So Far, Our Indianapolis-Ibadan Study Has Demonstrated That

SPECIFIC AIMS So far, our Indianapolis-Ibadan study has demonstrated that: 1. Incidence rates for Alzheimer disease (AD) and dementia are lower in the Yoruba than in the African-Americans. 2. Possession of the ε4 allele of ApoE is a marginally significant risk factor for dementia and AD in the African Americans. The association of ε4 to AD is weaker in Yoruba than in the African Americans and does not reach statistical significance. The ε2 allele of ApoE appears to be protective in the African Americans but not in the Yoruba. 3. A constellation of factors often associated with vascular risk including a history of hypertension, diabetes, and high cholesterol levels is less common in the Yoruba than in the African- Americans. 4. There is an interaction between cholesterol, ApoE genotype and AD in the African Americans. In our renewal grant, we are proposing to more intensively study risk factors which may explain the differences in incidence rates. As these risk factors are likely to be multiple and complex, involving genetic, environmental as well as genetic and environmental interactive influences, larger cohorts than those we currently possess will be required to test our hypotheses. Beginning in the year 2001, we will have approximately 800 survivors in Indianapolis and 800 in Ibadan from our original cohort sizes of 2,212 (Indianapolis) and 2,487 (Ibadan). We propose to enrich our sample by recruiting 2,000 African- Americans, age 70 years and over, from the Medicare rolls in Indianapolis and 2,000 Yoruba, age 70 years and over, from a district in Ibadan for a total of 2,800 subjects in Indianapolis and 2,800 subjects in Ibadan. We propose to measure ApoE genotypes and ApoE promoter haplotyes on all subjects in both cohorts. We also propose to measure a number of biochemical values known to be associated with cardiovascular risk in all subjects. In addition, through collaboration with the Indiana University Hypertension Center we will continue to measure the variants of the angiotensinogen gene (AGT) and the angiotensin I-converting enzyme (ACE) gene. We will continue to collect our current clinical, neuropsychological and socio-demographic data on the new cohorts. With this new data we propose to test the following hypotheses. Primary Aims: 1. Possession of the ε4 allele of ApoE is a stronger risk factor for AD in African Americans than in the Yoruba. The ε2 allele is protective for AD in the African Americans but not in the Yoruba. 2. Vascular risk factors increase the risk of dementia, AD and cognitive decline within each population site. The lower prevalence of these factors accounts for some of the differences in rates of AD and dementia between sites. 3. The interaction between ApoE genotypes and vascular risk factors alters the strength of the association between the ε4 and ε2 alleles and AD and accounts for some of the variation in AD rates between the populations. Secondary Aims. We propose: 1. To continue to develop measurements of social engagement and activity levels which can be applied validly across sites. We predict that increased levels of social engagement and physical activity will be protective for incident AD and dementia, and cognitive decline at both sites. 2. To continue to evaluate natural history of cognitive and social functioning in two community- dwelling cohorts and to identify factors which may predict decline in cognitive and social functioning. 3. To determine if ApoE promoter haplotype is a risk factor for AD and correlate this risk with promoter transcriptional activity. 4. To store blood, plasma and DNA samples for future genetic and biological studies. BACKGROUND AND SIGNIFICANCE AD is likely to be caused by a combination of aging, genetic and environmental factors. The search for risk factors would be greatly expedited if populations could be identified with significantly lower or significantly higher rates of disease. However, the evidence that such populations exist is scanty. There have been many studies conducted on the prevalence of dementia and AD throughout the world although very few have been conducted in non-industrialized countries. These studies have reported widely different prevalence rates but these variations have generally been considered to be due to methodological issues.1 One persistent finding has been the reported variation in dementia subtypes in Japan where vascular dementias predominate. There are currently three comparative international studies, including ours, that use similar methodology at each site and include developing countries or migrant populations. Investigators of the Indo-U.S. Cross National Study have reported overall prevalence rates of 1.36% for dementia and 0.62% for AD for an rural Indian population.2 These rates are much lower than those reported for the U.S. residents and similar to but even lower than the rates we report from Ibadan. Investigators of the Ni-Hon-Sea Study have reported rates