Sex differences in Alzheimer disease — the gateway to precision medicine

• Published in: Nature reviews. Neurology Vol. 14; no. 8; pp. 457 - 469
• Main Authors: Ferretti, Maria Teresa, Iulita, Maria Florencia, Cavedo, Enrica, Chiesa, Patrizia Andrea, Schumacher Dimech, Annemarie, Santuccione Chadha, Antonella, Baracchi, Francesca, Girouard, Hélène, Misoch, Sabina, Giacobini, Ezio, Depypere, Herman, Hampel, Harald
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 692/499; 692/53; 692/699/375/132; Alzheimer Disease - epidemiology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Biomarkers; Care and treatment; Demographic aspects; Disease Progression; Drug development; Female; Gender differences; Humans; Male; Medicine; Medicine & Public Health; Neurology; Precision Medicine; Review Article; Risk Factors; Sex Characteristics; Women; Switzerland
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/s41582-018-0032-9

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. In this Review, Ferretti et al. discuss the evidence for sex-related differences in Alzheimer disease symptoms, progression, risk factors and treatment, and consider how understanding sex differences is crucial in developing precision medicine. Key points Men and women with Alzheimer disease (AD) exhibit different cognitive and psychiatric symptoms, and women show faster cognitive decline after diagnosis of mild cognitive impairment (MCI) or AD dementia. Levels of amyloid-β measured with PET-based brain imaging and with biochemical analysis of cerebrospinal fluid do not differ between the sexes. Brain atrophy rates and patterns differ along the AD continuum between the sexes; in MCI, brain atrophy is faster in women than in men. The prevalence and effects of cerebrovascular, metabolic and socio-economic risk factors for AD are different between men and women. No data are available on sex differences in the efficacy and safety of drugs used in recently completed phase III clinical trials for mild to moderate AD. Systematic studying and reporting of sex differences in disease symptomatology, biomarkers, progression, risk factors and treatment responses will be crucial for the development and implementation of precision medicine in AD.