The association between polymorphisms in the alpha-2-macroglobulin (a2m) gene and Alzheimer's disease remains in doubt because of conflicting results in independent case-control and family studies. We examined the association between Alzheimer's disease and alpha2m polymorphisms in Caribbean Hispanic families. The odds of having the alpha2m deletion/insertion polymorphism was increased 3-fold for family members with Alzheimer's disease compared to healthy family members, rising to 5-fold after adjusting for APOE-epsilon4. In contrast, there was no relationship between the alpha2m Val1000Ile polymorphism and Alzheimer's disease in these families. The inconsistencies in studies cited above and the modest association between alpha2m and Alzheimer's disease found in the Caribbean Hispanic families reported here, suggest that the overall effect of this gene on susceptibility is small and may be limited to certain populations or families.