Observational studies that have examined the association of plasma lipid levels with cognitive function,6,17,28,30,56 animal studies,57,58 and studies relating plasma lipid-lowering treatment to cognitive functioning6,11,30,59,60 have also been conflicting. We previously reported associations between high levels of LDL-C and decreased levels of HDL-C and vascular dementia,32 and low levels of total cholesterol and risk of AD,32 but no association of HDL-C, triglyceride, or LDL-C levels with AD,32 amnestic or nonamnestic MCI,33 or cognitive test performance over time.34 In the present study, higher levels of HDL-C were associated with a decreased risk of AD. This association was characterized by a threshold effect with a clear reduction in disease risk in persons in the highest HDL-C level quartile (>56 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) even after adjusting for vascular risk factors and lipid-lowering treatment. As mentioned earlier, in a previous study among 1168 participants who were recruited from the same community between 1992 and 1994, we observed no association between HDL-C level and AD.32 The current report is the first to report prospective analyses from the cohort recruited in 1999 through 2001. The analyses by Moroney et al22 and Reitz et al,32 which focused on dementia, the same outcome we focus on in the current article, both reported a modest inverse relationship between HDL-C level and AD risk in the 1992-1994 cohort, although not statistically significant. The 7-year difference between the 1992-1994 cohort and the 1999-2001 cohort is important because period effects were likely to influence the latter cohort. One significant period effect is the widespread use of lipid-lowering medications in the 1990s following the reporting of the landmark Scandinavian Simvastatin Survival Study (4S) in 1994.35 This study sparked the widespread use of HMG-COA inhibitors. The introduction of HMG-COA inhibitors and other therapies is known to have influenced trends in cardiovascular morbidity and mortality in developed countries.61 We do not have data to directly address how secular trends in the 1990s affected differences between the 1992-1994 and 1999-2001 cohorts. However, it seems reasonable to speculate that persons in their 60s who survived to 1992 were different compared with the same demographic group in the 1990s. Compared with the 1992-1994 cohort,33 the 1999-2001 cohort had a similar mean age (75.5 vs 75.9 years), higher mean years of education (10.9 vs 8.8), a lower proportion of Hispanic (34.1% vs 45.1%) and black (30.6% vs 32.9%) individuals, a higher proportion of non-Hispanic white individuals (33.5% vs 21.5%), higher mean HDL-C level (48.3 mg/dL vs 47.2 mg/dL), lower prevalence of current smoking (9.4% vs 10.6%) and heart disease (18.8% vs 34.1%), and a higher proportion of persons treated with lipid-lowering treatment (23.4% vs 14.5%). With the exception of the ethnic differences, the differences in characteristics are in line with the secular trends in better cardiovascular health and use of lipid-lowering treatment mentioned previously. We believe that that this is why the inverse relation of HDL-C level with AD risk was not statistically significant in the 1992-1994 cohort and is significant in the 1999-2001 cohort.