genetics of Alzheimer's disease
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Genetics
only 3 genes deterministic for AD, APP, PSEN1 & PSEN2[12]
Genetic loci associated with Alzheimer's disease
- chromosome 21 (FAD1)
- gene for the amyloid precursor protein (APP) [21q21.3-q22.05]
- Down's syndrome involves trisomy 21
- autosomal dominant, early-onset Alzheimer disease
- SNP rs63750847-A in the APP gene leading to T673A substitution in APP protein associated with diminished risk of Alzheimer disease[10]
- Uppsala APP mutation (del 690-695) results in autosomal dominant familial AD[23]
- chromosome 19 (FAD2)
- gene for apolipoprotein E [19q13.2]
- late onset AD
- presence of apo E4 allele associated with 3-fold increase in prevalence of neuropatholgically-defined AD[1]
- homozygous apo E4 allele associated with 15-fold increased risk of AD[28]
- most patients with AD do not carry the apo E4 allele[12]
- 48% overall, 61% in Northern Europe[14]
- a single copy of Klotho KL-VS is associated with reduced risk of Alzheimer's disease & amyloid-beta in cognitively intact elderly 60-80 years who carry APOE4[20]
- apoE4 allele may lead to degeneration of brain capillary pericytes & breakdown of blood-brain barrier[21]
- homozygous apo E2 allele associated with very low risk of AD[19]
- proinflammatory gut microbiota (Collinsella) may promote AD development through interaction with APOE[29]
- chromosome 14: gene for presenilin-1 [14q24.3] (FAD3)
- autosomal dominant
- homozygous Christchurch (APOEch) mutation in APOE3 may be protective[18]
- chromosome 1: gene for presenilin-2 [1q31-q42] (FAD4)
- chromosome 6: TREM2 (6p21.1) variant rs75932628 confers a 3-fold increase in risk for Alzheimer disease[10]
- chromosome 12: gene unknown (FAD5)
- chromosome 10q: (may be insulin-degrading enzyme) (FAD6)
- chromosome 10p: gene unknown (FAD7)
- chromosome 20p: gene unknown (FAD8)
- chromosome 7q22.1 RELN (reelin) prevents prevents tangled strands of mt-tau from sticking together to form neurofibrillary tangles[27]
- rare variant in RELN (H3447R, termed COLBOS confers resilience to autosomal dominant Alzheimer's disease despite extremely elevated amyloid plaque burden[27]
- mitochondrial susceptibility to Alzheimer disease
- chromosome 6: polymorphism in MTHFD1L gene ?[7]
- uncertain significance
- BDNF gene Val66Met associated with
- faster cognitive decline in Alzheimer's disease[15]
- lower BDNF production
- decreased hippocampal volume
- amyloid may exacerbate[15]
- rare polymorphism in PLD3 increases risk for late-onset Alzheimer's disease[11]
- RAB10 variants modify risk for Alzheimer's disease[17]
- knockdown of RAB10 decreases Abeta42 & Abeta42/Abeta40 in neuroblastoma cells
- RAB10 expression is elevated in brain of patients with Alzheimer's disease
- Rs142787485 in RAB10 confers protection against Alzheimer's disease[17]
- rare coding variant in ABI3 is associated with late-onset Alzheimer's disease
- deletion of ABI3 significantly increases beta-amyloid plaques, & decreases microglia clustering around the amyloid plaques[24]
- genetically identical twins show comparable tau PET load & spacial distribution[25]
- several loci shared by gastrointestinal disorders with Alzheimers disease:
- other implicated genes
Telomere length in leukocytes, cells NOT implicated in AD, found to be shorter in AD patients than controls. Among patients with AD, but NOT controls, telomere length was shorter in those patients with the apoE4 allele. Shorter telomere length was associated with increased mortality[2]
VV genotype (I450V) in humans promotes longevity & is protective against cognitive decline (Alzheimer's disease).[3]
APP A673T variant carriers with reduced levels of plasma beta-amyloid[16]
More general terms
More specific terms
Additional terms
- apolipoprotein-E gene
- APP gene
- familial Alzheimer's disease (FAD)
- presenilin-1 (PS-1) gene
- presenilin-2 (PS-2) gene (E5-1, STM2, ALG-3 {mouse homolog})
References
- ↑ 1.0 1.1 Polvikoski et al, Prevalence of Alzhmeimer' disease in very elderly people: a prospective neuropathological study Neurology 56:1690, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11425935
- ↑ 2.0 2.1 Honig LS et al, Shorter telomeres are associated with mortality in those with apoE4 and dementia. Ann Neurol 2006, 60:181 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16807921
- ↑ 3.0 3.1 Medical Knowledge Self Assessment Program (MKSAP) 15, American College of Physicians, Philadelphia 2009
- ↑ Barzilai N et al, A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 2006, 67:2170 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17190939
- ↑ 5.0 5.1 Harold D et al Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Sep 6. [Epub ahead of print] PMID: https://www.ncbi.nlm.nih.gov/pubmed/19734902
- ↑ Reuters Sept 6, 2009
- ↑ 7.0 7.1 Yahoo News http://news.yahoo.com/s/hsn/20100415/hl_hsn/newalzheimersgeneidentified
- ↑ 8.0 8.1 Naj AC et al Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease Nature Genetics April 2011 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21460841 <Internet> http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.801.html
Hollingworth P et al Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease Nature Genetics April 2011 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21460840 <Internet> http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.803.html - ↑ Jonsson T et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012 Jul 11 http://www.nature.com/nature/journal/v488/n7409/full/nature11283.html
