The transforming growth factor-beta1 (TGF-beta1) is involved in post-ischemic neuronal rescue and in beta-amyloid turn-over. We hypothesized that the risk for dementia and related neuropathologies is modified by the TGF-beta1 functional genetic variants. The association of the TGF-beta1+29T-->C polymorphism with dementia was examined in a sample of 261 cases and 491 controls from the Honolulu-Asia Aging Study, including 282 subjects with autopsy data. Dementia was assessed in 1991 and 1994 by a multi-step protocol and standardized diagnostic criteria. The analysis was adjusted for demographic and vascular factors. Compared to the TT genotype, the TC and the CC genotypes were associated with a reduced risk for vascular dementia (OR(TC)=0.28, 95% confidence interval (CI): 0.1-0.9; OR(CC)=0.28, CI: 0.1-0.9), microinfarcts (OR(CC)=0.31, CI: 0.13-0.71) and cerebral amyloid angiopathy (OR(CC)=0.48, CI: 0.2-0.9). The CC genotype was associated with an increase risk of neocortical plaques (OR(CC)=4.34, CI: 1.6-11.8). These preliminary data suggest that the TGF genetic variability may be important in the risk of vascular related dementia.