DOWN SYNDROME & ALZHEIMER DISEASE--FAMILIAL AGGREGATION

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Alzheimer disease is the most common cause of old-age-associated dementia, affecting as many as 2 million people. This study will investigate the hypothesis that there are shared genetic influences on susceptibility to Down syndrome (DS) and Alzheimer disease (AD) and will examine heterogeneity of risk for AD among relatives of individuals with DS. More than 90% of Down syndrome trisomies are associated with a non- disjunction event in maternal gametes. Therefore, if there are shared susceptibility factor(s) for AD and DS, an increased frequency of AD would be expected in maternal relatives for maternally derived DS cases, compared with their paternal relatives. In addition, the occurrence of a Down syndrome birth to a younger mother may indicate a susceptibility to accelerated aging, expressed not only in the birth of a child with DS but also in a higher risk for AD in her family. We hypothesize that maternal relatives of DS probands born to younger mothers (less than 35 vs 35+ years) will be at higher risk for AD, and that their AD may be expressed at earlier ages of onset. We will determine DS karyotype (trisomy, translocation, mosaicism) and identify parental origin (maternal versus paternal) of the non- disjunction event leading to trisomy in the DS cases, using a combination of cytogenetic and molecular polymorphism studies. We will determine whether the frequency of AD is increased in first- and second- degree relatives of individuals with DS compared with relatives of a matched control group of developmentally disabled people without DS. Ascertainment of dementia among relatives will be accomplished in two stages. Possible cases of AD will be identified by a semi-structured interviewed with 3 relatives of the proband. We will then evaluate the suspected cases of AD and a random sample of all relatives by neurological and neuropsychological examination to obtain a differential diagnosis of dementia and by medical record review or death certificate review. We will use lifetable analysis and logistic regression to compare risk for AD in: 1) relatives of DS cases and relatives of controls; 2) maternal relatives of maternally derived trisomy 21 DS cases and their paternal relatives, and in the corresponding maternal and paternal relatives of controls; 3) relatives of younger and older mothers at birth of individuals with DS. If familial aggregation is established, identification of a predisposing factor by linkage of AD and polymorphic DNA markers in these families would be an important next step.