Background US studies suggest that the fat-derived hormone, leptin, may be protective against the development of dementia, although reverse causation remains a concern. In short, early pathological changes associated with dementia may lead to weight loss and a reduction in circulating leptin levels, which in turn may predict an increased risk of subsequent cognitive decline. Our objective was to investigate the complex relationship between leptin levels and cognitive decline in elderly Italians.

Methods We studied circulating fasting serum leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. Logistic regression models were used to determine the relationship between serum leptin levels and cognitive decline whilst adjusting for age, sex, baseline cognitive score, years in school, depressive symptoms, smoking, stroke, cardiovascular disease, hypertension, diabetes and length of follow-up. To address possible reverse causation we investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels.

Results The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73–0.97) in relation to baseline sex-standardised log-leptin levels. High leptin levels showed a non-significant trend towards a reduced risk of decline on the Trail-Making Tests A (RR=0.85, 95% CI 0.71–1.02) and B (RR=0.90, 0.79–1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels.

Conclusion High leptin levels were independently associated with a reduced risk of global cognitive decline in elderly Italians and there was no evidence for reverse causation. Further research is necessary to determine leptin’s potential role in preventing or treating Alzheimer’s disease and dementia.