originalarticles - journal of medical genetics · 60medgenet 1993 30: 640-646 originalarticles...

60 Med Genet 1993 30: 640-646

ORIGINAL ARTICLES

Genetic transmission of Alzheimer's diseaseamong families in a Dutch population basedstudy

Cornelia M van Duijn, Lindsay A Farrer, L Adrienne Cupples, Albert Hofman

Department ofEpidemiology andBiostatistics, ErasmusUniversity MedicalSchool, Rotterdam,The Netherlands.C M van DuijnA Hofman

Boston UniversitySchool of Medicine,Department ofNeurology, 80 EastConcord Street,Boston, MA 02118USA.L A Farrer

Department ofEpidemiology andBiostatistics, School ofPublic Health, BostonUniversity, Boston,Massachusetts, USA.L A FarrerL A Cupples

Department ofNeurology, HarvardMedical School,Boston,Massachusetts, USA.L A Farrer

Correspondence toDr Farrer.

Received 26 October 1992.Revised version accepted4 February 1993.

AbstractWe evaluated age at onset and trans-mission patterns of Alzheimer's disease(AD) in families of 198 patients who hadonset of symptoms before the age of 65years and were diagnosed before the age

of 70 years. Patients were ascertained in apopulation based study in The Nether-lands. The results suggest that the risk ofAD by the age of 90 in first degree rela-tives is 39% (95% confidence interval 27 to51). By the age of 90, this risk is 2.8 (95%confidence interval 1.5-5.2) times greaterthan the corresponding risk of 14% amongrelatives of age and sex matched controlsubjects. Segregation analysis indicatedthat patterns of familial clustering are

best explained by transmission of a majorautosomal dominant gene with reducedpenetrance and a multifactorial compon-ent. However, the single major locusmodel could be rejected in favour of themixed model only when a cohort effect forheritability was allowed for. The fre-quency of the AD susceptibility allele wasestimated to be 0.48% in the single majorlocus model and 0.31% in the mixedmodel. Although our study confirms thata dominant major gene is implicated inearly onset AD, the results suggest thatother genetic or perhaps non-genetic fac-tors may account for the disease in a

considerable number of patients.(J Med Genet 1993;30:640-6)

The tendency for Alzheimer's disease (AD) to

cluster in families is well recognised.' There isevidence for autosomal dominant inheritancein a considerable number of families withmultiple affected members.2 Identification ofdefects in the gene coding for ,B amyloid pro-cessing protein in patients from some families"7and evidence for linkage of early onset familialAD (FAD) to chromosome 148-" and lateonset FAD to chromosome 1912 has fuelledspeculation that the familial component in ADis accounted for by genetic transmission. How-ever, observations of sporadic occurrence inapproximately 50% of AD cases,'3'6 similarconcordance rates in the range of 50% for ADamong MZ and DZ twin pairs,'7-'9 and a signi-ficantly higher number of patients with a posit-

ive family history ofAD in first degree relativesamong MZ twin pairs concordant for AD thanin discordant MZ twins pairs20 suggest that thegenetic susceptibility to AD in many people iseither lacking or insufficient to cause symptoms.Differences in methodology may underlie thiswide range in risk estimates. On the other hand,it is also conceivable that these discrepanciesmay be because of heterogeneity.2'

Interpretation of familial risk data from sur-vey studies'42223 is difficult because of censor-ing of unaffected relatives. In other words,even elderly relatives who are unaffected at thetime of the study may yet develop or couldhave developed the illness at a later age. Sur-vival analysis studies2427 have quantified lifetime risk more accurately, but these methodsare unable to distinguish an inherited riskfactor from environmental transmission ordiscriminate between unifactorial and multi-factorial disease models.

