A New Weapon Against Alzheimer's Comes From Exercise

Aging weakens the brain's natural protection, facilitating memory decline and the onset of Alzheimer's disease. This study shows that physical exercise releases factors into the bloodstream capable of restoring this protection, even without direct physical activity. By acting on cerebral vessels, these factors rejuvenate the blood-brain barrier, improve cognition, and reduce signs of Alzheimer's disease, revealing a new and promising communication axis between the liver, blood, and brain.

With aging, the brain undergoes significant changes that affect memory, reasoning, and the ability to learn. One of the main problems is the weakening of the barrier that protects the brain from the blood, called the blood-brain barrier.

This barrier acts as a "safety filter": it allows the entry of essential nutrients but prevents toxic and inflammatory substances from reaching brain tissue. As we age, this protection becomes more permeable, facilitating damage to nerve cells and contributing to cognitive decline and diseases such as Alzheimer's.

For decades, studies have shown that physical exercise is one of the most effective ways to protect the brain throughout life. In older animals, physical activity improves memory, reduces brain inflammation, and strengthens connections between neurons. In humans, physically active people have a lower risk of developing dementia and cognitive decline.

However, many elderly people are unable to exercise regularly due to physical limitations or illnesses, which raises a crucial question: is it possible to obtain the benefits of exercise for the brain without physical activity?

Recent research has shown that exercise releases substances into the bloodstream that act as chemical messengers, carrying the benefits of exercise to distant organs, including the brain. Scientists have discovered that the blood of exercising animals, when transferred to sedentary animals, is able to improve the memory of the latter.

Among these substances, an enzyme produced by the liver stood out: it increases in the blood after exercise and is associated with cognitive improvement, even without directly entering the brain.

To understand how this enzyme works, the researchers used a combination of methods. First, they analyzed large genetic and molecular databases to identify proteins that increase with aging and could be targets of this enzyme. Then, they conducted experiments on young and old mice, manipulating the levels of these specific proteins.

They also assessed the animals' behavior in memory tests, analyzed the functioning of the blood-brain barrier, and examined cellular and genetic changes in the brain, especially in regions linked to memory.

Scientists have identified a protein present in the blood vessels of the brain that increases with age and damages the blood-brain barrier. When this protein was elevated, even in young animals, the barrier became more fragile and memory worsened. Conversely, when the activity of this protein was blocked, the blood-brain barrier strengthened again and cognitive performance improved, similar to the effects observed with physical exercise.

The study also investigated animal models that develop alterations similar to those of Alzheimer's disease. In these animals, increasing the beneficial enzyme induced by exercise or blocking the harmful protein in brain vessels reduced the accumulation of toxic proteins in the brain, improved communication between neurons, and partially restored memory.

Furthermore, analyses of human tissues showed that this harmful protein is increased in the brains of elderly people and even more elevated in individuals with Alzheimer's.

These findings reveal that the blood vessels in the brain play a central role in cognitive aging. More importantly, they show that some of the benefits of physical exercise can be replicated by biological interventions that act outside the brain, especially in the liver and blood circulation.

This paves the way for the development of new therapies capable of protecting memory and slowing neurodegenerative diseases, even in people who are unable to exercise regularly.

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Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature

Gregor Bieri, Karishma J.B. Pratt, Yasuhiro Fuseya, Turan Aghayev, Juliana Sucharov, Alana M. Horowitz, Amber R. Philp, Karla Fonseca-Valencia, Rebecca Chu, Mason Phan, Laura Remesal, Shih-Hsiu J. Wang, Andrew C. Yang, Kaitlin B. Casaletto, and Saul A. Villeda

Cell. 18 February 2026 

DOI: 10.1016/j.cell.2026.01.024

Abstract:

Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived exercise factor (exerkine) glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (GPLD1), a GPI-degrading enzyme, reverses aging- and Alzheimer’s-related memory loss by targeting the brain vasculature. GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins, necessitating the identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature as a GPLD1 substrate. Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated GPLD1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated the benefits of GPLD1 in old age, restoring youthful hippocampal transcriptional signatures and rescuing cognition. In an Alzheimer’s disease model, increasing GPLD1 or inhibiting TNAP ameliorated Aβ pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis.