Changes in Metabolism Tied to Risk of Subsequent Dementia

Pauline Anderson

July 28, 2021

Researchers have identified clusters of blood-based metabolites, molecules produced by cells during metabolism, which appear to predict subsequent dementia risk in new findings that may provide a prevention target.

Investigators found one of the clusters includes small high-density lipoprotein (HDL) metabolites associated with vascular dementia, while another cluster involves ketone bodies and citrate that are primarily associated with Alzheimer's disease (AD).

Ketone bodies, or ketones, are three related compounds — acetone, acetoacetic acid, and beta-hydroxybutyric acid (BHB) — produced by the liver during fat metabolism. Citrate is a salt or ester of citric acid.

These metabolite clusters are not only linked to the future development of dementia but also correlate with early pathology in those under age 60 years, study investigator Cornelia M. van Duijn, PhD, professor, epidemiology, Nuffield Department of Population Health, Oxford University, UK, told Medscape Medical News.

"These metabolites flag early and late pathology and may be relevant as targets for prevention of dementia," she noted.

The findings were presented here at the Alzheimer's Association International Conference (AAIC) 2021.

Weight Loss Before Dementia Explained?

For the study, investigators included 125,000 patients from the UK Biobank, which includes 51,031 who were over age 60 at baseline. Of these, 1188 developed dementia during a follow-up of about 10 years; 553 were diagnosed with AD and 298 with vascular dementia.

Researchers used a platform that covers 249 metabolic measures, including small molecules, fatty acids, and lipoprotein lipids.

They estimated risk associated with these metabolites, adjusting for age, sex, BMI, technical variables, ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication, and APOE4 genotypes.

Of the 249 metabolites, 47 (19%) were associated with dementia risk in those over age 60, after adjustment.

The investigators examined effect estimates for associations of metabolites with both AD and vascular dementia over age 60 versus hippocampal volume under age 60. They found a "very strong, very significant" association for AD, and a "marginally significant" association for vascular dementia, said van Duijn.

This would be expected, as there is a much stronger correlation between hippocampal and AD versus vascular dementia, she added.

"We not only see that the metabolites predict dementia, but also early pathology. This makes these findings rather interesting for targeting prevention," she said.

An analysis of total brain volume showed "very strong, very similar, very significant associations" for both AD and vascular dementia," added van Duijn.

The researchers found a major shift in various metabolites involved in energy metabolism in the 10-year period before the diagnosis of AD. These changes include low levels of branched-chain amino acids and omega-3 fatty acids and high levels of glucose, citrate, acetone, BHB, and acetate.

"This finding is in line with that in APOE models that show reduced energy metabolism over age in the brain," said van Duijn.

She added that high levels of some of these metabolites are associated with low body weight before dementia onset, which may explain the weight loss seen in patients before developing the disease.

"Our hypothesis is that the liver is burning the fat reserves of the patients in order to provide the brain with fuel," she explained.

Diet a Prevention Target?

The results also showed ketone bodies increase with age, which may represent the aging brain's "compensation mechanism" to deal with an energy shortage, said van Duijn. "Supplementation of ketone bodies, branched-chain amino and omega-3 fatty acids may help support brain function."

The fact that ketone bodies were positively associated with the risk of dementia is "a very important finding," she said.

Following this and other presentations, session co-chair Rima Kaddurah-Daouk, PhD, professor in psychiatry and behavioral sciences, Institute for Brain Sciences, Duke University, North Carolina, noted the research is "an important part of trying to decipher some of the mysteries in Alzheimer's disease."

The research contributes to the understanding of how nutrition and diet could influence metabolism and then the brain, and is "opening the horizon" for thinking about "strategies for therapeutic interventions," she said.

The study received funding support from the National Institute on Aging. The investigators have reported no relevant financial relationships.

AAIC 2021. Session: Genome, Gut Microbiome, and Metabolome Jointly Inform Alzheimer's Disease. Presented July 26, 2021.

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