High Leptin Levels May Protect Against Dementia

December 15, 2009 — Investigators have uncovered further evidence that leptin may protect against Alzheimer’s disease (AD), opening the door a little wider for a possible future target for therapeutic intervention.

The new study suggests that circulating leptin levels are associated with a reduced incidence of dementia, including AD. Study participants with the highest levels of leptin had a 6% risk of developing AD during 12 years compared with a 25% risk for those with the lowest leptin levels.

Produced in subcutaneous and visceral adipose tissue, leptin appears to promote weight loss by signaling caloric intake and fat stores to the hypothalamus. However, emerging animal research indicates that leptin could have a function outside the hypothalamus — in regions of the hippocampus that facilitate memory processes.

"It’s interesting and exciting because it’s a new pathway that was not previously suspected to be directly involved in AD in humans,” said lead author Sudha Seshadri, MD, associate professor of neurology, Boston University School of Medicine in Massachusetts. "Any new pathway is always of interest because exploring prevention and therapy based on existing pathways has not so far resulted in very effective measures."

To date, AD researchers have concentrated on reducing the deposition and accelerating the removal of beta-amyloid in the brain, as well as investigating the role of tau protein, said Dr. Seshadri.

The study is published in the December 15 issue of the Journal of the American Medical Association.

Inverse Relationship

The study involved 785 participants in the long-term Framingham Heart Study who provided baseline plasma leptin levels between 1990 and 1994 and were followed up for dementia until December 31, 2007. Participants' average age at baseline was 79 years, and 62% of them were female.

A subset of 198 subjects underwent volumetric brain magnetic resonance imaging between 1999 and 2005 while they were free of dementia. This provided investigators with a single measurement of total cerebral brain volume and temporal horn volume, which is inversely related to hippocampal volume. Both measurements are markers of early AD.

During a median follow-up of 8.3 years, 111 participants developed dementia, including 89 with AD. There was a strong inverse relationship between baseline leptin levels and the risk for dementia, which remained significant after adjusting for age, sex, waist to hip ratio, changes to waist to hip ratio, and other vascular and dementia risk factors.

The investigators used waist to hip ratio as the measure of body fat content because it is more strongly correlated with plasma leptin levels and with the risk for AD than body mass index.

The study showed that the incidence of dementia decreased across increasing sex-specific leptin quartiles. A person with a baseline leptin level in the lowest quartile had a 25% risk of developing AD after 12 years of follow-up, whereas the corresponding risk for a person in the top quartile was only 6%.

The study also found that higher leptin levels were associated with larger brain parenchymal and smaller ventricular volumes.

New Pathway

This research adds to the mounting evidence that leptin has functions in the brain beyond those involved in energy expenditure. One previous study found that leptin-deficient mice have a lower brain weight, an immature expression pattern of synaptic and glial proteins, and disrupted projection pathways within the hypothalamus, indicating that leptin is necessary for normal brain development.

Another study demonstrated that leptin increases apolipoprotein E (APOE)–dependent beta-amyloid uptake into cells. Still other research showed that long-term leptin treatment improved memory performance in animal models.

This new body of research seems to indicate that leptin might act along a new pathway relevant to cognitive function. "Leptin is something that clearly has a role in energy metabolism, and it seems to have a beneficial effect on some aspects of the brain," said Dr. Seshadri.

However, it’s not a simple relationship. The association of high leptin levels with a lower incidence of dementia was only significant among patients who were not obese. Obese people may have high levels of leptin, but they may be resistant to it, explained Dr. Seshadri. She likened this to patients with type 2 diabetes who may produce insulin, sometimes high levels of it, but cannot use it properly.

Relationship to Amyloid

Although the relationship between beta-amyloid and leptin remains unclear, Dr. Seshadri said some animal studies suggest that leptin interacts with APOE, which is a chaperone protein that helps clear beta-amyloid. However, she added, more research is needed before any definitive conclusions can be drawn.

The study results could open the door to new therapeutic approaches that boost leptin levels. However, Dr. Seshadri cautions against being overly hasty. “There have been many theories that have not actually been borne out.”

Still, she believes leptin has a valid place in future approaches. “It’s very likely that such a common and complex condition like AD of the elderly is going to have to be addressed through multiple measures, and leptin-related medications may be one of them.”

Potential Biomarker

Leptin could also be added to the list of potential biomarkers that physicians use at a regular checkup, said Dr. Seshadri. "We may be able to measure leptin levels along with other things like APOE and use that to predict risk."

One of the limitations of the study is that it included only older patients of European ancestry. Another is that it did not measure leptin in the cerebrospinal fluid, although the authors point out that the correlation between plasma and cerebrospinal fluid leptin is high. As well, the study did not include measures of physical activity, a potential confounder of the observed association.

The prevalence of dementia is expected to markedly increase during the next several decades.

Asked by Medscape Psychiatry to comment on the findings, John Ringman, MD, associate clinical professor of neurology, Mary Easton Center for Alzheimer Disease Research, University of California at Los Angeles, said the study was "well designed and well executed" and its results provide a "new key clue" about potential treatment targets for AD.

However, he noted that the study is observational and does not provide a cause-and-effect relationship.

"The pathology of Alzheimer disease is going on in the brain for years, even decades, before people get symptoms, so it’s impossible to conclude conclusively from [these] data whether the cause-effect relationship is not the other way around — that the Alzheimer disease is somehow causing decreased levels of leptin."

The authors have disclosed no relevant financial relationships.

JAMA. 2009;302:2565-2572.