It has been suggested that genetics maydiffer between early and late onset AD and thatthe early onset form (onset before 65 years)may be explained as an autosomal dominanttrait.2'28 Previous studies have been too smallto yield precise risk estimates for early onsetAD. Another problem in the interpretation ofearlier investigations is that case series havebeen hospital based. Since referral of thepatients to a particular hospital may have beenrelated to the history of dementia in the family,selection bias may have occurred when study-ing the extent of genetic involvement in thedisease. As to the pattern of genetic transmis-sion, to date only one formal segregationanalysis involving rigorously diagnosed caseshas been published.29 This study suggestedthat one or more major dominant genes may beimplicated in AD but that other genetic ornon-genetic mechanisms appear to play a sub-stantial role. However, these findings remainto be confirmed.2129We have studied the pedigrees of 198 patients

with an onset ofAD before the age of 65 and of198 age and sex matched controls. Patients andcontrols were derived from a Dutch populationbased study of risk factors for early onset AD.The purpose of this study was to clarify thegenetic transmission of early onset AD usingdata of a population based unbiased sample ofAD patients. The study aimed to estimate the

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Genetic transmission of Alzheimer's disease among families in a Dutch population based study

risk ofAD for first degree relatives of patientswith early onset AD and to delineate the modeof inheritance of early onset AD.

MethodsSUBJECTSFor this study, patients in whom the age atonset was before the age of 65 years and inwhom the diagnosis of AD was made beforethe age of 70 years in the period of January1980 to July 1987 were eligible. Details of thestudy design have been published earlier.30The study was population based and aimed atcomplete ascertainment of all cases with earlyonset AD living in two areas of The Nether-lands (the four northern provinces and theregion of the city of Rotterdam). All nursinghomes, psychiatric institutions, social-geriatricservices, neurologists, and facilities for com-puted tomography in the specified areas wereasked for patients with dementia in order toobtain full ascertainment of early onset cases.The patients were then seen by two physicianswho independently confirmed the diagnosis ofprobable AD using a standard protocol similarto NINCDS/ADRDA criteria.3' Only patientsfor whom there was consensus on the clinicaldiagnosis of probable AD were included in thestudy. Dementias other than AD (for example,multi-infarct dementia, Parkinson's disease,and dementia secondary to alcoholism, depres-sion, metabolic disorders, and other conditions)were excluded on the basis of the clinical history,neurological examination, and neuropsycho-logical and laboratory tests.The inclusion criteria for patients were: a

typically slow progressive decline of intellec-tual function31; a score on the Clinical Demen-tia Rating scale of more than 0.532; a score onthe Short Portable Mental Status Question-naire (SPMSQ) of less than 20 (out of 30 in theDutch version we have used)33; a score of 7 orless (out of 18) on the Hachinski scale34; noevidence of abnormalities on computed tomo-graphy other than cerebral atrophy, nor offocal dysfunction on electroencephalography.Of the 278 patients brought to our attention,201 satisfied these criteria. The family of onepatient refused cooperation and for two othersno informant could be found. In 198 (98%)patients, data on risk factors were obtainedalong with a serum sample. The age at onsetwas 55 years or younger in 56 patients,between 55 and 59 years in 76 patients, andbetween 60 and 65 in 66 patients.For each patient a reference subject was

selected and matched for age (within five years),gender, and place of residence. These controlswere drawn randomly from the populationregister of the municipality of the patient at thetime of diagnosis. All control subjects had aSPMSQ score of 20 or over. For controls, thefirst person asked consented in 103 cases (52%),in 68 (34%) it was the second selected person, in23 (12%) the third, and in four (2%) the fourth.

DATA COLLECTIONWe did not examine the relatives of the prob-ands because a considerable number of first

degree relatives were already dead at the timeof study. However, detailed data on familyhistory were collected by interviewing a nextof kin of the patient or control. This informantwas asked specifically about the occurrence ofdementia in all first degree relatives. To in-crease the validity of the family history data,the information was always verified by a sib ofthe patient or control. Four subjects bornoutside The Netherlands were excluded fromthe analysis because their sibs could not becontacted. Onset age of dementia was defined asthe age at which memory loss or change inbehaviour was first noted. For non-dementedrelatives, the censoring age was determined, thatis, the age at time ofthe study or the age at death.We questioned informants extensively on

the cause and the course of the dementia inaffected relatives. The diagnosis was checkedin independent medical records for dementedpersons who had been admitted to a hospital.Because relatives may have been diagnosedbefore standardised diagnostic criteria wereavailable, all relatives reported as dementedwere re-evaluated using data from multipleinformants and information derived frommedical records. Relatives with a history ofneurological, psychiatric, or metabolic dis-orders that may also lead to dementia (forexample, stroke, Parkinson's disease, epilepsy,depression, or alcoholism) were classified asunaffected. All other relatives with a type ofdementia that was reported as being irrevers-ible and progressive were classified as affectedwith possible AD. Medical records were avail-able for 36 (32%) of the affected relatives.Pedigrees of the families are available uponrequest.

