Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer's disease

Abstract

The aim of the study was to identify chromosomal regions that may harbor putative genetic variants influencing age at onset in familial late-onset Alzheimer's disease (LOAD). Data from a genome-wide scan that included genotyping of APOE were analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age at onset of 73.3 years multiply affected by LOAD. Two-point and multipoint analyses were conducted using variance component methods using 376 microsatellite markers with an average intermarker distance of 9.3 cM. Family-based test of association was also conducted for the same set of markers. Age at onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-epsilon4 lowered the age at onset by 3 years. Several candidate loci were identified. Using linkage analysis strategy, the highest logarithm of odds (LOD) scores were obtained using a conservative definition of LOAD at 5q15 (LOD = 3.1), 17q25.1 (LOD = 2.94), 14q32.12 (LOD = 2.36), and 7q36.3 (LOD = 2.29) in a model that adjusted for APOE-epsilon4 and other covariates. Both linkage and family-based association identified 17p13 as a candidate region. Family-based association analysis showed markers at 12q13 (p = 0.00002), 13q33 (p = 0.00043), and 14q23 (p = 0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age at onset of late onset Alzheimer's disease. The novel loci at 5q15, 17q25.1, 13q33, and 17p13 and the previously reported loci at 7q36.3, 12q13, 14q23, and 14q32 need further investigation.

Figure 1

a–c. Illustrative multipoint variance component linkage analysis for chromosomes 5, 7, and 17. For Model 2 (using affected members) under two different definitions of affection, the results are presented for the multipoint linkage analysis with and without APOE adjustment.