Protective Variants in Alzheimer’s Disease
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Purpose of Review
Over the last decade, over 40 loci have been associated with risk of Alzheimer’s disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action. Additionally, we recommend strategies for finding new protective variants.
Recent Genome-Wide Association Studies have identified both common and rare protective variants associated with AD. These include variants in or near APP, APOE, PLCG2, MS4A, MAPT-KANSL1, RAB10, ABCA1, CCL11, SORL1, NOCT, SCL24A4-RIN3, CASS4, EPHA1, SPPL2A, and NFIC.
There are very few protective variants with functional evidence and a derived allele with a frequency below 20%. Additional fine mapping and multi-omic studies are needed to further validate and characterize known variants as well as specialized genome-wide scans to identify novel variants.
KeywordsAlzheimer’s disease Protective SNP Genetic variants
Compliance with Ethical Standards
Conflict of Interest
Shea J Andrews and Brian Fulton-Howard each declare no potential conflict of interest.
Alison Goate reports a grant from the NIH (NIA 1 U01 AG049508).
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 12.•• Marioni R, Harris SE, McRae AF, Zhang Q, Hagenaars SP, Hill WD, et al. GWAS on family history of Alzheimer’s disease [Internet]. bioRxiv. 2018 [cited 2018 Nov 3]. p. 246223. Available from: https://www.biorxiv.org/content/early/2018/01/12/246223. Performed a meta-analysis of GWAS for clinical late-onset Alzheimer’s disease and family history of Alzheimer’s disease in a total sample size of 314,278. Identified 21 loci associated with AD—two of which are protective.
- 15.Ghani M, Reitz C, George-Hyslop PS, Rogaeva E. Genetic complexity of early-onset Alzheimer’s disease. In: Galimberti D, Scarpini E, editors. Neurodegenerative diseases: clinical aspects, molecular genetics and biomarkers. Cham: Springer International Publishing; 2018. p. 29–50.CrossRefGoogle Scholar
- 21.•• Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Naj AC, Boland A, et al. Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing [Internet]. bioRxiv. 2018 [cited 2018 Nov 6]. p. 294629. Available from: https://www.biorxiv.org/content/early/2018/04/05/294629. The largest GWAS of clinically diagnosed Alzheimer’s disease to date ( n = 89,769). Identified 24 loci associated with AD—four of which are protective.
- 22.Liu JZ, Erlich Y, Pickrell JK. Case-control association mapping by proxy using family history of disease. Nat Genet. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2017;49:325–31.Google Scholar
- 23.• Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert J-C, Chung J, Naj AC, et al. A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. Macmillan Publishers Limited; 2016;21:108–17. Performed an APOE stratified GWAS of Alzheimer’s disease and found a locus near the tau gene to be associated with reduced risk APOE e4- participants. Google Scholar
- 26.Dai Q-H, Gong D-K. Association of the polymorphisms and plasma level of CHI3L1 with Alzheimer’s disease in the Chinese Han population: a case-control study. Neuropsychobiology. 2018:1–9.Google Scholar
- 38.Groot C, Sudre CH, Barkhof F, Teunissen CE, van Berckel BNM, Seo SW, et al. Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology [Internet]. 2018; Available from: https://doi.org/10.1212/WNL.0000000000006503
- 42.Jiao B, Liu X, Zhou L, Wang MH, Zhou Y, Xiao T, et al. Polygenic analysis of late-onset Alzheimer’s disease from Mainland China. PLoS One. Public Library of Science; 2015;10:e0144898.Google Scholar
- 45.Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CAF, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. National Academy of Sciences; 2005;102:13461–13466.Google Scholar
- 48.Miyashita A, Koike A, Jun G, Wang L-S, Takahashi S, Matsubara E, et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One. Public Library of Science; 2013;8:e58618.Google Scholar
- 53.Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde.” Clin Anat 1995;8:429–431.Google Scholar
- 54.Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2012;488:96–9.Google Scholar
