Genetics of Dementia

Abstract

Dementia is a syndrome and not a single disease. It is caused by a primary brain disorders or a neurological/somatic disorders with brain involvement. Alzheimer disease is the most common dementia. Approximately 1% have early‐onset Alzheimer disease, often caused by mutation in the APP, PSEN1 or PSEN2 gene. Late‐onset Alzheimer disease has a complex inheritance. The APOE ɛ4 allele is a major risk factor for late‐onset Alzheimer disease, while the ɛ2 allele has a protective effect. Genome‐wide association studies indicate that BIN1, CRI, CLU and PICALM play a role in late‐onset Alzheimer disease, while other potential genes requires further investigation. Stroke is a syndrome and not a single disease. CADASIL is the most common autosomal dominant inherited cause of stroke and vascular dementia caused by mutations in the NOTCH3 gene. It is the stroke itself rather than the underlying vascular risk factors that cause the dementia.

Key Concepts:

  • Dementia is a syndrome and not a single disease.

  • Alzheimer disease is the most common primary brain disorders causing dementia.

  • Early‐onset (≤60‐year‐old) familial Alzheimer disease is caused by mutation in the APP, PSEN1 or PSEN2 gene in 30–50% of the families.

  • Late‐onset (>60 years old) Alzheimer disease have multifactorial inheritance.

  • Linkage and association studies have been largely unsuccessful, for reasons that include small sample size, low sensitivity to detect moderate effects and the substantial locus heterogeneity that underlies late‐onset Alzheimer disease.

  • The APOE ɛ4 allele is a major risk factor for late‐onset Alzheimer disease, while the ε2 allele has a protective effect.

  • Genome‐wide association studies indicate that BIN1, CRI, CLU and PICALM play a role in late‐onset Alzheimer disease.

  • Vascular dementia is the most common secondary brain disorder causing dementia.

  • Stroke is a syndrome and not a single disease and it is the stroke itself rather than the underlying vascular risk factors that cause the dementia.

  • CADASIL is the most common autosomal dominant inherited cause of stroke and vascular dementia caused by mutations in NOTCH3.

Keywords: Alzheimer disease; CADASIL; dementia; stroke; inheritance

References

American Psychiatric Association (2001) Diagnostic and Statistic Manual of Mental Disorders, 4th edn. Washington: American Psychiatric Association.

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

Butler AW, Ng MY, Hamshere ML et al. (2009) Meta‐analysis of linkage studies for Alzheimer's disease – a web resource. Neurobiological Aging 30(7): 1037–1047.

Calero M, Rostagno A, Matsubara E et al. (2000) Apolipoprotein J (clusterin) and Alzheimer's disease. Microscopy Research and Technique 50(4): 305–315.

Chabriat H, Joutel A, Dichgans M et al. (2009) CADASIL. Lancet Neurology 8(7): 643–653.

Corder EH, Saunders AM, Risch NJ et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics 7(2): 180–184.

Donnelly P (2008) Progress and challenges in genome‐wide association studies in humans. Nature 456(7223): 728–731.

Farrer LA, Myers RH, Connor L et al. (1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. American Journal of Human Genetics 48(6): 1026–1033.

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

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

Gerrish A, Russo G, Richards A et al. (2011) The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. Journal of Alzheimer's Disease 28(2): 377–387. Oct 25 [Epub ahead of print].

Ghiso J, Matsubara E, Koudinov A et al. (1993) The cerebrospinal‐fluid soluble form of Alzheimer's amyloid beta is complexed to SP‐40,40 (apolipoprotein J), an inhibitor of the complement membrane‐attack complex. Biochemical Journal 293(Pt 1): 27–30.

Goate A, Chartier‐Harlin M‐C, Mullan M et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349(6311): 704–706.

Harold D, Abraham R, Holliingwoth P et al. (2009) Genome‐wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics 41(10): 1088–1093. http://www.molgen.ua.ac.be/ADMutations

Joutel A, Corpechot C, Ducros A et al. (1996) Notch3 mutations in CADASIL, a hereditary adult‐onset condition causing stroke and dementia. Nature 383(6602): 707–710.

Lambert JC, Heath S, Even G et al. (2009) Genome‐wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics 41(10): 1094–1099.

Levy‐Lahad E, Wasco W, Poorkaj P et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269(5226): 973–977.

Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456(7218): 18–21.

Markus HS (2011) Stroke genetics. Human Molecular Genetics 20(R2): R124–R131.

May PC and Finch CE (1992) Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends in Neuroscience 15(10): 391–396.

Naj AC, Jun G, Beecham GW et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late‐onset Alzheimer's disease. Nature Genetics 43(5): 436–441.

Neale MC (1995) MX: Statistical Modeling, 3rd edn. Richmond, VA: Department of Psychiatry.

Pendlebury ST and Rothwell PM (2009) Prevalence, incidence, and factors associated with pre‐stroke and post‐stroke dementia: a systematic review and meta‐analysis. Lancet Neurology 8(11): 1006–1018.

Pericak‐Vance MA and Haines JL (2009) Beyond proof of principle: new genes for Alzheimer's disease through collaboration. Lancet Neurology 8(11): 977–979.

Prakash N, Hansson E, Betsholtz C et al. (2002) Mouse Notch 3 expression in the pre‐ and postnatal brain: relationship to the stroke and dementia syndrome CADASIL. Experimental Cell Research 278(1): 31–44.

Schulz UG, Flossmann E and Rothwell PM (2004) Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population‐based studies. Stroke 35(4): 819–824.

Seshadri S, Beiser A, Pikula A et al. (2010a) Parental occurrence of stroke and risk of stroke in their children: the Framingham study. Circulation 121(11): 1304–1312.

Seshadri S, Fitzpatrick AL, Ikram MA et al. (2010b) Genome‐wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(18): 1832–1840.

Sherrington R, Rogaev EI, Liang Y et al. (1995) Cloning of a gene bearing mis‐sense mutations in early onset familial Alzheimer's disease. Nature 375(6534): 754–760.

Sjögren T, Sjögren H and Lindgren ÅG (1952) Morbus Alzheimer and morbus Pick; a genetic, clinical and patho‐anatomical study. Acta Psychiatry Neurology Scandinavia (Suppliment) 82: 1–152.

Theuns J, Brouwers N, Engelborghs S et al. (2006) Promoter mutations that increase amyloid precursor‐protein expression are associated with Alzheimer disease. American Journal Human Genetics 78(6): 936–946.

Tournier‐Lasserve E, Joutel A, Melki J et al. (1991) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nature Genetics 3(3): 256–259.

Urdinguio RG, Sanchez‐Mut JV and Esteller M (2009) Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurology 8(11): 1056–1072.

Further Reading

The knowledge of genetics in dementia is expanding at a very fast pace, and for that reason textbooks will be outdated very fast. Thus, search engines such as MedLine, Ovid and/or PubMed with relevant search words is recommended.

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

* Required Field

How to Cite close
Russell, Michael Bjørn(Jul 2012) Genetics of Dementia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023871]