Higher levels of leptin, a hormone that helps maintain normal body weight, is associated with better signal-transmitting brain white matter in middle-aged adults, according to a study by The University of Texas Health Science Center at San Antonio (UT Health San Antonio).

“The findings support the known role of leptin variations in late-life dementia risk by relating its deficiency with changes in white matter structure, which is an early event in the process of cognitive impairment due to Alzheimer’s disease or vascular dementia,” said Claudia Satizabal, PhD, associate professor at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio.

Satizabal is lead author of the study titled, “Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age,” published Aug. 12 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. Other authors also are with the Biggs Institute, as well as Tufts Medical Center in Boston; the Framingham Heart Study; Boston University School of Public Health; University of California-Davis; National and Kapodistrian University of Athens; and Columbia University.

Obesity and Alzheimer’s

Alzheimer’s disease is the leading cause of dementia, impacting the lives of millions of people worldwide, the study notes. Increasing evidence suggests that midlife obesity is an important contributor to the risk of developing the disease.

This has led to a growing interest in untangling the mechanisms linking obesity to Alzheimer’s, which potentially extend through vascular, genetic and metabolic pathways. And the study of adipose or fatty tissue has led to significant insights.

Once viewed as a passive reservoir for energy storage, adipose tissue now is considered a part of the endocrine system, secreting a group of bioactive peptides known as adipokines, or cell-signaling molecules that play functional roles in the energy or metabolic status of the body, inflammation and obesity.

Leptin is an adipokine responsible for central control of food intake and energy homeostasis, and has been implicated in a variety of neurophysiological functions, including brain development, neurogenesis and neuroprotection.

Because of these effects, it has been considered a plausible mechanism in the pathway leading from obesity to Alzheimer’s disease. It is supported by findings tying higher leptin levels to lower risk for incident Alzheimer’s disease and mild cognitive impairment, as well as better structural brain indicators in older adults, the study notes.

Still, studies conducted in younger individuals have not detected associations between leptin and early indicators of brain damage preceding late-life dementia risk. Researchers in the new study at UT Health San Antonio aimed to gain further insights into the potential relationships of leptin with neurodegenerative and cerebrovascular burden.

Specifically, they investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults.

They conducted neuropsychological evaluations of 2,262 cognitively healthy participants from the Framingham Heart Study, a long-term cardiovascular cohort study of residents from Framingham, Massachusetts, spanning three generations and now a project of the National Heart, Lung and Blood Institute, in collaboration with Boston University.

The scientists measured concentrations of leptin, its soluble leptin receptor and their ratio, known as the free leptin index, indicating leptin bioavailability, using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols.

The results found a higher association of the soluble leptin receptor with lower fractional anisotropy, a biomarker of brain white-matter integrity, and peak-width skeletonized mean diffusivity, an imaging marker for white-matter injury. Correspondingly, a higher free leptin index was associated with higher fractional anisotropy.

These results were replicated in a study that included 89 cognitively healthy Hispanic participants from San Antonio, by MarkVCID, a consortium of U.S. academic medical centers whose mission is to identify and validate biomarkers for the small vessel diseases of the brain that produce vascular contributions to cognitive impairment and dementia (VCID).

Taken together, the researchers concluded that higher leptin bioavailability was associated with better white-matter integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk.