From the Hurvitz Brain Sciences Program (M.W.A., C.-Y.W., W.S., M.M., S.E.B., J.S.R.), Sunnybrook Research Institute; Rehabilitation Sciences Institute (M.W.A., J.S.R.), Department of Pharmacology & Toxicology (C.-Y.W., W.S.), University of Toronto, Ontario, Canada; Department of Neurology (G.T.C., R.F.B.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Psychology (T.P.), University of British Columbia, Vancouver, Canada; Center for Alzheimer Research and Treatment (CART) (R.F.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Melbourne School of Psychological Sciences (R.F.B.), University of Melbourne, Parkville, Victoria, Australia; Department of Neurology (P.P.), University of North Carolina at Chapel Hill School of Medicine; Division of Neurology (M.M., S.E.B., J.S.R.), Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto; Campbell Family Mental Health Research Institute (L.A.M.G.), The Centre for Addition and Mental Health; Department of Psychiatry (L.A.M.G.), Temerty Faculty of Medicine, Dalla Lana School of Public Health (G.E.), and Department of Psychology (G.E.), University of Toronto; Rotman Research Institute (G.E.), Baycrest Hospital; and Harquail Centre for Neuromodulation (J.S.R.), Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada.
Neurology. 2024 May;102(9):e209298. doi: 10.1212/WNL.0000000000209298. Epub 2024 Apr 3.
Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition.
We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French).
We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (β = 0.013, 95% CI 0.001-0.025, = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; β = -0.044, 95% CI -0.066 to -0.022, < 0.001), but not average (ages 49-52 years; β = -0.007, 95% CI -0.027 to 0.012, = 0.46) or later menopause (ages 53-65 years; β = 0.003, 95% CI -0.020 to 0.025, = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (β = -0.005, 95% CI -0.032 to 0.021, = 0.69).
Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.
越来越多的证据表明，阿尔茨海默病（AD）的风险存在性别差异。血管和激素因素可能共同导致成年女性 AD 风险增加。我们研究了绝经年龄、血管风险和雌激素激素替代疗法（HT）史是否共同影响认知功能，随访时间为 3 年。我们假设绝经年龄越早、血管风险越高，与随访时认知评分越低的协同作用越大，而含有雌激素的 HT 会减弱这种协同作用，从而保护认知功能。
我们使用了加拿大老龄化纵向研究中绝经后女性参与者和年龄匹配的男性参与者的数据。血管风险通过高血压、降压药物、低密度脂蛋白胆固醇升高、糖尿病、吸烟和肥胖的综合评分来计算。认知功能通过基线和 3 年随访时的总体认知综合得分来测量。线性模型测试了绝经年龄、血管风险和 HT 史与 3 年随访时认知功能的独立和交互关联，调整了基线认知功能、基线年龄、受教育年限和测试语言（英语/法语）。
我们纳入了 8360 名绝经后女性参与者（基线时平均年龄为 65.0±8.53 岁，平均绝经年龄为 50.1±4.62 岁）和 8360 名年龄匹配的男性参与者作为对照。绝经年龄和血管风险之间存在交互作用，即绝经年龄越早、血管风险越高，与随访时认知评分越低呈协同作用（β=0.013，95%CI0.001-0.025，=0.03）。在分层分析中，血管风险与绝经年龄较早的女性参与者的认知评分较低相关（绝经年龄 35-48 岁；β=-0.044，95%CI-0.066 至-0.022，<0.001），但与平均年龄（49-52 岁；β=-0.007，95%CI-0.027 至 0.012，=0.46）或较晚绝经年龄（53-65 岁；β=0.003，95%CI-0.020 至 0.025，=0.82）无关。绝经年龄较早的女性参与者中，血管风险与认知功能的负相关作用强于年龄匹配的男性参与者。HT 史并未进一步改变绝经年龄和血管风险与随访认知功能之间的协同关联（β=-0.005，95%CI-0.032 至 0.021，=0.69）。
内分泌和血管过程可能协同作用，增加成年女性认知能力下降的风险。这些发现对制定特定性别的痴呆症预防策略具有重要意义。
