Genomics of Alzheimer's disease implicates the innate and adaptive immune systems

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-beta (A beta) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere A beta clearance. Defective phagocytosis, endocytosis, and autophagy may drive A beta accumulation, which may be related to naturally-occurring antibodies to A beta (Nabs-A beta) produced by adaptive responses. Passive immunisation is providing efficiency in clearing A beta and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.

Automated summary

Alzheimer's disease is a chronic neurodegenerative disease characterized by cognitive impairment, behavioral alteration, and functional decline. Genetic studies have identified over 130 susceptibility loci associated with AD, implicating the role of innate and adaptive immunity in the pathogenesis of late-onset AD. These findings suggest that a systemic failure of cell-mediated amyloid-beta clearance contributes to AD onset and progression.