- 60.•• Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, et al. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience. Genome Med. 2017;9:100 Identified RAB10 as a protective gene using a novel linkage approach to identify resilience alleles in elderly cognitively normal APOE e4 carriers within densely affected AD families.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Zhang X, Huang TY, Yancey J, Luo H, Zhang Y-W. Role of Rab GTPases in Alzheimer’s Disease. ACS Chem Neurosci [Internet]. 2018; Available from: https://doi.org/10.1021/acschemneuro.8b00387
- 63.Hughes KL, Abshire ET, Goldstrohm AC. Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries. RNA Biol. 2018:1–13.Google Scholar
- 66.Yang X, Lytton J. Purinergic stimulation of K+-dependent Na+/Ca2+ exchanger isoform 4 requires dual activation by PKC and CaMKII. Biosci Rep [Internet]. 2013;33. Available from: https://doi.org/10.1042/BSR20130099
- 69.Singh MK, Dadke D, Nicolas E, Serebriiskii IG, Apostolou S, Canutescu A, Egleston BL, Golemis EA A novel Cas family member, HEPL, regulates FAK and cell spreading. Mol Biol Cell The American Society for Cell Biology; 2008;19:1627–36.Google Scholar
- 70.Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet. Public Library of Science; 2014;10:e1004606.Google Scholar
- 81.Magno L, Lessard CB, Martins M, Cruz P, Katan M, Bilsland J, et al. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph [Internet]. bioRxiv. 2018 [cited 2018 Nov 3]. p. 409706. Available from: https://www.biorxiv.org/content/early/2018/09/08/409706
- 82.•• Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49:1373–84 Identified PLCG2 as rare coding variant associated with reduced AD risk in a rare variant analysis in a three-stage case–control study of 85,133 subjects.CrossRefPubMedPubMedCentralGoogle Scholar
- 87.• Ghani M, Sato C, Kakhki EG, Gibbs JR, Traynor B, St George-Hyslop P, et al. Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer’s disease data set. Neurobiol Aging. 2016;42:217.e7–217.e13 Conducted a rare variant analysis in the MS4A gene cluster and found that controls had a higher burden of damaging missense substitutions and loss-of-function variants.CrossRefGoogle Scholar
- 95.Cascorbi I, Flüh C, Remmler C, Haenisch S, Faltraco F, Grumbt M, et al. Association of ATP-binding cassette transporter variants with the risk of Alzheimer’s disease | Pharmacogenomics [Internet]. [cited 2018 Nov 10]. Available from: https://doi.org/10.2217/pgs.13.18
- 110.Ren G, Bao W, Zeng Z, Zhang W, Shang C, Wang M, et al. RXRα nitro-ligand Z-10 and its optimized derivative Z-36 reduce β-amyloid plaques in AD mouse model. Mol Pharm [Internet]. 2018; Available from: https://doi.org/10.1021/acs.molpharmaceut.8b00096
- 111.Wang W, Nakashima K-I, Hirai T, Inoue M. Neuroprotective effect of naturally occurring RXR agonists isolated from Sophora tonkinensis Gagnep. on amyloid-β-induced cytotoxicity in PC12 cells. J Nat Med [Internet]. 2018; Available from: https://doi.org/10.1007/s11418-018-1257-z
- 112.Chernick D, Ortiz-Valle S, Jeong A, Swaminathan SK, Kandimalla K, Rebeck GW, et al. HDL mimetic peptide 4F mitigates Aβ-induced inhibition of ApoE secretion and lipidation in primary astrocytes and microglia. J Neurochem [Internet]. 2018; Available from: https://doi.org/10.1111/jnc.14554
- 119.• Lalli MA, Bettcher BM, Arcila ML, Garcia G, Guzman C, Madrigal L, et al. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer’s disease. Mol Psychiatry. 2015;20:1294–300 In a candidate gene study, rare variants in ABCA1 were found to be more frequent in controls than cases.CrossRefPubMedPubMedCentralGoogle Scholar
- 125.Zheng J-Y, Sun J, Ji C-M, Shen L, Chen Z-J, Xie P, et al. Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer’s disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling. Neurobiol Aging. 2017;54:112–32.CrossRefPubMedGoogle Scholar
- 127.Kamboh MI. A brief synopsis on the genetics of Alzheimer’s disease. Curr Genet Med Rep. Springer. 2018:1–3.Google Scholar
- 128.Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, et al. Whole exome sequencing study identifies novel rare and common Alzheimer’s-associated variants involved in immune response and transcriptional regulation. Mol Psychiatry. Nature Publishing Group. 2018;1.Google Scholar
- 129.Rathore N, Ramani SR, Pantua H, Payandeh J, Bhangale T, Wuster A, et al. Paired immunoglobulin-like type 2 receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease. PLoS Genet. Public Library of Science. 2018;14:e1007427.CrossRefPubMedPubMedCentralGoogle Scholar