Alzheimer Pathology Linked to Lower Body Weight

Allison Shelley

November 23, 2011

November 23, 2011 — Many patients with mild cognitive impairment are underweight, with a body mass index below 25 kg/m², report researchers.

Previous studies have shown that people who are overweight in middle age are more likely to develop Alzheimer's disease than people with a healthy weight. A new study suggests that the relation between Alzheimer risk and body mass index is more complex than that.

In their study published in the November 22 issue of Neurology, investigators showed that in vivo biomarkers of cerebral amyloid and tau are associated with lower body mass index in those with mild cognitive impairment.

"These results suggest that Alzheimer's disease brain changes are associated with systemic metabolic changes in the very earliest phases of the disease," senior investigator Jeffrey Burns, MD, from the University of Kansas School of Medicine in Kansas City, said in a news release.

This might be due to damage in the hypothalamus, which plays a role in regulating energy metabolism and food intake, he noted.

Metabolic Changes

The preclinical and earliest stages of Alzheimer's disease are associated with lower body mass, accelerating sarcopenia, and fat mass reduction, the authors explain. Autopsy evidence shows that neuropathologic changes are associated with low and declining body mass — even in individuals with normal cognition — suggesting that Alzheimer's disease–related neurodegenerative brain changes influence body composition.

Conflicting evidence between body mass and late-life cognitive decline has been puzzling. Being overweight in midlife is associated with an increased risk for cognitive impairment and dementia, but weight problems late in life are associated with reduced cognitive risk — the so-called obesity paradox. Mortality studies suggest that chronic disease associated with obesity drives death risk, whereas the association of low body mass with mortality might be an artifact of preexisting disease.

In this study, Dr. Burns' team analyzed cross-sectional data from 506 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative. They used positron emission tomography with Pittsburgh compound B or cerebrospinal fluid analyses for beta-amyloid peptide and total tau.

They assessed the relation of biomarkers and global Pittsburg compound B uptake with body mass index, using linear regression controlling for age and sex.

In the overall sample, beta-amyloid peptide, tau, tau/beta-amyloid ratio, and global Pittsburgh compound B uptake were associated with body mass index. Patients with the lowest body weight tended to have more of these markers.

Markers of Increased Alzheimer's Disease Burden

Biomarker Beta P Value
Beta-Amyloid Peptide   0.181 .001
Tau –0.179 .001
Tau/Beta-Amyloid Ratio –0.180 .001
Global Pittsburgh Compound B Uptake –0.272 .005

In people with mild cognitive impairment, more patients who had a low body mass index than who were overweight had signs of beta-amyloid plaques (85% vs 48%). This relation was also found in people without cognitive problems. Fewer overweight individuals had biomarker levels signaling pathophysiology (< .01).

"Our data in cognitively healthy participants demonstrate that low body mass index is associated with pathophysiologic markers," the authors note. "Interestingly, the vast majority of our cohort was not at the extremes of body mass index, with less than 17% of the overweight group classified as obese and few participants with a body mass index less than 20. Nevertheless, we observed robust relationships between body mass and the presence and burden of Alzheimer's disease biomarkers."

Future studies should investigate whether this relation reflects a systemic response to an unrecognized disease, Dr. Burns added, "or a long-standing trait that predisposes a person to developing the disease."

The findings also suggest that mild cognitive impairment in those who are overweight might more likely be the result of heterogeneous pathophysiology, not Alzheimer's disease alone.

This study was funded by the University of Kansas Alzheimer Disease Center, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Burns reports serving on the speakers' bureau for Novartis; working as a consultant for Medacorp Consulting, Johnson County Clinical Trials, and PRA International; and receiving research support from Elan Corporation, Janssen, Wyeth, Pfizer, Danone, and the Dana Foundation.

Neurology. 2011;77:1913-1920. Abstract


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