Familial Alzheimer Disease Among Caribbean Hispanics: A Reexamination of Its Association With APOE

Romas, Stavra N.; Santana, Vincent; Williamson, Jennifer; Ciappa, Alejandra; Lee, Joseph H.; Rondon, Haydee Z.; Estevez, Pedro; Lantigua, Rafael; Medrano, Martin; Torres, Mayobanex; Stern, Yaakov; Tycko, Benjamin; Mayeux, Richard

Objectives: To reexamine the association between the apolipoprotein E ϵ4 allele (APOE ϵ4) and familial Alzheimer disease (AD), and to search for novel genes that may be associated with susceptibility in Caribbean Hispanic families with a history of AD.

Methods: Families were identified in Caribbean Hispanic communities in the greater New York City area, the Dominican Republic, and Puerto Rico. Each family in the study cohort included at least 2 living relatives with a history of dementia. All family members underwent neuropsychological testing and medical and neurological examinations to establish the presence or absence of dementia and to specify the type of dementia.

Results: Over a 2½-year period, 203 families were identified. Of these, 19 families had at least 1 family member with onset of dementia before age 55 years, with 8 of the 19 families showing an association with a previously unreported presenilin mutation. Multiple cases of AD were identified in 29 families. Overall, there were 236 affected sibling pairs with AD available for analysis. The average age at onset was 74 years. The presence of APOE ϵ4 was strongly associated with AD.

Conclusions: Both early-onset and late-onset familial AD occur in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics is strongly associated with APOE ϵ4. Future attempts to identify additional susceptibility genes should consider the effects of APOE ϵ4.

A FAMILY HISTORY of Alzheimer disease (AD) is one of the strongest risk factors for the disease. The lifetime risk of AD for family members of patients approaches 50% in some studies, which suggests an age-dependent autosomal dominant mode of inheritance.1,2 Mutations in genes on chromosomes 1, 14, and 21 are associated with familial early-onset AD, often with an autosomal dominant pattern of inheritance.3,4 However, these genes account for only 10% of all AD. The discovery that a polymorphism in the APOE (apolipoprotein E) gene on chromosome 19 was associated with susceptibility to both sporadic and familial late-onset AD5 led to the search for other potential susceptibility genes. Sites for potential susceptibility genes on chromosome 12 have been identified,6 and, more recently, sites on chromosome 10 have also been identified.7-9 Attempts to confirm the linkage between chromosome 12 and AD have been variable,10-12 and the association with α2-macroglobulin, a candidate gene in the area, has also been inconsistent.13-16 Familial AD may be the result of complex inheritance involving many genes with incomplete penetrance or a combination of genetic and environmental factors.

Hispanics are one of the most rapidly increasing ethnic groups in the United States. The elderly Hispanic population is expected to double in the United States by the year 2010 and increase 11-fold by 2050.17 Compared with other ethnic groups, Caribbean Hispanics have an increased prevalence and incidence of AD,18-20 as do Mexican Americans.21 Yet the reason for this increase in disease frequency is unknown. No specific environmental factors have been identified, which suggests a genetic explanation.

The association between AD and the APOE ϵ4 allelic polymorphism has been weaker in late-onset AD among Caribbean Hispanics compared with whites in New York City20,22,23 but not in Miami, Fla.24,25 We began the family study not only to identify the chromosomal location of additional susceptibility genes in Caribbean Hispanics, but also to reinvestigate the heterogeneity of the APOE association in this population.



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Archives of Neurology

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February 11, 2022