):2179-2191.
[52]LEE H, KIM K, LEE Y C, et al. Associations between vascular risk factors and subsequent Alzheimer’s disease in older adults[J].Alzheimers Res Ther, 2020, 12(1):117.