The genetic risk factors, molecular pathways, microRNAs, and the gut microbiome in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. It is a multifaceted condition resulting from interplay of genetic mutations (e.g., APP, PSEN1, PSEN2) that account for less than 5% of cases, several genetic risk variants such as APOE4, TREM2, CD33, CLU, SORL1, and CR1 contribute to disease susceptibility and epigenetic factors, which may mediate the influence of environmental and lifestyle factors over time. Other critical contributors such as aging, protein misfolding and aggregation (amyloid-β and tau), molecular and transcriptomic dysregulation affecting neuronal function, and modifiable lifestyle factors like diet, physical activity, and environmental exposures presents challenges in accurate diagnosis and management. Research has predominantly focused on the diverse molecular pathways in the pathogenesis of AD, with particular attention given to the amyloidogenic pathways, tau pathology, calcium signalling, endolysosomal pathways, and others, whether they are directly or indirectly involved. Apart from these known molecular pathways, miRNAs are gaining attention as important regulators, which have been implicated in moderating the expression of mRNA targets involved in various processes associated with the clearance of pathogenic β-amyloid proteins. A mounting body of research suggests the possible role of gut microbiota in AD which regulates inflammation, neurotransmitters, and the blood-brain barrier. Gut dysbiosis can trigger neuroinflammation and amyloid-beta aggregation, making microbiome composition a potential early AD biomarker. This review aims to explore briefly the diverse risk encompassing genetic polymorphisms, altered molecular pathways implicated in AD pathogenesis, miRNA regulatory mechanisms, and the potential impact of gut microbiota on AD risk.