Researchers find high leptin levels may protect against Alzheimer's disease and dementia

Dementia is increasingly recognized as a life-course illness where a variety of lifestyle choices interact with genetic, vascular and other risk factors to affect risk of disease. Given the rapid aging of developed and developing societies, it is projected that the prevalence of dementia will dramatically increase during the next five decades. Therefore, it is a public health priority to explore pathophysiological pathways underlying the development of dementia and its most common cause, AD.

According to the BUSM researchers, a growing body of evidence suggests that leptin has beneficial effects on brain development and function. It appears to mediate structure and functional changes in the hippocampus and to improve memory function. Leptin also has been shown to increase apolipoprotein E-dependent B amyloid uptake into the cell and reduce brain extracellular concentrations of B-amyloid, the major component of the neuritic plaques that are a histopathological hallmark of AD.

Using participants from the original cohort of the Framingham Heart Study, the researchers measured leptin concentrations in 785 persons without dementia. A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin levels were measured. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. The researchers found that elevated leptin levels was associated with higher total cerebral brain volume and lower temporal horn volume and higher leptin levels were prospectively associated with a lower incidence of AD and dementia.

"Over a 12-year follow-up, this corresponds to an absolute AD risk of 25 percent for persons with the lowest levels of leptin compared to a six percent risk for persons with the highest levels," said senior author Sudha Seshadri, MD, an associate professor of neurology at BUSM and an investigator at The Framingham Heart Study.

"If our findings are confirmed by others, leptin levels in older adults may serve as one of several possible biomarkers for healthy brain aging and, more importantly, may open new pathways for possible preventive and therapeutic intervention," she added.

The BUSM researchers believe further exploration of the molecular and cellular basis for the observed association may expand their understanding of the pathophysiology underlying brain aging and the development of AD.

Funding for this study was provided by the National Heart, Lung and Blood Institute, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.

Dr. Seshadri and the Neurology study group would like to thank the Framingham Heart Study participants and staff whose extraordinary commitment and dedication makes such scientific insights possible.