ESTIMATION OF LIFE TIME RISK AND AGE ATONSET DISTRIBUTIONRisks of dementia and the age at onset distri-bution for first degree relatives of the ADprobands and control subjects were estimatedusing a maximum likelihood procedure.35 Thismethod considers not only affected personswith known onset ages and unaffected personswith known censoring ages (that is, those per-sons typically included in a Kaplan-Meier sur-vival analysis36), but also persons for whomonset age or censoring age data are missing.This method also allows for the possibilitiesthat a proportion of relatives asymptomatic atthe time of study may be susceptible andexpress the disease later in life and that somedead relatives may have died from causes unre-lated to AD although they may have developedsymptoms had they survived. Parameter es-timates for the estimated life time risk andmean onset age were compared between ADrelatives and control relatives and among sub-groups of AD relatives at the oldest onset agecommon to both groups. Since asymptoticallythese maximum likelihood statitics have nor-mal distributions, a large sample Z statisticwas used.37 For the purpose of these analyses,probands were stratified by age at onset of 58years because this age was calculated usingmaximum likelihood as the most parsimoniouscut off between families with early onset FAD

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van Duijn, Farrer, Cupples, Hofman

Table 1 Variables considered in segregation analysis.

q Gene frequency for major locusd Degree of dominance at major locust Segregation between genotype classes or distributionsTI, T2, T3 Probability of transmission of susceptibility allele among subjects homozygous for the mutant allele, heterozygotes,

and normal homozygotes, respectivelyH Polygenic heritability in offspringZ Ratio of heritability between parents and offspring (that is, cohort effects)n Ascertainment probability which equals the probability that a person in the population who has the trait becomes a

probandL Liability for disease based on prevalence of the trait in the population by age and sex

and late onset FAD.2 Life time risk of AD tofirst degree relatives and, hence, the inferredmode of transmission, differed in these twogroups of families.

SEGREGATION ANALYSIS METHODSSegregation analysis is the evaluation ofmodels of transmission accounting for the dis-tribution of a trait in families. This approachuses a maximum likelihood method38 whichpermits joint consideration of several indepen-dent parameters of the transmission model(table 1). A variety of single gene models,polygenic models, mixed models (that is, liab-ility to AD determined by a major locus com-ponent, a polygenic background, and randomenvironment),3940 and sporadic models weretested using the computer programPOINTER.4' These data represent a biasedsample because all families were selected onthe basis of at least one affected member. Anascertainment correction was applied whichconsidered the type of ascertainment and theascertainment probability, t42 (table 1). Al-though all AD cases diagnosed before 70 yearsand living in the catchment area were identi-fied, ascertainment approaches single selectionbecause the likelihood for any family havingmore than one living affected member diag-nosed before 70 years is very small (in fact,only one family had multiple probands).Hence, X was assumed to be 0.001. As the riskof AD increases rapidly with age and theaverage censoring age was higher in parentsthan in sibs, bias may occur when studying thetransmission patterns of disease within afamily. To adjust for the age related increasedrisk of AD, parents of all probands were con-sidered lost to follow up after the age of 81years, which was the oldest observed onset ageamong sibs. Those with an onset of diseaseafter the age of 81 were considered unaffectedand lost to follow up at the age of 81. The ageand sex adjusted cumulative incidence up tothe age of 81 in control subjects was used todetermine liability of developing AD for eachsubject (table 2). Data were analysed under

Table 2 Liability classes used in segregation analysis.

Age range (years)Cumulative

Class Men Women incidence

1 0-55 0-60 0.0043402 56-62 61-62 0.0079733 63-70 63-69 0.0156554 71 + 70-73 0.0276845 - 74-75 0.0347196 - 76-77 0.0420977 - 78-79 0.0567918 - 80 + 0.066011

different assumptions for i and cumulativeincidence. Results of these analyses did notchange any of the conclusions.

