Alzheimer Disease, Genetics of


In almost 20 years of ongoing research, the genetic cause of Alzheimer disease (AD) is understood for less than 5% of all cases. For the remainder of AD sufferers, multiple genetic and environmental factors probably play a role in contributing to disease onset, severity and progression. To date, only the gene encoding apolipoprotein E (APOE) is recognized as a major genetic risk factor, but numerous other candidates have emerged. What we have learned from these findings is discussed as are the results from recent genome linkage studies on affected sibling pairs which have yielded new chromosomal regions of interest and in turn new candidate genes alongside those reported from ongoing candidate gene association studies.

Keywords: dementia; linkage; familial; sporadic; Alzgene

Figure 1.

Schematic of the amyloid precursor protein (APP) encoded for by APP. The Aβ region which is produced from APP is highlighted and magnified to show the amino acid sequence it consists of, the cleavage sites within and around Aβ in where the α‐, β‐ and γ‐secretases operate and also the underlined and numbered (according to 770 amino acid splice variant of APP) amino acids positions of some of the first APP mutations identified the location of which coincides with sites of secretase activity. Modified with permission from Kehoe .



Ashford JW and Mortimer JA (2002) Non‐familial Alzheimer's disease is mainly due to genetic factors. Journal of Alzheimer's Disease 4(3): 169–177.

Bertram L, Blacker D, Mullin K et al. (2000) Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 290(5500): 2302–2303.

Bertram L, McQueen M et al. (2007) The Alzgene database. Alzheimer Research Forum. accessed on 10th September 2007.

Blacker D, Bertram L et al. (2003) Results of a high‐resolution genome screen of 437 Alzheimer's disease families. Human Molecular Genetics 12(1): 23–32.

Blomqvist ME, Reynolds C et al. (2006) Towards compendia of negative genetic association studies: an example for Alzheimer disease. Human Genetics 119(1–2): 29–37.

Chalmers K, Wilcock GK et al. (2003) APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein. Neuropathology and Applied Neurobiology 29(3): 231–238.

Chen K, Reiman EM et al. (2007) Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates. American Journal of Psychiatry 164(6): 916–921.

Coon KD, Myers AJ et al. (2007) A high‐density whole‐genome association study reveals that APOE is the major susceptibility gene for sporadic late‐onset Alzheimer's disease. Journal of Clinical Psychiatry 68(4): 613–618.

Curtis D, North BV et al. (2001) A novel method of two‐locus linkage analysis applied to a genome scan for late onset Alzheimer's disease. Annals of Human Genetics 65(Pt 5): 473–481.

Daw EW, Payami H et al. (2000) The number of trait loci in late‐onset Alzheimer disease. American Journal of Human Genetics 66(1): 196–204.

Ertekin‐Taner N, Graff‐Radford N et al. (2000) Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late‐onset Alzheimer's disease pedigrees. Science 290(5500): 2303–2304.

Farrer LA, Bowirrat A et al. (2003) Identification of multiple loci for Alzheimer disease in a consanguineous Israeli‐Arab community. Human Molecular Genetics 12(4): 415–422.

Ferri CP, Prince M et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366(9503): 2112–2117.

Gatz M, Reynolds CA et al. (2006) Role of genes and environments for explaining Alzheimer disease. Archives of General Psychiatry 63(2): 168–174.

Gordon D, Haynes C et al. (2006) Increase in linkage information by stratification of pedigree data into gold‐standard and standard diagnoses: application to the NIMH Alzheimer Disease Genetics Initiative Dataset. Human Heredity 61(2): 97–103.

Hamshere ML, Holmans PA et al. (2007) Genome‐wide linkage analysis of 723 affected relative pairs with late‐onset Alzheimer's disease. Human Molecular Genetics 16(22): 2703–2712.

Hardy J and Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297(5580): 353–356.

Holmans P, Hamshere M et al. (2005) Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease. American Journal of Medical Genetics Part B: Neuropsychiatry Genetics 135(1): 24–32.

Holtzman DM, Bales KR et al. (2000) Apolipoprotein E isoform‐dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the USA 97(6): 2892–2897.

Ioannidis JP, Ntzani EE et al. (2001) Replication validity of genetic association studies. Nature Genetics 29(3): 306–309.

Kehoe PG (2003) The renin‐angiotensin‐aldosterone system and Alzheimer s disease? Journal of the Renin–Angiotensin–Aldosterone System 4(2): 80–93.

