By Makoto Ishii, MD, PhD

Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College

Dr. Ishii reports he is a stockholder in Regeneron.

SYNOPSIS: In a population-based, prospective study of subjects ≥ 70 years of age, increasing weight loss per decade from midlife to late-life was associated with an increased risk of incident mild cognitive impairment.

SOURCE: Alhurani RE, Vassilaki M, Aakre JA, et al. Decline in weight and incident mild cognitive impairment: Mayo Clinic Study of Aging. JAMA Neurol 2016;73:439-446.

Alzheimer’s disease (AD) currently remains an incurable disease. Identifying patients with increased risk or with the earliest clinical manifestations of AD could present a significant effect on finding new strategies for the prevention and treatment of AD. Mild cognitive impairment (MCI) is an early prodromal stage of dementia, where every year approximately 5-15% of patients suffering from MCI will progress to dementia. Previously, weight loss has been reported to increase dementia risk and precedes the cognitive decline, but it remains unclear if greater weight loss from midlife to late-life is a prodromal manifestation of dementia that is associated with incident MCI.

Alhurani et al investigated whether greater weight loss was associated with incident MCI using participants from the Mayo Clinic Study of Aging, an ongoing, prospective, population-based study initiated on Oct. 1, 2004. Eligible subjects, who were 70-89 years of age at study initiation and without dementia or in hospice care, were recruited randomly and underwent follow-up evaluations every 15 months. Inclusion criteria included normal cognition at baseline evaluation, at least one follow-up evaluation, and data available on maximum weight and height in midlife. All participants were administered the Clinical Dementia Rating Scale and the Functional Activities Questionnaire, and underwent extensive neuropsychological and neurological evaluation. A diagnosis of MCI, dementia, or normal cognition was made by consensus. Body mass index (BMI) was computed from the measured height and weight at each evaluation, and the maximum weight and height in midlife were determined from the medical records of each participant. At the baseline visit, researchers obtained all demographic variables, medical history, smoking and alcohol use, and apolipoprotein E4 (APOE4) carrier status by genotyping.

Of the 1,895 cognitively normal participants at baseline (50.3% men; mean age, 78.5 years), 524 (27.7%) participants developed incident MCI over a mean follow-up of 4.4 (standard deviation, 2.4) years. Participants who developed MCI were older, more likely to be APOE4 carriers, and more likely to present with diabetes, hypertension, or coronary artery disease compared with those participants who remained cognitively normal. Furthermore, the mean weight change was greater for those who developed incident MCI than those who remained cognitively normal (-2.0 [5.1] vs. 1.2 [4.9] kg; P = 0.006). Men who developed incident MCI had greater mean loss of weight per decade than men who did not (-2.1 [5.3] vs. -1.0 [4.6]; P = 0.02), but there was no significant difference in women (-1.9 [4.8] vs. -1.5 [5.3]; P = 0.12).

After adjusting for sex, education, and APOE4 carrier status, a greater decline in weight from midlife was associated with an increased risk of incident MCI (hazard ratio [HR], 1.04; 95% confidence interval, 1.02-1.06; P < 0.001). A weight loss of 5 kg/decade corresponded to a 24% increased MCI risk (HR, 1.24). Additionally, adjusting simultaneously for potential confounding factors such as alcohol problems, depressive symptoms, statin use, diabetes, hypertension, coronary heart disease, cigarette smoking, and stroke, still resulted in the same association between weight change and MCI. The effect sizes were greater in men than in women, but they were significant in both sexes. Interestingly, the authors observed a consistent association between weight loss and MCI, regardless of whether the participants were underweight, normal weight, overweight, or obese at midlife.

COMMENTARY

This study is consistent with other prospective studies that found a correlation between weight loss and increased dementia risk. Importantly, the authors hypothesized that weight loss may represent a prodromal or early manifestation of MCI, and, therefore, weight loss should occur regardless of midlife weight. Overall, the findings were consistent with this hypothesis and provide further evidence that weight loss is an early clinical manifestation of AD.

The strength of this paper is that it is a well-designed prospective population study with a relatively large cohort that had the ability to assess body weights from medical records of the participants for midlife and from direct measurements in late-life. Therefore, this study avoided confounding factors that may exist in other studies, such as lack of clarity on age at assessment of weight, BMI, and onset of dementia. A limitation of this study is that the diagnosis of MCI or dementia was based on a clinical diagnosis rather than on established pathological markers, leaving the possibility for misclassification. Another limitation is that it was not possible to determine whether the weight loss was intentional or unintentional, although the consistent association of weight loss with incident MCI across all midlife weight classes suggests that it is likely unintentional.

Finally, this study could not address the causal mechanism of the weight loss in prodromal stages of dementia. Clinicians speculate that dysfunction in factors that regulate body weight, such as leptin and other hormones, could contribute. Alternatively, amyloid and/or tau deposition in brain regions that control appetite and/or systemic metabolism, such as the hypothalamus or olfactory bulb, could play a role in weight loss. Future investigations using molecular approaches in mouse models and well-designed human studies are likely to help elucidate the mechanisms underlying weight loss in AD, which may eventually lead to the development of new diagnostic and therapeutic approaches against AD.