of dementia and AD in Washington and Hawaii similar to those of most U.S. and European studies and different from previous reports from Japan where vascular dementias predominate.3,4 However, the recently published prevalence rates of dementia and AD from Hiroshima are similar to the findings from Washington state and Hawaii. We have previously reported prevalence rates of dementia and AD significantly lower in the Yoruba than those of the African Americans.5 Prevalence rates, however, are dependent on other factors such as differences in life expectancy or in survival of demented and non-demented subjects between sites. We are now reporting significantly lower four-year incidence rates of both dementia and AD in the Yoruba as compared to African Americans residing in Indianapolis. To our knowledge, this is the first report of incidence rates differing between populations in industrialized and non-industrialized countries or in migrant populations. Now that we have established incidence rate differences between the populations, the next task is to provide a rationale to explain these differences. The recent advances in molecular genetics have transformed our understanding of the etiology of AD. Three types of familial autosomal dominant AD are associated with gene mutations on chromosomes 21,14 and I. These findings are extremely important for the development and the understanding of the pathophysiological mechanisms of AD but account for only a very small proportion of all AD cases. There is evidence that a gene located on chromosome 12 may also be implicated in AD.6 Apolipoprotein ε (ApoE) is a serum lipoprotein known to play an integral role in cholesterol transport and to direct the mobilization and redistribution of cholesterol during membrane remodeling. Its three common isoforms are encoded by alleles 2, 3, and 4 on chromosome 19. The ε4 allele has now been identified as an important risk factor for the most common forms of late onset AD in a dose-dependent fashion; i.e., individuals possessing two copies of the allele have a greater risk for AD (up to 8 fold and more) than individuals with a single copy (2 to 4 fold) as compared to ε3 homozygotes. Case control studies have suggested that the ApoE ε4 association may account for 30 – 40% of all cases.7 Population-based studies, although still highly significant, have suggested lower estimates of the proportion of cases of AD accounted for by this association (10 – 20%). The association between ApoE ε4 and AD is one of the most consistent findings in AD research being confirmed in many studies throughout the world. One of the intriguing features of the studies conducted so far is the marked variations in frequency of the ApoE ε4 allele found in different populations and ethnic groups. It is not clear yet what effect these population frequency variations have on the rates of AD in these populations. In our Indianapolis-Ibadan study, the frequencies of the ApoE allele were almost identical in the two populations. In contrast to the previous studies of Caucasian and other population groups, we have found only a marginally significant association between the ε4 allele, dementia and AD in the African American population. This is consistent with the results from the multi-ethnic comparative studies being conducted in New York. In the Yoruba we have found no significant association between the ε4 allele and AD for either the heterozygous or homozygous states (see progress report). A few studies have suggested that the ApoE ε2 allele may confer a protective effect but this has not been observed in all studies. We find that the possession of the ε2 allele appears to be protective for AD in the African Americans but not in the Yoruba. In addition to the allele-specific expression of ApoE on AD, there is recent evidence that polymorphisms in the regulatory region of ApoE are associated with the risk of developing AD.8 We are currently exploring this possibility (see progress report). A major aim of our proposal is to confirm the ApoE genotype - AD association differences between sites and to explore additional genetic and environmental factors which may explain these findings. Possible ApoE-Environmental Interactions. The difference in cholesterol levels between the Yoruba and the African American made us consider an ApoE cholesterol interaction. The evidence for this is somewhat conflicting. Two prior studies from Finland and from the U.S. had reported a significant interaction between ApoE and cholesterol.9,10 The Finnish authors suggest that cholesterol in fact mediated some of the effects of ApoE ε4 on AD. Other studies, however, have not found any ApoE- cholesterol interactions. In a preliminary study, we also found a significant interaction between total serum cholesterol, ApoE genotype and AD risk in the African American population. Increased total serum cholesterol was associated with increased AD risk in subjects with no ε4 alleles.

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