- ↑ 10.0 10.1 10.2 Jonsson T et al Variant of TREM2 Associated with the Risk of Alzheimer's Disease N Engl J Med. November 14, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23150908 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1211103
Guerreiro R et al TREM2 Variants in Alzheimer's Disease N Engl J Med. November 14, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23150934 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1211851
Neumann H and Daly MJ. Variant TREM2 as risk factor for Alzheimer's disease. N Engl J Med 2012 Nov 14 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23151315 - ↑ 11.0 11.1 Cruchaga C et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 2013 Dec 11 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24336208
- ↑ 12.0 12.1 12.2 12.3 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - ↑ Goldman JS, Hahn SE, Catania JW et al Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011 Jun;13(6):57-605. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21577118 corresponding NGC guideline withdrawn Jan 2017
- ↑ 14.0 14.1 Ward A, Crean S, Mercaldi CJ et al Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology. 2012;38(1):1-17. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22179327 Free Article
- ↑ 15.0 15.1 15.2 Kneisel K Gene Linked to Steeper Cognitive Declines in AD - Decline exacerbated by greater b-amyloid burden. MedPage Today. May 4, 2017 https://www.medpagetoday.com/Neurology/AlzheimersDisease/65016
Boots EA, Schultz SA, Clark LR et al BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention. Neurology 2017;88:1-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28468845 - ↑ 16.0 16.1 Martiskainen H, Herukka SK, Stancakova A et al Decreased plasma beta-amyloid in the Alzheimer's disease APP A673T variant carriers. Ann Neurol. 2017 May 26. PMID: https://www.ncbi.nlm.nih.gov/pubmed/28556232
- ↑ 17.0 17.1 17.2 Ridge PG, Karch CM, Hsu S et al Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience. Genome Medicine. Nov 29 2017 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29183403 Free PMC Article
- ↑ 18.0 18.1 Arboleda-Velasquez JF, Lopera F, O'Hare M et al Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine (2019) Nov 4. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31686034 https://www.nature.com/articles/s41591-019-0611-3
- ↑ 19.0 19.1 Reiman EM, Arboleda-Velasquez, Quiroz YT et al Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nature Communications volume 11, Article number: 667 (2020) PMID: https://www.ncbi.nlm.nih.gov/pubmed/32015339 Free PMC Article https://www.nature.com/articles/s41467-019-14279-8
- ↑ 20.0 20.1 Belloy ME, Napolioni V, Han SS et al Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurol. Published online April 13, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32282020 https://jamanetwork.com/journals/jamaneurology/fullarticle/2763599
Dubal DB, Yokoyama JS. Longevity Gene KLOTHO and Alzheimer Disease - A Better Fate for Individuals Who Carry APOE epsilon4 JAMA Neurol. Published online April 13, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32282012 https://jamanetwork.com/journals/jamaneurology/fullarticle/2763597 - ↑ 21.0 21.1 Montagne A, Nation DA, Sagare AP et al APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 2020. 581:71-76 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32376954 https://www.nature.com/articles/s41586-020-2247-3
- ↑ 22.0 22.1 Prokopenko D, Morgan SL, Mullin K et al Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development. Alzheimer's & Dementia. 2021. April 2 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33797837 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12319
- ↑ 23.0 23.1 de la Vega MP, Giedraitis V, Michno W et al The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation. Sci Transl Med. 2021 Aug 11;13(606):eabc6184 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34380771 https://stm.sciencemag.org/content/13/606/eabc6184
- ↑ 24.0 24.1 Mobley I New research finds ABI3 gene function in Alzheimer's disease. Front Line Genomics. Nov 8, 2021 https://frontlinegenomics.com/new-research-finds-abi3-gene-function-in-alzheimers-disease/
- ↑ 25.0 25.1 Coomans EM, Tomassen J, Ossenkoppele R et al Genetically identical twins show comparable tau PET load and spatial distribution. Brain. Jan 12, 2022 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35022652 https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac004/6504924
- ↑ Adewuyi EO, O'Brien EK, Nyholt DR et al A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders. Commun Biol 2022, 5, 691. July 18 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35851147 https://www.nature.com/articles/s42003-022-03607-2
- ↑ 27.0 27.1 27.2 Lopera F, Marino C, Chandrahas AS et al Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023. May 15. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37188781 https://www.nature.com/articles/s41591-023-02318-3
- ↑ 28.0 28.1 Riedel BC, Thompson PM, Diaz Briton R Age, APOE and sex: Triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol. 2016 Jun;160:134-47 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26969397 PMCID: PMC4905558 Free PMC article https://www.sciencedirect.com/science/article/abs/pii/S0960076016300589
- ↑ 29.0 29.1 Cammann D, Lu Y, Cummings MJ et al Genetic correlations between Alzheimer's disease and gut microbiome genera. Sci Rep. 2023 Mar 31;13(1):5258. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37002253 PMCID: PMC10066300 Free PMC article. https://www.nature.com/articles/s41598-023-31730-5