Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Abstract

Alzheimer’s disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world’s population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ~20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

“…The association of the APOE gene has been the most consistent observation in AD genetics with the presence of an APOE ε4 allele significantly more common among individuals diagnosed with AD, whereas the ε2 allele is considered protective (Liu et al, 2013; Naj and Schellenberg, 2016). Through genome-wide association studies (GWASs), around 20 genetic loci had been discovered, which affect risk of LOAD (Lambert et al, 2013).…”

“…Hallmarks of AD were originally identified postmortem from histopathological signs of neuritic plaques, composed of amyloid-β, and neurofibrillary tangle formation; postmortem examination of brain tissue for these hallmarks remains the most definitive diagnosis of AD. Clinical diagnosis is accurately verified in more than 85% of cases (Naj and Schellenberg, 2016). …”

“…Follow-up studies based on the GWAS have identified other potential candidate AD risk genes not previously identified, including the TRIP4, SPPL2A (Ruiz et al, 2014), and ABI3 genes (Sims et al, 2017). Next-generation sequencing has also enabled the identification of rare variants, one of the most consistent being the R47H variant in the TREM2 gene locus (Guerreiro et al, 2013; Jonsson et al, 2013) which affect the risk of AD previously not identified in GWAS (Giri et al, 2016; Lambert et al, 2013; Naj and Schellenberg, 2016). Although most studies utilize Caucasian populations, further risk variants have been identified through next-generation sequencing in African-American individuals within the gene AKAP9 (Giri et al, 2016; Logue et al, 2014).…”

From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration

“…It is caused by degeneration of hippocampal and cortical neurons and associated with the presence of intracellular tangles of hyperphorsphorylated tau and extracellular plaques of β-amyloid (Aβ) peptides. Familial cases of AD are rare (1%) and are due to mutations in the genes coding for the amyloid precursor protein (APP), or for presenilins (PS1 and PS2), aspartyl proteases of the γ-secretase complex, involved in APP processing and Aβ formation (Naj et al, 2017).…”

Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

“…This hypothesis draws on the importance of cholesterol and other lipids in amyloid pathways [1], population genetics findings including the strong association of the apolipoprotein E ( APOE ) ε4 allele and other lipid-related genetic variants with AD [2–4], and animal and cellular experiments suggesting that statins may have roles in combating amyloid deposition, tau phosphorylation, and brain inflammation [5]. …”