Recent Advances and Future Directions in Alzheimer's Disease Genetic Research

Alzheimer's disease (AD) is a complex neurodegenerative condition which, despite its high prevalence and socioeconomic impact on the world, has an etiology that remains poorly understood. The genetic causes of AD are complex and have been continuously studied for decades. They range from rare pathogenic, highly penetrant mutations in early-onset (EOAD) forms, which account for 5% of the cases to multiple-risk alleles across different genes in late-onset (LOAD) forms. Monogenic causes of EOAD allocate within APP, PSEN1, and PSEN2 genes in 10-15% of cases. The most significant risk factor in LOAD heritability is the APOE ε4 allele, as well as numerous loci within genes involved in immunity, endocytosis, lipid metabolism, and amyloid and tau processing. LOAD can also be attributed to the accumulation of somatic mutations, which may be detected by analysis of brain-derived cell-free DNA (cfDNA) in plasma. This review offers a comprehensive overview of the genetic architecture of Alzheimer's disease, with particular focus on the molecular mechanisms underlying both early- and late-onset forms of the condition. An improved understanding of the genetic etiology of AD can aid better prevention, earlier diagnosis, and novel therapeutic approaches. This can be achieved by analyzing understudied populations, performing case-control studies with appropriately matched controls, and surveying brain-derived cell-free DNA in plasma, with the latter having the potential to contribute to the implementation of liquid biopsy in dementology.