Sex differences in Alzheimer disease — the gateway to precision medicine

Abstract

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.

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.

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Fig. 1: Brain atrophy in women and men with amnestic mild cognitive impairment.
Fig. 2: Implications of AD sex differences for clinical practice.

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Acknowledgements

H.H. was supported by the AXA Research Fund, the Fondation Partenariale Sorbonne Université, the Fondation pour la Recherche sur Alzheimer, Paris, France and the programme ‘Investissements d’avenir’ (ANR-10-IAIHU-06; Agence Nationale de la Recherche-10-IA, Agence Institut Hospitalo-Universitaire-6; awarded to H.H.). Further support was provided by the Colam Initiatives and the Fondation pour la Recherche sur Alzheimer, Paris, France (awarded to H.H. and P.A.C.) and the programme ‘PHOENIX’, led by the Sorbonne University Foundation and sponsored by the Fondation pour la Recherche sur Alzheimer (awarded to H.H. and E.C.). H.G. acknowledges support from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. H.G. is also the holder of an investigator award from the Fonds de Recherche du Québec-Santé. M.T.F. is supported by a research fellowship by the Synapsis Foundation–Alzheimer Research Switzerland (ARS). M.F.I. acknowledges support from the Fonds de Recherche du Québec-Santé and from the Herbert H. Jasper Postdoctoral Research Fellowship from the Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal. The authors thank A. Kato (Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland) and L. Kulic (Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland) for encouragement and help with the first draft of the manuscript and A. Herrmann (Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK) for continuous support, insightful discussions and editorial work. The authors thank the contributors to the Alzheimer Precision Medicine Initiative Working Group (Supplementary Box 1). The initial idea and draft of this Review was conceived by the Women’s Brain Project (a non-profit organization advocating for women’s brain and mental health; www.womensbrainproject.com) as part of its advocacy and scientific activity.

Review criteria

We searched PubMed and Google Scholar for articles published in English without time limitations with the search terms “Alzheimer AND gender (or sex or women or female)”, “Amyloid AND gender (or sex or women or female)”, “plaques AND gender (or sex or women or female)”, “tau AND gender (or sex or women or female)”, “atrophy AND Alzheimer AND gender (or sex or women or female)”, “cognitive decline AND gender (or sex or women or female)”, “risk AND Alzheimer AND gender (or sex or women or female)”, “stroke AND Alzheimer AND gender (or sex or women or female)”, “cardiovascular AND Alzheimer AND gender (or sex or women or female)”, “cerebrovascular AND gender (or sex or women or female)”, “diabetes AND Alzheimer AND gender (or sex or women or female)”, “depression AND Alzheimer AND gender (or sex or women or female)” and “APOE AND Alzheimer AND gender (or sex or women or female)”. We also searched in the reference lists of identified articles for additional relevant publications. The final reference list was generated by choosing only papers published since 2012. Papers preceding 2012 were included only if considered by the authors to be landmark studies. Papers were selected on the basis of their perceived relevance to the topics covered in this Review.

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M.T.F., E.G. and H.H. conceived the paper. All authors contributed to the literature search and to the writing. M.T.F., E.C. and P.A.C. designed the figures. E.G., H.H., H.D., H.G. and S.M. provided guidance for specific areas of competence and overall paper design. A.C.S. contributed to the paper with her own expertise and points of view; the views and opinions expressed herein are those of the author and do not reflect the view of the Swiss Agency for Therapeutic Products (Swissmedic).

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Correspondence to Maria Teresa Ferretti.

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Competing interests

H.H. is a Senior Associate Editor for the journal Alzheimer’s & Dementia. He has received fees for lecturing from Biogen and Roche; research grants from Pfizer, Avid, and MSD Avenir (all three paid to his institution); travel funding from Axovant, Eli Lilly, Functional Neuromodulation, GE Healthcare, Oryzon Genomics and Takeda and Zinfandel; and consultancy fees from Anavex, Axovant, Cytox, Functiona Neuromoduation, GE Healthcare, Jung Diagnostics, Oryzon Genomics and Takeda and Zinfandel. He participated in scientific advisory boards of Axovant, Cytox, Eli Lilly, Functional Neuromodulation, GE Healthcare, Oryzon Genomics, Roche Diagnostics and Takeda and Zinfandel. He is a co-inventor on several patents related to markers and the diagnosis of neurodegenerative disease (numbers 8916388, 8298784, 20120196300, 20100062463, 20100035286, 20090263822, 7547553, 20080206797, 20080199966 and 20080131921) but has received no royalties. All other authors declare no conflicts of interest.

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Ferretti, M., Iulita, M.F., Cavedo, E. et al. Sex differences in Alzheimer disease — the gateway to precision medicine. Nat Rev Neurol 14, 457–469 (2018). https://doi.org/10.1038/s41582-018-0032-9

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