Role of the gut microbiome in mediating sex-specific differences in the pathophysiology of Alzheimer's disease

• Published in: Neurotherapeutics Vol. 21; no. 6; p. e00426
• Main Authors: Saha, Piyali, Sisodia, Sangram S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.07.2024
• Subjects: Alzheimer's disease; Gut microbiome; Sex hormones and precision medicine; Sex-specific effects; Sex hormones and precision medicine; Sex-specific effects; Alzheimer's disease; Gut microbiome
• ISSN: 1878-7479; 1878-7479
• DOI: 10.1016/j.neurot.2024.e00426

Alzheimer's disease (AD) presents distinct pathophysiological features influenced by biological sex, with women disproportionately affected due to sex-specific genetic, hormonal, and epigenetic factors. This review delves into three critical areas of sex differences in AD: First, we explore how genetic predisposition and hormonal changes, particularly those involving sex-specific modifications, influence susceptibility and progression of the disease. Second, we examine the neuroimmune dynamics in AD, emphasizing variations in microglial activity between sexes during crucial developmental stages and the effects of hormonal interventions on disease outcomes. Crucially, this review highlights the significant role of gut microbiome perturbations in shaping AD pathophysiology in a sex-specific manner, suggesting that these alterations can further influence microglial activity and overall disease trajectory. Third, we provide a viewpoint that advocates for personalized therapeutic strategies that integrate the understanding of hormonal fluctuations and microbiome dynamics into treatment plans in order to optimize patient outcomes. Figure: This figure illustrates the complex interplay between estradiol, amyloid plaques, and microglia in the context of the brain in females with Alzheimer's Disease (AD). Estradiol, produced by the ovaries, exerts neuromodulatory effects and influences brain functions, impacting amyloid plaques, a hallmark of AD. Active microglia, the brain's resident macrophages, contribute to neuroinflammation and amyloid clearance. The enzyme glucuronidase, produced by the gut microbiome and involved in the hydrolysis of glucuronides, affects circulatory estradiol levels. Disruptions in the gut microbiome modulate glucuronidase levels, thereby influencing estradiol levels and consequently affecting brain function. Gut hormones produced by the gastrointestinal tract influence brain function through the gut-brain axis, affecting inflammation and amyloid-beta deposition. This complex interaction underscores the significant role of hormonal, immunological, and microbiome-related factors in the pathogenesis of AD in females. [Display omitted]