A person's "bioenergetic age"—or how youthfully their cells generate energy—might be a key indicator of whether they're at risk of developing Alzheimer's disease, new research from Weill Cornell Medicine shows. The study , published Feb. 24 in Nature Communications, suggests healthy living can turn back the bioenergetic clock for some people, helping them fend off Alzheimer's as effectively as a new drug called lecanemab.
"That's quite big because it means some people can lower their risk without the uncertain side effects of current treatments," said senior author Dr. Jan Krumsiek , associate professor of physiology and biophysics and computational genomics in the Institute for Computational Biomedicine at Weill Cornell Medicine. The study's first author, Dr. Matthias Arnold, is head of the computational neurobiology team at Helmholtz Munich.
The new findings bring us a step closer to solving a long-standing puzzle. One of the early warning signs of Alzheimer's is that brain cells start losing their ability to produce and use energy efficiently, such as metabolizing glucose (sugar). But some people don't show disease symptoms for years. This delay between abnormalities in energy pathways and the onset of symptomatic disease suggests there is a "bioenergetic capacity" that provides a buffer for these individuals. Their bodies and brains are better at keeping energy levels up even when problems start.
"In these cases, people can be unusually healthy when we look at their cognition," said Dr. Krumsiek, who is also a member of the Englander Institute for Precision Medicine . "They make it to old age without the kind of declines that usually creep in."
But could the researchers identify individuals with this beneficial higher bioenergetic capacity and help those without it?
A New Tool to Predict Risk of Alzheimer's
Dr. Krumsiek and his colleagues turned to a group of molecules called acylcarnitines, which are associated with declining cognition and breaking down or metabolizing fats and proteins for energy. To test if high acylcarnitine levels in the blood could predict who's at risk of developing Alzheimer's, the researchers used data from a large-scale study called the Alzheimer's Disease Neuroimaging Initiative .
"It was fascinating," Dr. Krumsiek said. "Dividing research participants into groups based on their specific acylcarnitine levels highlighted people with more severe Alzheimer's disease and others with fewer symptoms." This led the researchers to define a bioenergetic clock based on acylcarnitines—how old a person's metabolism acts, compared to actual age. Higher bioenergetic age is linked to higher acylcarnitine levels, worsened Alzheimer's pathology, cognitive decline and brain atrophy.
The researchers also quantified cognitive decline using a common test called the mini-mental state examination, on which a score below 24 out of 30 points indicates impairment. They found that people with low acylcarnitine levels to begin with declined more slowly, losing about 0.5 points less per year than people with high acylcarnitine levels. The benefit is on par with the Alzheimer's drug lecanemab.
To some degree, a person's bioenergetic clock ticks forward at a rate determined by their genetics, but having a healthy lifestyle—for example, eating a plant-based diet and exercising —can help keep acylcarnitine levels low, which means a younger bioenergetic age, Dr. Krumsiek explained.
They went on to identify a subgroup of participants, about 30% of the Alzheimer's Disease Neuroimaging Initiative, with older bioenergetic age but favorable genetic background. These individuals may benefit more from early lifestyle interventions designed to decrease their bioenergetic age and potentially delay or prevent the onset of Alzheimer's.
Next Steps
Moving forward, Dr. Krumsiek hopes to home in on the lifestyle interventions most effective for lowering bioenergetic age. For example, eating a low-carb diet may help maintain metabolic health, but just how low would carbohydrate consumption have to be for a person to see benefits?
The study also points to an inexpensive, rapid test that could determine a person's acylcarnitine levels. "It's fortunate that these blood tests—originally developed to identify metabolic and mitochondrial disorders in newborns—can also help assess a person's bioenergetic age," Dr. Krumsiek said. "If we can repurpose this technology for older adults, that could provide a way to start personalized treatment earlier."
