The genetic landscape of early and late-onset Alzheimer’s disease - a review

Abstract

Alzheimer's disease(AD) is a multifactorial neurodegenerative disorder characterized by the progressive loss of neurons and synaptic dysfunction, primarily affecting the cortex and hippocampus. The etiology of AD is complex, involving the continuous and intricate interaction between genetic and non-genetic environmental factors. Genetic predisposition plays a significant role, with approximately 60-80% of AD risk attributed to hereditary factors. Familial early-onset AD(EOAD), with autosomal-dominant mutations in APP, PSEN1, and PSEN2, represents about 1-5% of cases and typically manifests before age 65. Rare autosomal-recessive mutations, like A673V(APP gene), are also implicated. Late-onset AD(LOAD), more common, is influenced by a combination of genetic and environmental factors, with the APOE ε4 allele being a major risk factor. Protective factors, such as the APOE ε2 allele and rare mutations like Ala673Thr, can reduce AD risk. The interplay between genetic variants, environmental influences, and pathological processes underpins the disease's progression. This study highlights the importance of understanding the genetic and non-genetic determinants of AD to advance personalized treatment and early detection strategies. Future research and personalized medicine approaches are essential for mitigating AD risks and improving management outcomes.