Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment.

Introduction: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer’s disease (AD) and non-AD dementia and (2) determinants of progression to dementia. Methods: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. Results: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2–20.3)/1000 person-years (AD: 11.5 [9.6–13.7], non-AD: 6.1 [4.7–7.7]), compared with 14.2 (11.3–17.6) in controls (AD: 10.1 [7.7–13.0], non-AD: 4.1 [2.6–6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1–1.1]), lower Mini-Mental State Examination (0.7 [0.66–0.8]), and apolipoprotein E ε4 (1.8 [1.3–2.5]) increased the risk of dementia. Discussion: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.

Background-. A better understanding is needed concerning the risk factors and markers of disease

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