Exploring the role of sex differences in Alzheimer's disease pathogenesis in Down syndrome

• Published in: Frontiers in neuroscience Vol. 16; p. 954999
• Main Authors: Andrews, Elizabeth J, Martini, Alessandra C, Head, Elizabeth
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 12-08-2022; Frontiers Media S.A
• Subjects: Age; Alzheimer's disease; amyloid beta; Amyloid precursor protein; Chromosome 21; Dementia; Dementia disorders; Down syndrome; Down's syndrome; Drug development; estrogen; Estrogens; Females; Gender differences; Gender identity; Hormone replacement therapy; hormones; Intellectual disabilities; Magnetic resonance imaging; Males; Medical imaging; Menopause; metabolism; Neurodegenerative diseases; Neurofibrillary tangles; Neuroimaging; Neuroscience; Pathogenesis; Population; Quality of life; Sex differences; tau tangles; vascular; Womens health; estrogen; tau tangles; hormones; inflammation; metabolism; aging; vascular; amyloid beta
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2022.954999

Women are disproportionately affected by Alzheimer's disease (AD), yet little is known about sex-specific effects on the development of AD in the Down syndrome (DS) population. DS is caused by a full or partial triplication of chromosome 21, which harbors the amyloid precursor protein (APP) gene, among others. The majority of people with DS in their early- to mid-40s will accumulate sufficient amyloid-beta (Aβ) in their brains along with neurofibrillary tangles (NFT) for a neuropathological diagnosis of AD, and the triplication of the APP gene is regarded as the main cause. Studies addressing sex differences with age and impact on dementia in people with DS are inconsistent. However, women with DS experience earlier age of onset of menopause, marked by a drop in estrogen, than women without DS. This review focuses on key sex differences observed with age and AD in people with DS and a discussion of possible underlying mechanisms that could be driving or protecting from AD development in DS. Understanding how biological sex influences the brain will lead to development of dedicated therapeutics and interventions to improve the quality of life for people with DS and AD.