Increasing weight loss between midlife and late life is a marker for mild cognitive impairment, according to a report published online Feb. 1 in JAMA Neurology.

“While weight loss may not be causally related to MCI [mild cognitive impairment], we hypothesize that weight loss may represent a prodromal stage or an early manifestation of MCI,” wrote Dr. Rabe E. Alhurani of the department of neurology, Mayo Clinic, Rochester, Minn. and his associates.

Some recent studies have reported a link between weight loss and dementia, “but overall, the findings of different studies have been inconclusive,” they noted.

To examine any association between weight loss over time and incident MCI, the investigators analyzed information in the population-based Mayo Clinic Study of Aging database, which covered approximately 10,000 residents of Olmsted County, Minn., who were aged 70-89 years at the beginning of the study in 2004. They focused on 1,895 participants who were cognitively normal at entry into the study and whose medical records included data on weight and height from midlife (age 40-65 years) onward. All these study subjects underwent physical examination and extensive neuropsychological evaluation every 15 months for a mean of 4.4 years.

A total of 524 study participants developed MCI during follow-up. The mean weight loss since midlife was significantly greater for people who developed MCI (–2.0 kg) than for those who remained cognitively normal (–1.2 kg). After the data were adjusted to account for patient sex, education level, and apolipoprotein E epsilon-4 allele status, loss of weight after midlife was robustly associated with incident MCI, so that a loss of 5 kg per decade corresponded to a 24% increase in risk of MCI, Dr. Alhurani and his associates reported (JAMA Neurol. 2016 Feb 1. doi: 10.1001/jamaneurol.2015.4756).

These findings remained consistent across all categories of baseline weight, regardless of whether the participants were underweight, normal weight, overweight, or obese at enrollment. The effect sizes of the associations were greater in men than in women but were significant in both sexes.

This study could not establish causality, but the researchers speculated that the association between weight loss and MCI could be due to three possible mechanisms. First, the weight loss could stem from the “anorexia of aging,” meaning that dysfunctional production of certain hormones – such as cholecystokinin, leptin, cytokines, dynorphin, neuropeptide Y, and serotonin – or dysfunctional dietary intakes and energy metabolism could lead patients to eat less, which could in turn raise MCI risk.

Second, “neuropsychiatric symptoms such as depression and apathy, which are prodromal and predictors of MCI and dementia, may contribute to decreased appetite and weight loss prior to the diagnosis of these conditions,” they suggested.

Third, weight loss and MCI could share an etiology. Researchers have reported finding protein deposits, including deposits of Lewy bodies, tau, or amyloid, in the olfactory bulb and central olfactory pathways before the onset of dementia, and olfactory dysfunction is a marker for cognitive impairment and dementia. “Impairment in smell with related changes in taste may contribute to decreased appetite, reduced dietary intake, and the weight loss observed with MCI, Alzheimer dementia, and other neurodegenerative conditions,” Dr. Alhurani and his associates wrote.

This study was supported by the National Institutes of Health, the Mayo Foundation for Medical Education and Research, the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program, the National Center for Advancing Translational Sciences, and the Rochester Epidemiology Project. Potential conflicts of interest reported by individual investigators included research support from the NIH, the Alzheimer Drug Discovery Foundation, and the Lewy Body Association; serving on a data safety monitoring board for Janssen, Lundbeck, Pfizer, and the Dominantly Inherited Alzheimer Network study; serving as an investigator for clinical trials sponsored by TauRX, Lilly, and the Alzheimer’s Disease Cooperative Study; serving as a consultant for Roche, Merck, Genentech, Biogen, and Eli Lilly; and receiving publishing royalties for the textbook, “Mild Cognitive Impairment.”