CHROMOSOME-14 AND LATE-ONSET FAMILIAL ALZHEIMER-DISEASE (FAD)

Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loc i responsible for early-onset FAD have been identified: the amyloid pr ecursor protein gene on chromosome 21 and the as-yet-unidentified locu s on chromosome 14. The genetics of late-onset FAD is unresolved. Maxi mum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset greater-than-or-equ al-to 60 years, to determine whether the chromosome 14 locus is respon sible for late-onset FAD. The markers used were D14S53, D14S43, and D1 4S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-de pendent penetrance, an affected-only analysis, and age-dependent penet rance with allowance for possible age-dependent sporadic cases. No evi dence for linkage was obtained under any of these conditions for the l ate-onset kindreds, and strong evidence against linkage (LOD score les s-than-or-equal-to -2.0) to this region was obtained. Heterogeneity te sts of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linka ge to chromosome 14 with genetic heterogeneity. The positive results a re primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindre ds (P < .02). No evidence for linkage was found for the entire late-on set family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (me an age at onset greater-than-or-equal-to 60 years and <70 years). Thes e results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a ro le in a subset of these kindreds.