Untangling Genetic Risk for Alzheimer’s Disease

Pimenova, Anna A.; Raj, Towfique; Goate, Alison M.

doi:10.1016/j.biopsych.2017.05.014

Cited by 223Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Untangling Genetic Risk for Alzheimer’s Disease

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Pimenova, Anna A., Raj, Towfique, Goate, Alison M.·2018·Biological Psychiatry

DOI 10.1016/j.biopsych.2017.05.014PMC PMC5699970

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Abstract

Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder caused by fully penetrant single gene mutations in a minority of cases, while the majority of cases are sporadic or show modest familial clustering. These cases are of late onset and likely result from the interaction of many genes and the environment. More than 30 loci have been implicated in AD by a combination of linkage, genome-wide association, and whole genome/exome sequencing. We have learned from these studies that perturbations in endolysosomal, lipid metabolism, and immune response pathways substantially contribute to sporadic AD pathogenesis. We review here current knowledge about functions of AD susceptibility genes, highlighting cells of the myeloid lineage as drivers of at least part of the genetic component in late-onset AD. Although targeted resequencing utilized for the identification of causal variants has discovered coding mutations in some AD-associated genes, a lot of risk variants lie in noncoding regions. Here we discuss the use of functional genomics approaches that integrate transcriptomic, epigenetic, and endophenotype traits with systems biology to annotate genetic variants, and to facilitate discovery of AD risk genes. Further validation in cell culture and mouse models will be necessary to establish causality for these genes. This knowledge will allow mechanism-based design of novel therapeutic interventions in AD and promises coherent implementation of treatment in a personalized manner.

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Functional studies that reveal how risk variants contribute to disease lag far behind the rapidly growing catalogue of genetic risk variants.
“While the catalogue of such risk variants is growing rapidly, functional studies that uncover how these variants contribute to disease are lagging far behind1–3.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [3]
Non-coding risk variants in humans often occur in non-conserved sequences, precluding direct mouse modeling, and it is challenging to determine which coding gene or genes they affect.
“Non-coding risk variants in humans often occur in non-conserved sequences in the genome, precluding direct mouse modeling of these variants, and it is challenging to determine through which coding gene or genes these variants affect disease risk3.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [3]
More than 30 Alzheimer's disease-risk loci have been identified via genetic linkage, candidate gene, genome-wide association studies, and whole genome/exome sequencing studies.
“To date, more than 30 Alzheimer’s disease-risk loci have been identified via a combination of genetic linkage, candidate gene, genome-wide association studies (GWAS), and whole genome/exome sequencing (WGS/WES) studies6.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [6]
Of the Alzheimer's disease risk loci, over 50% of gene variants validated by functional genomics are implicated in microglial and innate immune cell function, including the top two risk genes, APOE and TREM2.
“Of these risk loci, over 50% of gene variants validated by functional genomics are implicated in microglial and innate immune cell function, including the top two risk genes, APOE and TREM2.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [6]

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ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function
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Rare coding mutations identified by sequencing of <scp>A</scp>lzheimer disease genome‐wide association studies loci
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Amyloid precursor protein mutation E682K at the alternative β‐secretase cleavage β′‐site increases Aβ generation†
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Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations
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“Deep sequencing in African Americans carrying risk and p rotective alleles at ABCA7 led to the identification of a 44 base pair deletion in LD wit h he high risk allele, which results in a frameshift (85).”
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Blockage of CR1 prevents activation of rodent microglia
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“and reduces lysosomal degradation of BACE1 thereby increasing Aβ production (101).”
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Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk
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Selected Findings from the Religious Orders Study and Rush Memory and Aging Project
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Authors: Pimenova, A. A., Raj, T., & Goate, A. M.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Goate, Alison M.
ORCID: Pimenova, Anna A.
Raj, Towfique
Goate, Alison M.
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2018-02
Volume: 83
Issue: 4
Pages: 300-310
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2017.05.014
PMC: PMC5699970
OpenAlex: W2617930056
Cited by: 223
References: 147
Citations by year: 2026: 10 · 2025: 15 · 2024: 25 · 2023: 42 · 2022: 31 · 2021: 31 · 2020: 28 · 2019: 25 · 2018: 13 · 2017: 3
FWCI: 2.32
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (P50AG005138, U01AG049508, U01AG052411, RF1AG054011, P30AG066514)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: Alzheimer's disease, genetic risk, late-onset Alzheimer's disease, sporadic Alzheimer's disease, familial Alzheimer's disease, genetic susceptibility loci, endolysosomal pathway, lipid metabolism, immune response, myeloid cells, non-coding variants, functional genomics, epigenetics, endophenotypes, systems biology, causal variants, personalized treatment
MeSH terms: Alzheimer Disease, Animals, Humans, Genome-Wide Association Study

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Untangling Genetic Risk for Alzheimer’s Disease

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