The multiplex model of the genetics of Alzheimer’s disease

Abstract

Genes play a strong role in Alzheimer's disease (AD) with late-onset AD showing heritability of 58-79% and early-onset AD over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 40 loci are now implicated for AD, suggesting that AD is a disease of multiple components as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD (LOAD) heritability has been captured and allows the calculation of the accumulation of AD genetic risk through polygenic risk scores (PRS). PRS predicts disease with up to 90% accuracy and is an exciting tool in our research armoury that could allow selection of those with high PRS for clinical trials and precision medicine, as well as the cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflex's the combination of some, or all, of these model components (genetic and environmental), in a tissue specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell/synaptic loss observed in AD.

Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease

“…The genetic linkage and association studies have identi ed some AD susceptibility genes, a number of which are related to cholesterol metabolism or transport [3,17,32]. Lipid metabolism play an important pathway involved in the development of AD [32,33].…”

The Alzheimer’s disease protective P522R variant ofPLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function

“…The heritability of AD is estimated at 58-79% (Gatz et al , 2006), demonstrating a strong genetic influence on the development of AD. Genome wide association studies (GWAS) have identified genomic regions associated with LOAD (Harold et al , 2009, Hollingworth et al , 2011, Lambert et al , 2013, Sims et al , 2017, Sims et al , 2020. As well as these common variants, a number of rare genetic variants have been reported which implicate immunity and a crucial role for microglia in disease development.…”

“…With this in mind it is important to consider how PLCγ2 function may effect microglial responses in the context of amyloid deposition and other neuroinflammatory components of dementia seen in AD. Deficiency in TREM2, an upstream receptor that signals through PLCγ2, has been previously linked to increased risk of AD (Sims et al , 2020, Guerreiro et al , 2013. PLCγ2 also sits downstream of CSF1R, inhibitors or which are currently in trials in the context of Alzheimer's disease.…”

Monocyte-specific changes in gene expression implicate LACTB2 and PLIN2 in Alzheimer’s disease

“…However, most cases of AD are late onset (LOAD) and occur after the age of 65. Although one of the strongest risk factors for AD (both EOAD and LOAD) is being a carrier of the E4 allele of the APOE gene (Corder et al, 1993) , recent GWAS have shown that variants in more than 50 loci are implicated in LOAD (Sims et al, 2020). Hence, it seems likely that multiple variants, each of small effect, acquired over a lifetime, may contribute to disease onset, defining LOAD as a polygenic trait (Escott-Price et al, 2015).…”

“…These AD-risk genes are involved in multiple diverse biological pathways: such as the immune response, cholesterol metabolism, amyloid protein processing and APP metabolism (Jones et al, 2010;Kunkle et al, 2019;Sims et al, 2020) However, the mechanisms involved in the mis-regulation of gene expression that leads to AD have not been elucidated.…”