The tumor necrosis factor receptor superfamily, member 6 gene (TNFRSF6) is situated on chromosome 10q, near the region indicated in several AD linkage studies. In a previous study a significant association was found between a promoter variant within the TNFRSF6 gene and Alzheimer disease (AD). To further investigate the TNFRSF6 region, 34 SNPs within 180 kb were first genotyped in an exploratory set of 121 early-onset dementia cases and 152 controls in order to establish the extent of linkage disequilibrium (LD) and the major haplotypes in the region. This analysis showed that the LD was clustered in two large blocks within each of which a limited number of haplotypes represented most of the diversity. Haplotype tagging markers were chosen and genotyped in an additional 204 late onset AD cases and 177 controls. Tests of association were performed for single markers for case/control status and for a quantitative measure of cognitive ability [Mini-Mental State Examination (MMSE) scores] within cases only. The previously associated marker, located in the promoter of TNFRSF6, now gave significant association with cognitive status in the Scottish early-onset dementia samples (p = 0.005) with the strongest signals being evident in the APOE-e4 carrier subgroup, thus providing a second independent positive result for this marker. The same marker was also significantly associated with cognitive performance in the Swedish APOE-e4 carriers (p = 0.014), providing a third independent signal. Association analysis was also performed using the major haplotypes in the region, employing both case/control status and MMSE scores. The haplotype analysis did not give further significant findings. These results together with previous data suggest that a promoter marker in TNFRSF6 plays a moderate but demonstrable role in AD etiology.