ResultsSURVIVAL ANALYSIS RESULTS

Over a life span of 90 years, the risk fordementia to first degree relatives of AD pro-bands is 39% (SE 6) which is significantlygreater than the corresponding risk of 14%(SE 4) among relatives of controls subjects(table 3). The mean onset ages for the twogroups were not significantly different. Thesefindings suggest that although the relative pro-portions of early onset and late onset cases aresimilar among relatives of AD probands andrelatives of controls, the risk ofAD is higher inrelatives of AD cases at all ages (fig 1). Therelative risk for Alzheimer's disease by the ageof 90 for those with a first degree affectedrelative is 2.8 (95% confidence interval 1.5-5.2).Among first degree relatives of the AD

cases, the risk of developing AD was higher inwomen than in men at all ages. By the age of86, women have a 15% higher risk than men ofdeveloping AD. Moreover, the mean age ofonset was significantly higher in women (79.8years) than men (73.0 years). Parents of ADcases had 1.4 times (0.26/0.18) the risk of sibsfor developing AD by the age of 81 but thisdifference was not significant. At all ages, therisk of AD was higher among parents thanamong sibs (fig 2). Although first degree rel-atives of probands with an onset of diseasebefore the age of 58 tended to have a higherrisk of dementia, further stratification showedthat this finding could be attributed to the 70%risk among female relatives of early onsetcases. Similar risks and onset ages were foundamong relatives of male and female probands.

SEGREGATION ANALYSIS RESULTS

Formal testing of 15 hypotheses regardingtransmission ofAD in families was carried outby segregation analysis. The maximum likeli-hood estimates of the parameters (described intable 1) for each model are presented in table 4.Values in parentheses were fixed in accordancewith the model being tested. The -2 loglikelihood values for the corresponding modelswere compared by a likelihood ratio (x2) test ina sequential fashion. The hypothesis that sus-ceptibility to AD is not transmitted is stronglyrejected when compared to models of multifac-torial (X2 =237.15, p<0.0001) or mendelian(x2= 254.75, p <0.0001) inheritance. Amongmodels postulating a single major locus or a

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Table 3 Estimated life time risk of Alzheimer's disease (AD) and the age at onset distribution among first degreerelatives among stratified groups ofAD probands and controls.

RiskNo of relatives in group Oldest Onset age (y)

Comparison onset Lifetime Comparisongroup Affected Unaffected age (y) risk (SE) risk (SE)* Zt Mean (SE) Zt

All 127 1181 90 0.39 (0.06) 0.39 (0.06) 3.47§ 77.7 (1.6) 1.54Controls 32 1187 90 0.14 (0.04) 0.14 (0.04) 81.4 (1.8)Males 48 620 86 0.22 (0.04) 0.22 (0.04) 2.341 73.0 (1.9) 2.60+Females 79 561 90 0.56 (0.10) 0.37 (0.05) 79.8 (1.8)Parents 81 306 90 0.42 (0.06) 0.26 (0.06) 1.37 75.7 (1.8) 1.36Sibs 46 875 81 0.18 (0.05) 0.18 (0.05) 71.4 (2.6)Proband onset A58 68 566 90 0.48(0.09) 0.48(0.09) 1.40 78.5 (2.1) 0.50Proband onset >58 59 615 90 0.32(0.07) 0.32(0.07) 76.9(2.4)Males, proband onset 58 24 311 83 0.20(0.05) 0.20(0.05) 0.26 70.4(2.8) 0.27Males, proband onset >58 24 309 86 0.24(0.06) 0.22(0.06) 75.1 (2.4)Females, proband onset 58 44 255 90 0.70(0.12) 0.70(0.12) 1.63 79.8(1.9) 0.22Females, proband onset >58 35 306 90 0.40(0.14) 0.40(0.14) 78.9 (3.7)Male proband families 49 416 90 0.39 (0.09) 0.37 (0.08) 0.09 77.8 (2.6) 0.18Female proband families 78 765 89 0.38(0.07) 0.38(0.07) 77.2(2.0)

* Risk at maximum age common to both groups (that is, the smaller of the two oldest onset ages).t Test for difference between comparison groups.I p<0.01 §p<0.001

mixed model for AD, recessive inheritance isvery unlikely (model 4 v model 7: X=126.14,

