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

Abstract

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-β (Aβ) 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 Aβ clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aβ accumulation, which may be related to naturally-occurring antibodies to Aβ (Nabs-Aβ) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aβ 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.

Keywords: Amyloid plaques; Endo-lysosomal network; Microglia; Monocytes; Neurodegeneration; Polygenic risk score; Single nucleotide polymorphism.

Fig. 1

Microglial genes and pathways involved in AD pathogenesis implicated by AD genomics. Microglial cells maintain CNS homeostasis by sensing, endocytosing (left), phagocytosing (right) apoptotic cells, debris, synapses, and Aβ. GWAS, WGS, WES and integrative analyses with transcriptomics, epigenomics and proteomics have nominated many genes (circled in orange) involved in phagocytic recognition, focal adhesion, actin cytoskeletal rearrangement, endo-lysosomal network, phago-lysosomal network, and, auto-lysosomal network (mid), and transcriptional responses in microglia