Leptin is a peptide hormone secreted by adipocytes. It has been shown to modulate production and clearance of amyloid beta (Abeta) in rodent models. We sought to determine if serum leptin was associated with cognitive decline in the elderly. We studied 2871 well-functioning elders, aged 70-79, who were enrolled in a prospective study. Serum leptin concentrations were measured at baseline and analyzed by mean+/-1S.D. Clinically significantly cognitive decline over 4 years was defined as > or =5-point drop on the Modified Mini Mental State Exam (3MS). Compared to those in the lower leptin groups, elders in the high leptin group had less cognitive decline, 20.5% versus 24.7% (OR=0.79; 95% CI 0.61-1.02, p=0.07). After adjustment for demographic and clinical variables, including body mass index and total percent body fat, those in the high leptin group had significantly less likelihood of cognitive decline, OR=0.66 (95% CI 0.48-0.91). We conclude that in elderly individuals, higher serum leptin appears to protect against cognitive decline, independent of comorbidites and body fat.