---Relatives ofADpatients p<0.0001; model 9 v model 12: XI= 17.62,Relatives of controls j p<0.0001). Hypotheses suggesting that sus-

ceptibility to AD is determined by multifac-I " torial inheritance only are also rejected in

favour of the mixed models (model 2 v model12: XI = 17.62, p = 0.0005; model 3 v model 14:2%=l0.98, p=0.012). Among the mixed

models, mendelian transmission of the diseaseis not rejected, that is, Tl, T2, and t3 do not

Tt 1Tll differ significantly from 1, 0.5, and 0, respect-ively (model 12 v model 13: x2= 1.38, p = 0.71;model 14 v model 15: X2= 0.01, p>0.9). Singlemajor locus inheritance (model 7) can be

, p/1 rejected in favour of the mixed model 14 onlywhen a cohort effect (that is, Z, the parent tochild heritability ratio) is not constrained to

0 40 50 60 70 80 90 one (X2= 16.50, p=0.0003). The best modelAge (years) fitted to our data (model 14) suggests that theAge(years) ~~~~AD susceptibility allele at the major locus has a

Estimated life time incidence of Alzheimer's disease (AD) in first degree frequency of 0.31% and behaves in an auto-rAD probands and control subjects. Vertical lines show standard errors at somac ominant manneheAD suti-

alue for onset in affected relatives. somal dommant marmer. The AD susceptibi-lity allele at the major locus is 61% penetrant.In this model, approximately 2% of the vari-ance in patterns of familial aggregation of ADis accounted for by the major locus and 21% isaccounted for by a multifactorial component.Therefore it may be inferred that 77% of the

---Parents of AD patients J variance is unaccounted for. Assuming a singleSibs of AD patients major locus (model 7), 4% of the variance is

. accounted for by the major locus and 96% ofl the variance is unaccounted for.1I

30 40 50 60Age (years)

Figure 2 Estimated life time incidence of Alzheimer's disesibs of AD probands. Vertical lines show standard errors ataffected relatives.

l 1 Discussion1i0tOur study indicates that the risk ofAD by the

Iii age of 90 in first degree relatives of patientswith clinically diagnosed early onset AD is39%, and this risk is almost three times greaterthan the corresponding risk among relatives of

ATIT control subjects. On the basis of this compar-ison alone, one would conclude that suscepti-bility to AD has a strong genetic component,but it is unlikely that an autosomal dominant

...................... model can fully explain transmission ofAD in70 80 90these families because the risk is much lessthan 50%. However, given the wide con-

each age value for onset in fidence interval on this estimate (27-51 %), arisk of 50%, and, hence, dominant inheritance

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Table 4 Segregation analysis of Alzheimer's disease.

Model Hypothesis d t q H Z T, T2 T3 -2lnL+C

1 Sporadic - - (0) (0) (1.0) - _ - -788.66

Multifactorial2 No cohort effect - - (0) 0.62 (1.0) - - - -1025.813 Cohort effect - - (0) 0.49 2.01 - - - - 1048.93

Single locus4 Recessive (0) 15.27 0.03911 (0) (1.0) (1.0) (0.5) (0) - 917.275 Codominant (0.5) 4.08 0.00476 (0) (1.0) (1.0) (0.5) (0) -1043.316 Dominant (1.0) 2.08 0.00439 (0) (1.0) (1.0) (0.5) (0) -1042.357 Unrestricted d 0.33 6.08 0.00483 (0) (1.0) (1.0) (0.5) (0) -1043.418 Unrestricted d and T 0.42 5.31 0.00389 (0) (1.0) 1.0 0.59 0 - 1044.93

Mixed model9 Recessive major locus (0) 0.02 0.0021 0.62 (1.0) (1.0) (0.5) (0) -1025.8110 Codominant major (0.5) 4.05 0.0047 0.04 (1.0) (1.0) (0.5) (0) - 1043.37

locus11 Dominant major locus (1.0) 2.06 0.0040 0.13 (1.0) (1.0) (0.5) (0) -1042.6012 Unrestricted d 0.37 5.45 0.0046 0.04 (1.0) (1.0) (0.5) (0) - 1043.4313 Unrestricted d and T 0.22 10.76 0.0032 0.04 (1.0) 1.0 0.63 0 -1044.81

