Metabolic age emerges as powerful predictor of future dementia

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Metabolic age emerges as powerful predictor of future dementia

A large UK Biobank study involving more than 223,000 participants found that individuals whose metabolomic age exceeded their chronological age faced significantly higher risks of all-cause, vascular, and unspecified dementia, as well as earlier disease onset.

Participants with both accelerated metabolomic ageing and high genetic susceptibility -- particularly carriers of 2 APOE ε4 alleles -- had more than a 10-fold increased risk of dementia.

The findings were published in Alzheimer’s & Dementia.

“Our findings suggest that metabolomic ageing clocks capture distinct biological information relevant to dementia risk,” said Julian Mutz, MD, King’s College London, London, United Kingdom. “As blood plasma-based clocks are scalable and minimally invasive, they could potentially be part of mid-life screening or used to help refine the selection of individuals to take part in research into prevention or disease-modifying trials for dementia.”

The researchers analysed data from 223,496 participants in the UK Biobank to investigate whether accelerated metabolomic ageing in midlife was associated with future dementia risk and age of onset. Plasma metabolites collected at baseline were used to calculate a metabolomic age score, known as the MileAge delta, which measured the difference between a participant’s predicted biological age and actual chronological age. Investigators then tracked incident dementia diagnoses through linked health records and examined how metabolomic ageing interacted with genetic susceptibility, including APOE genotype and dementia polygenic risk scores.

During follow-up, 3,976 participants developed dementia. Individuals with a higher MileAge delta faced significantly increased risks of all-cause, vascular, and unspecified dementia, with accelerated metabolomic ageing also linked to earlier onset of cognitive disease, including Alzheimer’s disease. Key metabolic contributors included lipids, lipoproteins, and amino acids. 

The study also found strong additive effects between metabolic and genetic risk factors, with participants carrying 2 APOE ε4 alleles and a high MileAge delta showing more than a 10-fold increased risk of all-cause dementia. 

“The association between MileAge delta and earlier dementia onset highlights the potential of the MileAge clock to predict not only dementia risk but also timing of disease onset,” the authors wrote. “This is relevant because of the long preclinical period of neurodegenerative diseases. Notably, MileAge delta was associated with an earlier Alzheimer's disease onset, despite not being associated with incident Alzheimer's disease. This could suggest that the MileAge clock captures indicators of speed of progression of Alzheimer's disease. While this finding warrants cautious interpretation and replication in independent cohorts, it broadly aligns with findings from deCODE genetics showing that proteomic risk scores capture short-term disease processes, while genetic risk scores capture long-term disease risk.”

Reference: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71280

SOURCE: King’s College London