Lee JH, Cheng R et al. (2006) Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease. Archives of Neurology 63(11): 1591–1598.

Lee JH, Mayeux R et al. (2004) Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics. Molecular Psychiatry 9(11): 1042–1051.

Li YJ, Scott WK et al. (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. American Journal of Human Genetics 70(4): 985–993.

Love S (2004) Contribution of cerebral amyloid angiopathy to Alzheimer's disease. Journal of Neurology Neurosurgery and Psychiatry 75(1): 1–4.

Lowin A, Knapp M et al. (2001) Alzheimer's disease in the UK: comparative evidence on cost of illness and volume of health services research funding. International Journal of Geriatric Psychiatry 16(12): 1143–1148.

Miners JS, Van Helmond Z et al. (2006) Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. Journal of Neuropathology and Experimental Neurology 65(10): 1012–1021.

Myers A, Holmans P et al. (2000) Susceptibility locus for Alzheimer's disease on chromosome 10. Science 290(5500): 2304–2305.

Myers A, Wavrant De‐Vrieze F et al. (2002) Full genome screen for Alzheimer disease: stage II analysis. American Journal of Medical Genetics 114(2): 235–244.

Olson JM, Goddard KA et al. (2002) A second locus for very‐late‐onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. American Journal of Human Genetics 71(1): 154–161.

Pericak‐Vance MA, Bass MP et al. (1997) Complete genomic screen in late‐onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 278(15): 1237–1241.

Pericak‐Vance MA, Grubber J et al. (2000) Identification of novel genes in late‐onset Alzheimer's disease. Experimental Gerontology 35(9–10): 1343–1352.

Pritchard JK and Cox NJ (2002) The allelic architecture of human disease genes: common disease‐common variant … or not? Human Molecular Genetics 11(20): 2417–2423.

Reiman EM, Webster JA et al. (2007) GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54(5): 713–720.

Roses AD (1998) Alzheimer diseases: a model of gene mutations and susceptibility polymorphisms for complex psychiatric diseases. American Journal of Medical Genetics 81(1): 49–57.

Sadowski MJ, Pankiewicz J et al. (2006) Blocking the apolipoprotein E/amyloid‐beta interaction as a potential therapeutic approach for Alzheimer's disease. Proceedings of the National Academy of Sciences of the USA 103(49): 18787–18792.

Scott WK, Hauser ER et al. (2003) Ordered‐subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. American Journal of Human Genetics 73(5): 1041–1051.

Sillen A, Forsell C et al. (2006) Genome scan on Swedish Alzheimer's disease families. Molecular Psychiatry 11(2): 182–186.

Stuck AE, Rubenstein LZ et al. (1998) Bias in meta‐analysis detected by a simple, graphical test. Asymmetry detected in funnel plot was probably due to true heterogeneity. BMJ 316(7129): 469; author reply 470–471.

Tang JL and Liu JL (2000) Misleading funnel plot for detection of bias in meta‐analysis. Journal of Clinical Epidemiology 53(5): 477–484.

Ulery PG, Beers J et al. (2000) Modulation of beta‐amyloid precursor protein processing by the low density lipoprotein receptor‐related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. Journal of Biological Chemistry 275(10): 7410–7415.

Further Reading

Bertram L et al. (2004) Alzheimer's disease: one disorder, too many genes? Human Molecular Genetics 13 Spec No 1: R135–R141.

Dewji NN (2005) The structure and functions of the presenilins. Cellular and Molecular Life Sciences 62(10): 1109–1119.

Kamboh MI (2004) Molecular genetics of late‐onset Alzheimer's disease. Annals of Human Genetics 68(Pt 4): 381–404.

Myers AJ et al. (2001) The genetics of late‐onset Alzheimer's disease. Current Opinion in Neurology 14(4): 433–440.

Selkoe DJ (2000) The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins. Neurologic Clinics 18(4): 903–922.

Selkoe DJ (2004) Alzheimer disease: mechanistic understanding predicts novel therapies. Annals of Internal Medicine 140(8): 627–638.

Sisodia SS et al. (2001) Gamma‐secretase: never more enigmatic. Trends in Neuroscience 24(suppl. 11): S2–6.

St George‐Hyslop PH (2000) Molecular genetics of Alzheimer's disease. Biological Psychiatry 47(3): 183–199.

Tanzi RE et al. (2005) Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120(4): 545–555.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kehoe, Patrick G(Sep 2008) Alzheimer Disease, Genetics of. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020228]