1994 Continuing Review SPECIFIC AIMS Our recently completed prevalence study of dementia and Alzheimer's Disease (AD) in Indianapolis and Ibadan revealed in initial data analysis a significantly lower prevalence of both dementia and AD in the Yoruba speaking community sample, age 65 years and older in Ibadan as compared to the African American combined community and nursing home sample age 65 years and older in Indianapolis. (Ibadan age adjusted prevalence for dementia 1.76%, for AD 1.11%, Indianapolis age adjusted prevalence for dementia 5.74% community only, 9.06% combined sample for AD, 3.04% community only, 5.68% combined sample). The purpose of this study is to explore possible explanations for this finding by conducting longitudinal follow- up studies of individuals diagnosed cognitively impaired and demented and by conducting a second incidence study in year three. The two communities of related ethnic origin, with different environments and cultures offer a unique opportunity for these studies. The specific aims of the proposal are: Primary 1.To conduct a second incidence study of dementia, AD and cognitive impairment in the two samples, three years after the first incidence study. Hypothesis: There will be a lower incidence of both AD and dementia and of cognitive impairment in Ibadan as compared to Indianapolis. 2.To conduct an annual follow-up study for five years of individuals identified as demented or as cognitively impaired during the initial prevalence and incidence studies. Hypothesis: There will be a slower progression of the dementing symptoms both functional impairment and cognitive decline in the Ibadan subjects as compared to the subjects in Indianapolis. A smaller proportion of cognitively impaired individuals will develop dementia in Ibadan than in Indianapolis. 3. To follow all subjects to determine age specific mortality rates in the two samples. Hypothesis: Age specific mortality rates will be higher in Ibadan than in Indianapolis in individuals with the diagnosis of cognitive impairment and dementia as compared to the mortality rates for the non- cognitively impaired group. 4. To collect blood and type for ApoE alleles in all subjects in both samples. Hypothesis:a) The presence of the ApoE-ε4 allele will be more strongly associated with AD and with cognitive impairment in Indianapolis than in Ibadan. b) There will be statistically significant interaction between ApoE genotyping and some risk factors such as smoking in the two sites. 5. To continue brain autopsy studies in both sites. Hypothesis: Plaques, tangles and other histopathological hallmarks of AD will occur in lower frequency and severity in the clinically diagnosed demented patients in Nigeria than in the African American patients. 6. To complete the data analysis of the current prevalence and incidence study of dementia. Hypothesis:a) The incidence of both dementia and cognitive impairment will be lower in Indianapolis than in Ibadan. b) Risk factors for dementia and cognitive impairment will be identified that are site specific as well as occurring in both sites. Developmental Aims: 1. To continue to collect data on other putative risk factors. 2.To collect blood samples from the subjects in both sites which will be available to allow other genotyping or other biochemical measurements such as lipid measurements to occur as hypotheses are generated. 3.To construct an algorithm from our screening instrument which will be able to identify with a high degree of accuracy both dementia and AD in the two populations. 4.To refine the criteria for cognitive impairment based upon predicted value in determining outcome. 5.To assess the effects of education, occupation life time learning and social interaction on dementia in the two sites. Data analyses is not quite complete in Ibadan with approximately 60 clinical assessments not having full consensus diagnosis. The final analysis will be available prior to review. Our results will be shared for 1994 Continuing Review multi-site comparisons with the members of the WHO age associated dementia study (Dr. Amaducci, P.I.) and with Drs. Levy and Richards who are conducting a study of Jamaican subjects living in London (See accompanying letters). BACKGROUND AND SIGNIFICANCE Alzheimer's Disease is likely to be caused by a combination of aging, genetic and environmental factors. The search for risk factors for AD would be greatly expedited if populations could be identified with significantly lower or significantly higher rates of the disease. However the evidence that such populations exist so far has been scanty. While different rates of dementia and AD have been reported in different countries for example Japanese studies generally report lower prevalence rates of AD than North America and European studies, few studies have used identical methodologies, although the Ni-Hon-Sea study is now applying standardized protocols to Japanese samples (Graves and Kukull, 1994). There also remains the still not well explained differences in the prevalence of dementia, between New York and London in a study which used identical methods and criteria in both sites (Gurland et al, 1983). There are only a few studies comparing rates of dementia in African Americans to whites in the United States with two reports suggesting that in biracial community populations the prevalence of dementia is higher among blacks than among whites (Schoenberg et al, 1985; Heyman et al, 1991). We have now demonstrated significant differences in prevalence rates of both dementia and AD between the African American sample of Indianapolis and the Yoruba speaking sample of Ibadan, Nigeria. (See progress report). As genetic and environmental factors are not likely to be acting independently this finding affords us the opportunity to study the interaction of genetic and environmental factors in two populations originating from the similar geographic area and now living in two very different environments, although we recognize that intermarriage has occurred between African Americans and other American groups. The evidence that AD is at least in part genetically based has increased dramatically over the past two years. Previously familial forms of early onset AD had been linked to two loci on chromosome 21 (St. George Hyslop et al, 1987) and on chromosome 14 (Schellenberg et al, 1992, 1993). These subtypes however accounted for only a very small proportion of the overall individuals with AD. More recently considerable evidence has accumulated that the ε4 allele of ApoE gene on chromosome 19 constitutes a major susceptibility factor for the development of the familial and sporadic forms of late onset AD (Saunders et al, 1993). The risk for AD is higher and the age of onset lower for ε4 heterozygotes and especially for ε4 homozygotes (Corder et al, 1993). We have now extended this association to African Americans where earlier studies using smaller samples had failed to show an association. (See progress report). The finding of the association between ε4 allele and the risk for AD has been described by the Alzheimer's Association National Public Policy Forum as "the most exciting research breakthrough since Congress expanded its commitment to Alzheimers research." As pointed out by several senior investigators the results demonstrate more than ever the need for investigations that are community based, longitudinal in design and involve more than one ethnic group in order to understand the true risk susceptibility for and biological significance of the ApoE-ε4 allele in the etiology of AD. It should also be pointed out that in our study as in the other studies a large percentage of individuals with AD (in our study 44%) did not possess the ε4 allele and some individuals with the ε4 allele (in our study 22%) did not develop AD suggesting that other risk factors are also likely to be involved in the pathogenesis of the disease. The frequency of the ApoE-ε4 allele is reported to be high (30%) in Nigerians (Sephernia et al, 1989) yet the presence of AD appears to be low (Osuntokun et al, 1994). It should be noted that ApoE-ε4 allele predispose also to atherosclerosis which again occurs as of now in relatively low frequency in Nigeria suggesting the presence of an environmental/genetic interaction also in this disease (Ogunnowo et al, 1989). Apart from family history and age, little is known with any certainty about other risk factors for AD although associations with the disease have been reported for severe head trauma, depression, hypothyroidism and a history of Down syndrome or Parkinson's disease (Breteler et al, 1992). The relationship between education and occupation with AD has been controversial. Several cross sectional studies have found an association between AD and limited educational attainment (Zhang et al, 1990, Fratiglione et al, 1985). It has been suggested that advanced educational attainment may supply a brain 1994 Continuing Review reserve either through an acquired set of skills or repertoire or as a result of increased synaptic density in the neocortex on the basis of stimulation which delays the onset of the symptoms for four to five years (Katzman, 1993; Friedland, 1993). This hypothesis has been supported by the finding of an inverse relationship between education and parieto-temporal perfusion deficits in cerebral blood flow studies on AD subjects (Stern et al, 1992). Other prevalence studies do not support this association however (Knoefel et al, 1991). It is interesting to note that the two most recent incidence studies