General transmission14 Mendelian major locus 0.61 3.12 0.0031 0.21 4.67 (1.0) (0.5) (0) - 1059.91

with cohort effects15 Unrestricted model 0.67 2.86 0.0032 0.21 4.69 1.0 0.51 0 -1059.92

as the sole mechanism for AD transmissioncannot be excluded without doing a formalpedigree analysis.Other studies242643 have reported life time

risks that approach 50%, but these values maybe inflated because of estimation bias associ-ated with a paucity of unaffected persons whosurvive to very late ages (sample size issue) andascertainment biased towards cases with a pos-itive family history. In contrast, the life timerisk for AD of 39% is in remarkable agreementwith the maximum risk estimate of 39%obtained by Farrer et al,27 despite the dif-ferences between the studies in ascertainmentand age of onset of probands.Although the risk of dementia was higher

among parents than sibs at all ages, survivalanalysis also showed that life time risks toparents and sibs by the age of 81 were statistic-ally indistinguishable, a finding consistentwith other studies.2426 The raised risk tofemales is still apparent after adjusting fordifferential survival between men and women.Although this difference may reflect enhancedgenetic expression among women,'924 the riskof 70% among female relatives of probandswith onset < 58 years is higher than expectedfor autosomal dominant inheritance, suggest-ing the existence of excess phenocopies amongwomen.

Other complex segregation analysis suggeststhat patterns of familial clustering are bestexplained by a mixed model, in which there istransmission of a major autosomal dominantgene and a multifactorial component. Thesefindings are consistent with the results of thesurvival analysis in table 3. As Z is signific-antly greater than one, the polygenic compon-ent seems to be stronger in the parentalgeneration than in the offspring generation inDutch families. This trend is in agreementwith the higher risk estimates for parents thanfor sibs at all ages (fig 2). Biologically, thestrong generational effect is difficult to inter-pret. It may be argued that our method forcorrecting the censoring bias may not haveadequately accounted for the fact that themajority of the unaffected sibs are relativelyyoung (mean= 59.0 [SE 18.8], median= 64)and, therefore, still have substantial risk of

developing AD. If the generational effect isignored, there is no significant evidence formultifactorial inheritance and familial aggre-gation in this population is consistent with asingle major gene model.At present two formal segregation analyses

have been published.2944 McGuffin et al" couldnot reject multifactorial inheritance as themode of transmission in a segregation analysisof two Scandinavian studies.2245 However,these studies were carried out before the avail-ability of operational diagnostic criteria andstandardised methods for reliable classificationof unexamined cases. Also patients with Pick'sdisease confirmed at necropsy were included inthese analyses. Our findings are consistentwith the segregation analysis findings of Farreret al,29 who studied segregation of AD in firstdegree relatives of 232 cases with early or lateonset AD. Models postulating no transmissionand multifactorial inheritance only wererejected in both studies. However, in the studyof Farrer et al,29 who assumed a very conserv-ative cumulative incidence (0.0065), the evid-ence for multifactorial inheritance in themixed models was independent of the cohorteffect. A reanalysis of their data using a cumul-ative incidence of 0.17, which is more com-patible with the incidence ofAD reported in aUS population based epidemiological study,46gave estimates for q (0.0023), h (0.21), and t2(0.50), which are very similar to the presentstudy (unpublished results).There may be several caveats to the inter-

pretation of our findings including diagnosticuncertainty (particularly among unexaminedrelatives) and robustness of the parameter es-timates. Specifically with regard to the lifetime risk estimates, it has been shown thatdefinition of onset of disease may influence therisk estimates.47 Although our definition mayhave led to an underestimation of the truerisk,47 a shift in the assignment of onset agewould have little impact on the conclusionsfrom the segregation analysis.The pitfalls of segregation analysis of late

onset disorders are well recognised (for adetailed discussion of the methodologicalissues regarding segregation analysis see refer-ence 29). We cannot exclude the possibility

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that a considerable percentage of the variancein patterns of familial aggregation of AD notaccounted for by autosomal dominant or

multifactorial inheritance may be explained byerroneous pedigree information (for example,diagnostic uncertainty or censoring). In sup-port of our results, we used rigorous andstandardised diagnostic criteria and scrutin-ised the data under several different assump-tions of disease prevalence and ascertainmentprobability. Furthermore, we used multipleinformants which has been shown to increasethe reliability of family history data.48 Anotherimportant strength of our study is the popula-tion based design, which makes it unlikely thatselection bias has occurred.

