Context  The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD).

Objective  To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors.

Design, Setting, and Participants  Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed.

Main Outcome Measure  Incidence of dementia and AD during follow-up until December 31, 2007.

Results  During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance.

Conclusion  Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

Author Affiliations: Framingham Heart Study, Framingham, Massachusetts (Drs Lieb, Beiser, Vasan, Wolf, and Seshadri); Department of Biostatistics, School of Public Health (Dr Besier), Departments of Neurology (Drs Beiser, Au, Auerbach, Wolf, and Seshadri) and Preventive Medicine and Epidemiology (Dr Vasan), School of Medicine, Boston University, Boston, Massachusetts; Boston VA Healthcare System and Division of Aging, Brigham and Women's Hospital, Boston, Masschusetts (Dr Tan); Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland (Dr Harris); Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts (Dr Roubenoff); and Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento (Dr DeCarli).