Endophenotypes in normal brain morphology and Alzheimer's disease: a review

• Published in: Neuroscience Vol. 164; no. 1; pp. 174 - 190
• Main Authors: Reitz, C, Mayeux, R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 24.11.2009
• Subjects: Age of Onset; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Apolipoproteins E - genetics; Brain - pathology; brain morphology; Cognition Disorders - genetics; Cognition Disorders - pathology; cognitive impairment; Dementia - genetics; Dementia - pathology; endophenotypes; Humans; LDL-Receptor Related Proteins - genetics; Membrane Transport Proteins - genetics; Neurology; Phenotype; CIND; Alzheimer Disease Assessment Scale-Cognitive subscale; ADAS-Cog; LOAD; cognitive reserve; QTL; dizygotic; IDE; quantitative trait loci; monozygotic; cognitive impairment no dementia; insulin degrading enzyme; DZ; CCMS; sortilin-related receptor; APOE; Alzheimer's disease; California Verbal Learning Test; Swedish Adoption/Twin Study of Aging; CVLT; SATSA; endophenotypes; late-onset Alzheimer's disease; MZ; SORL1; CR; brain morphology; MCI; apolipoprotein E; Cache County Study of Memory in Aging; cognitive impairment; mild cognitive impairment
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2009.04.006

Abstract Late-onset Alzheimer's disease is a common complex disorder of old age. Though these types of disorders can be highly heritable, they differ from single-gene (Mendelian) diseases in that their causes are often multifactorial with both genetic and environmental components. Genetic risk factors that have been firmly implicated in the cause are mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, which are found in large multi-generational families with an autosomal dominant pattern of disease inheritance, the apolipoprotein E ( APOE )ε4 allele and the sortilin-related receptor (SORL1) gene. Environmental factors that have been associated with late-onset Alzheimer's disease include depressive illness, various vascular risk factors, level of education, head trauma and estrogen replacement therapy. This complexity may help explain their high prevalence from an evolutionary perspective, but the etiologic complexity makes identification of disease-related genes much more difficult. The “endophenotype” approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes for complexly inherited traits. The usefulness of endophenotypes in genetic analyses of normal brain morphology and, in particular for Alzheimer's disease will be reviewed as will the implications of these findings for models of disease causation. Given that the pathways from genotypes to end-stage phenotypes are circuitous at best, identifying endophenotypes more proximal to the effects of genetic variation may expedite the attempts to link genetic variants to disorders.