It is important to note that widely usedcomputer programs for segregation analysis(for example, POINTER,4' PAP,49 SAGE,50and MENDEL5") are limited to conventionalgenetic models for transmission of diseasewhich allow for inheritance through a majorgene with two alleles and multifactorial in-heritance. More complex genetic models (forexample, major gene with multiple alleles forsusceptibility, oligogenic models in which thedisease is determined by a small number ofunlinked loci, and models involving epistasisin which expression of the major susceptibilityallele is masked by another gene) are not con-sidered. A method for segregation analysis of atwo locus disease trait has been developed52and successfully applied in at least one in-stance,53 but simulation studies have shownthat the method has limited power to distin-guish between a fully penetrant recessive-recessive model and single locus models withreduced penetrance.54 This is one avenue forfuture research in the genetics of AD.The results of our study shed light on the

issue of heterogeneity. The notion that earlyonset AD is a distinct genetic entity is an

attractive idea. Age at onset and genetic link-age studies support the existence of an autoso-mal dominant gene for very early onset familialAD (age of onset before 55 years).2>" Clinic-ally, however, the cut off age for early onsetAD is considered to be 65 years. Our findingsof the age of onset and segregation analysissuggest that autosomal dominant inheritancedoes not fit all cases with an onset ofAD beforethe age of 65. Furthermore, comparison of ourfindings with the results of a study ofpredomi-nantly late onset AD29 suggests that at thislevel of analysis there is no apparent distinc-tion in frequency of the autosomal dominantallele between cases of early onset and lateonset AD. Similarity of the genetic models forearly onset and late onset familial AD is consis-tent with the observed wide range in onset ages

among affected relatives in both groups. It ispossible that mechanisms determining suscep-

tibility to AD may be the same for early andlate onset illnesses, but that the age at onset

may be influenced by other genetic or non-

genetic factors as has been proposed in Hunt-ington's disease.5556The evidence for a multifactorial effect is

weak in our study of early onset AD, but thisneeds to be confirmed in independent studies.

Given the low frequency of the AD susceptib-ility allele and the lack of strong environmentalrisk factors, the origin of familial aggregationofAD in some families remains an unresolvedissue. Other complex forms of genetic suscept-ibility not accounted for by the present metho-dology may be implicated. The finding ofreduced penetrance for the major dominantallele in the present study is indeed compatiblewith an oligogenic model.Our findings are also of interest in light of

the recent linkage studies of familial AD.Familial early onset AD must be geneticallyheterogeneous, because the mutant gene insome families maps to chromosome 148--"whereas patients in other families have defectswithin the f amyloid processing protein genelocated on chromosome 21.1' Although thepossibility of multiple loci has not been ex-amined, our analysis and the segregationanalysis by Farrer et aP29 predict that it isunlikely that one dominant allele underlies thegenetic basis in all cases. The hypothesis thatnon-mendelian inheritance may be involved inthe genetic transmission ofAD is supported bythe finding of a strong association betweenApo E4 and late onset AD.57A challenge to genetic epidemiologists in the

future may be to disentangle the various gen-etic and non-genetic factors implicated in AD.Oligogenic models and epistatic models arestill to be explored. A profitable strategy infuture research may be to incorporate existingclues about the multifactorial component, suchas associations with the Apo E4,57 HLA-A2,58age of the father at the time of birth,59 andother risk factors,6' in a regressive modelanalysis.6' In this way, it may be possible todistinguish meaningful subgroups whichwould be useful for a variety of clinical andresearch applications.

We thank Drs Wim Schulte, Teun Tanja, RobHaaxma, Arie Lameris, and Rolf Saan for theircontributions to this study. We are also grate-ful to Helen de Bruijn, Micheline de Haes,Jeanette Kamman, Hanneke van Meurs, andCaroline Valkenburg for help in data collec-tion. Dan Kiely provided excellent technicalassistance and Jemma Williams expertly pre-pared the manuscript. We thank Dr Richard HMyers for discussing the data with us. Thiswork was supported by The NetherlandsOrganization for Scientific Research (NWO),the Eurodem EC Concerted Action on theEpidemiology of Dementia, PHS grantAG09029. LAF is a fellow of the Alfred PSloan Foundation.1 St George-Hyslop PH, Myers RH, Haines JL, et al. Famil-

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