Alzheimer's disease risk genes and mechanisms of disease pathogenesis

By Celeste M. Karch, A. Goate. Biological Psychiatry, 2014

1,238 citations recorded by the source corpus.

Here, we review the genetic risk factors for late onset Alzheimer's disease (AD) and their role in AD pathogenesis. Recent advances in our understanding of the human genome, namely technological advances in methods to analyze millions of polymorphisms in thousands of subjects, have revealed new genes associated with AD risk: ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4 RIN3, SORL1, ZCWPW1. Emerging technologies to analyze the entire genome in large datasets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathological features of AD. Together, understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/4e27a0b3f3002c4115dcd30501fbd5001943b650

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In Cellular and Molecular Neuroscience

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Citations in the corpus

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “Numerous SNPs and rare coding variants in immune-related genes thought to be implicated in microglial function have been identified as risk factors for AD in whole genome sequencing and GWAS analyses (see for review (Efthymiou and Goate, 2017; Karch and Goate, 2015), including TREM2, CR1, SHIP1, BIN”
Alzheimer's disease (2018, background): “mally adapted from [8] with permission”
Neuroinflammation in Alzheimer's disease: Current evidence and future directions (2016, background): “An association has been demonstrated between mRNA expression of CD33, a member of the sialic acid-binding Ig-like lectin family, increased in microglia, and advanced cognitive decline, and this also seems to be involved in Ab phagocytosis [35].”
Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021 (2021, neutral): “The ε4 allele of ApoE is associated with increased AD risk, whereas the ε2 allele is protective (40, 42).”
Alzheimer’s disease: experimental models and reality (2017, background): “Genome-wide association studies (GWAS) have identified over 20 loci that confer increased risk for sAD, including genes involved in innate immunity, cholesterol metabolism and synaptic/neuronal membrane function, suggesting that the pathogenesis of sAD is quite heterogeneous [28, 52, 75].”
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques (2016, background): “Recent genome-wide association studies have identified rare variants of genes that encode immune receptors as risk factors (Guerreiro and Hardy, 2014; Karch and Goate, 2015).”
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models (2015, background): “However, recent genome-wide association studies linked polymorphisms in inflammation-related genes to increased AD risk, supporting the conclusion that inflammation can be a causative factor in disease pathology (Karch and Goate, 2015).”
The neuropathological diagnosis of Alzheimer’s disease (2019, background): “Other risk factors for LOAD including TREM2, ADAM10 and PLD3 have been identified using genome wide association studies to implicate nearly 30 genes that not only affect APP and tau directly but also modulate cholesterol metabolism, endocytosis and immune response, among those with known functions [”