Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-041The Genetics of Alzheimer’s DiseaseBrenda L. Plassman 1 and John C. S. Breitner 21 Duke University Medical Center, Durham, NC, and 2 Johns Hopkins University, Baltimore, MD, USAKnowledge of the genetics of Alzheimer’s disease (AD) hasadvanced in recent years. Like many other diseases of late life, ADexhibits a complex pattern of inheritance. It is difficult to localizegenes that cause such diseases, however, partly because onlyrecent generations are available to be genotyped and phenotyped.This chapter will provide a general overview of the current state ofknowledge in the genetics of AD and related dementias, andsuggest approaches to interpretation of future findings in this area.FAMILY AND TWIN STUDIESThe striking early evidence for genetic causes of AD was based ona few multigenerational kindreds with many individuals with thedisease (for review, see ref. 1). Most of these families had onset ofdisease before the age of 65, and were thus arbitrarily classified ashaving ‘‘early onset’’. These multigenerational kindreds with socalledfamilial AD probably represent no more than 1–2% of allAD cases, but their existence strongly suggested that genes wereimportant in at least some cases of AD.Other early work supporting a genetic etiology of AD wasbased on the presence of a positive family history of the disease inclinical and population-based AD samples. Most of these studiesshowed an increased risk of AD in first-degree relatives, rangingfrom 25% to 50%, as compared with 10% or less for non-dementedcontrols 2 . This finding suggested an up to five-fold increase in riskof AD among relatives of individuals with the disease.The early family studies focused on families at greater risk ofdeveloping AD. Recently, however, some researchers have takenanother approach to the problem by investigating families whoappear to have a lower risk of AD 3 . They have shown that thefirst-degree relatives of individuals who reached the age of 90 andwere not demented had a reduced liability to AD from age 60 on,as compared with the families of younger non-dementedindividuals. The message here is that genes may either promoteor reduce the risk of AD.Twin studies have provided other evidence for genetic causes ofAD. Members of identical (monozygotic) twin pairs share 100%of their genome, while fraternal (dizygotic) twin pairs share 50%of their genes on average. The twin design assumes that the degreeof similarity in the early life environments of identical andfraternal twin pairs are the same. Based on this so-called ‘‘equalenvironments assumption’’, the twin design compares concordancerates for disease in identical (monozygotic) twin pairs withthat in fraternal (dizygotic) pairs. Higher concordance in identicalpairs, then, implies genetic influences. The magnitude of suchinfluences can be estimated in complex models that simultaneouslyassess the proportion of disease liability attributable toshared or unique environmental causes, as well as stochasticvariation 4 .Like the early family studies, twin studies of AD have generallyimplied genetic causation without identifying particular genes orloci. The heritability of AD (proportion of disease liabilityattributable to genes) has been estimated from ongoing studies ofAD in three population-based twin registries: (a) the NAS–NRCTwin Registry in the USA 5 ; (b) the Swedish Twin Registry 6 ; and(c) the Norwegian Twin Registry 7 . Based on tetrachoric correlationanalyses, current estimates of heritability for AD in thesestudies range from 0.33 to 0.74 5–7 . We suggest that the wide rangeof these estimates of heritability may reflect the differences in theage distribution of twins in the three registries. We speculate thatthe lowest heritability estimate (0.33) from our work mayunderestimate the true heritability of AD because of the atypicallyyoung age (mean onset age=67 years) of AD cases in the NAS–NRC sample. Others have shown that the risk of developing AD,for a relative of a proband with AD, increases with age at leastuntil the mid-80s 8 . Consistent with this, we have found that theestimates of heritability in the NAS–NRC Registry have graduallyincreased over the past few years. As the Registry approaches thetypical age of risk for AD of the late 70s, 80s and even beyond, weanticipate that heritability in the NAS–NRC sample willapproximate that of the other two studies and the consensusestimate of heritability will likely be between 0.5 and 0.65.MOLECULAR GENETICSAutosomal genes with dominant expressionMotivated by the findings from family and twin studies, moleculargenetic techniques have now identified mutations at three geneticloci that are associated primarily with early onset AD. Initialinterest in the molecular genetics of AD focused on chromosome21, because aging Down’s syndrome patients (trisomy 21) oftenexhibit the brain pathology seen in AD patients 9,10 . The firstidentified AD mutation was found in the b-amyloid precursorprotein (APP) located on chromosome 21 11 . This mutationsubstitutes isoleucine for valine at codon 717 in exon 17 11 . Sincethe first report of this missense mutation, a number of other APPmutations have been identified (for review, see ref. 12). But, intotal, the APP mutations appear to account for the disease in lessthan 20 families worldwide.The second genetic locus to show linkage to AD was found onchromosome 14 13,14 and was termed presenilin-1 (PS-1) 15 . Over 40mutations in the PS-1 locus have now been reported in at least 82families world-wide 16 . Like the APP mutations, PS-1 mutationsPrinciples and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd