For a number of years there has been evidence that leptin, a hormone involved in the regulation of appetite and fat metabolism in the body, might play a role in preventing Alzheimer's Disease. The strongest evidence has come from animal research. Laboratory rats genetically deficient in leptin have problems with memory and learning. A critical step in learning, called long term potentiation, is disturbed in these animals. Leptin has been found to reduce accumulation of amyloid plaque and abnormal forms of the protein tau in brains of mice genetically altered to develop Alzheimer's-like damage. Amyloid plaque and tangles of tau are hallmarks of Alzheimer's Disease in the human brain. Leptin also helps maintain neurons in rat brain by directing them away from a process called apoptosis, or what some scientists refer to as programmed cellular suicide.
It has been known that people who have Alzheimer's Disease tend to have low levels of leptin in their blood. There have also been findings that the amount of grey matter, where neurons reside, varies directly with levels of leptin in the blood. However, the significance of these finding in human subjects has been unclear. Now, in the December 16th issue of the Journal of the American Medical Association, there is a study more strongly suggesting that low levels of leptin may contribute to the pathology of Alzheimer's. It was found that normal individuals who have low levels of leptin in their blood are more likely than others to later develop the disease. These results suggest that a way to prevent Alzheimer's would be to administer leptin to increase levels of the hormone in the blood. Unfortunately, it may not be so simple.
Leptin was discovered in 1994 after scientists pursued the question of why a certain strain of mouse was prone to becoming extremely obese. It turned out that this mouse lacked a gene required to make a specific protein. When this protein was administered to the mice deficient in that gene, their voracious appetite for food decreased. They lost weight and returned to normal size. The protein was thus called leptin, which is derived from the Greek word for thin.
At first there was excitement in the medical community over the possibility that leptin might be the long awaited "thin" hormone that would be a powerful and natural treatment for obesity. Doctors assumed that, as in the mice, some obese humans might lack the ability to produce adequate amounts of the hormone. It was hoped that by administering leptin to those obese patients, they would regain a normal appetite and drop to a normal, healthy weight. Unfortunately, injecting leptin into their blood did not curb their appetites. Moreover, much to the surprise of researchers, it was found that the vast majority of obese humans were not deficient in leptin. Rather, these individuals often had abnormally high levels of leptin in their blood.
Leptin is produced primarily in visceral fat cells, and it was learned that the amount of fat stored within an individual fat cell determined how much leptin that cell produces and excretes into the blood. The reason obese people have so much leptin in the blood is that they have so much fat stored away in their fat cells. Since leptin cut appetite and weight in mice, and obese people had high levels of leptin, focus shifted toward the question of how the body could lose its ability to respond to leptin's command to stop eating. This loss of response to leptin is referred to as leptin resistance. It seems likely that if leptin acts to reduce the risk of developing Alzheimer's, then such risk might be increased either by an actual lack of leptin or merely by a reduction of leptin's effect due to leptin resistance.
The physiological mechanisms by which the brain becomes resistant to leptin
are not entirely known. Too much leptin, as may be seen in the obese, may itself cause the brain to stop responding to the substance. This is a common physiological phenomenon called tachphylaxis. Too much fructose in the diet can disturb the activity of leptin in tissue. High levels of insulin, which are seen in the pre-diabetic condition known as Metabolic Syndrome, interfere with the effectiveness of leptin in the brain.
There is also evidence that certain factors may prevent leptin from getting into the brain in sufficient amount. In obese people, the amount of leptin in the brain is low in comparison with levels in the blood. It has been learned that high levels of fat, particularly saturated fat, in the blood make it difficult for leptin to be transported into the brain The substance C-reactive protein, a recently recognized risk factor for heart disease, is known to bind to leptin and prevent its transport into the brain. C-reactive protein also tends to be elevated in Metabolic Syndrome and other conditions marked by inflammatory processes.
Because of the phenomenon of leptin resistance, it may not always be possible to benefit from administration of extra leptin. Might it be possible to synthesize a drug that mimics the beneficial effects of leptin on the brain and body, but bypasses leptin resistance? Perhaps, but I am not optimistic. Medication is never an adequate substitute for natural substances and processes in the body. It is wiser to pursue conditions which optimize the activity of natural leptin in the brain. The activity of leptin can be optimized by maintaining ideal weight. It can also be enhanced by replacing saturated fat with unsaturated fat. Reducing saturated fat not only increases the transport of leptin into the brain, it also slightly increases levels of leptin in the blood, which in itself has been suggested to decrease the risk of Alzheimer's. Leptin activity can further be maintained by avoiding Metabolic Syndrome and the high fasting insulin levels and increased blood levels of fat as triglycerides that it brings.
The approach to optimizing leptin activity to decrease the risk of Alzheimer's should be built on healthy lifestyle choices. This in turn should be based on a proper diet, particularly the so-called Mediterranean diet that is low in saturated fat, low in high glycemic index carbohydrates, and high in good fats such as olive oil and fish oils. Add exercise, stress reduction, adequate sleep; and a healthy outlook on life. Reliance on high technology and appeals to the miraculous are unnecessary.