Doctoral student Marta Arbizu presents recent scientific evidence analyzing physical activity as a modifiable risk factor in preclinical Alzheimer’s disease.
Introduction to the study on preclinical Alzheimer’s disease
Alzheimer’s disease (AD) does not begin when the first memory symptoms appear. Years earlier, silent changes are already taking place in the brain, such as the accumulation of amyloid and tau, which progressively lead to more advanced stages of the disease. This initial phase, characterized by imperceptible cognitive changes but affected biology and known as preclinical Alzheimer’s disease, represents a window of greater likelihood of success for intervening and modifying the course of the disease.
Among potentially modifiable factors, physical activity stands out. Numerous studies have shown that physically active people have a lower risk of developing dementia. However, one fundamental question had remained unanswered:
does physical activity really act on the biological mechanisms of Alzheimer’s disease in humans, and if so, how?
A study recently published in Nature Medicine provides strong answers to this question, using objective measures of physical activity and an exceptionally long longitudinal follow-up period.
How was this study on physical activity and preclinical Alzheimer’s disease conducted?
The study was based on the Harvard Aging Brain Study, a cohort including cognitively healthy older adults at study entry. In total, 296 people participated and were followed for up to 14 years with annual assessments.
The most noteworthy aspects of the design were:
- Physical activity measured objectively with a pedometer, avoiding questionnaire-related biases.
- Longitudinal assessment of:
- Brain β-amyloid using PET.
- Tau protein in the inferior temporal cortex, a key region in the early stages.
- Cognition (PACC5) and functioning (CDR-SOB): cognition was assessed with the PACC5, a battery sensitive to very subtle cognitive changes in preclinical stages of Alzheimer’s disease, while functioning was measured with the CDR-SOB, a clinical scale that quantifies the impact of these changes on independence and activities of daily living.
- Specific analyses in people with elevated amyloid, that is, those at biological risk for Alzheimer’s disease.
This approach made it possible to analyze not only whether physical activity was associated with better cognitive performance, but also which brain processes mediated this effect.
What are the key findings of this study?
Physical activity does not reduce amyloid
One of the clearest findings of the study is that walking more is not associated with less amyloid accumulation, either at baseline or during follow-up.
This result is important because it rules out the idea that the benefit of physical activity acts directly by “clearing” amyloid from the brain. In addition, it is already well established that clearing amyloid does not reverse the disease; in this sense, the finding is consistent with the fact that anti-amyloid drugs may be effective at reducing amyloid but have not had an impact on the development of Alzheimer’s disease.
More steps, less tau accumulation
The study’s central finding is that, in people with elevated amyloid:
- Greater physical activity is associated with slower tau accumulation in the inferior temporal cortex.
- This region is particularly relevant because tau spread is closely associated with subsequent cognitive decline.
In other words, physical activity appears to slow one of the processes most directly linked to neurodegeneration.
Tau explains the cognitive benefit
The analysis goes one step further and demonstrates that:
- Lower tau accumulation explains 84% of the effect of physical activity on slowing cognitive decline.
- In the case of functional decline, tau explains approximately 40% of the effect, suggesting that other factors, such as functional reserve or overall physical condition, also contribute.
This finding provides strong biological evidence of how physical activity protects the brain in the very early stages of Alzheimer’s disease.
How much activity is needed? A key message
One of the most clinically and publicly relevant aspects is the dose–response relationship:
- Clear benefits compared with sedentary behavior are already observed at 3,000–5,000 steps per day.
- The protective effect reaches a “ceiling” between 5,000 and 7,500 steps per day.
- Going substantially beyond that number does not provide clear additional benefits for tau or cognition.
This finding challenges the popular 10,000-steps-a-day message and offers a realistic, achievable goal for older or sedentary adults.
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What are the clinical implications of these findings?
The results of this study have very concrete implications:
Prevention in preclinical stages
Identifying people at biological risk for Alzheimer’s disease and promoting modest but sustained increases in physical activity could delay the onset of clinically meaningful cognitive decline by several years.
Clinical trial design
The study suggests that physical activity–based interventions could be particularly effective when targeting:
- Sedentary people.
- People with elevated amyloid.
It also supports the use of tau PET as a response biomarker.
More realistic public health messages
Setting achievable goals improves adherence and reduces the perception that “if I do not do a lot, it is not worthwhile.”
How does this advance relate to NeuronUP?
At NeuronUP, evidence-based cognitive stimulation and rehabilitation have been provided for years. This study reinforces a key idea: the optimal intervention for Alzheimer’s disease should be comprehensive and early.
Physical activity and cognitive stimulation do not compete; instead, they complement each other:
- Physical activity may slow neurobiological processes such as tau accumulation.
- NeuronUP tools help strengthen cognitive reserve, monitor performance, and personalize interventions.
Integrating both approaches opens the door to more effective prevention and monitoring programs, especially in preclinical stages.
Conclusion
This study demonstrates that objectively measured physical activity is associated with less progression of tau pathology and slower cognitive decline in people at risk for Alzheimer’s disease, even without directly affecting amyloid. It also shows that an extreme level of activity is not necessary to obtain benefits.
Overall, these findings reinforce a hopeful and practical message: small, sustained lifestyle changes can have a real impact on the trajectory of Alzheimer’s disease, especially when combined with cognitive stimulation strategies such as those offered by NeuronUP.
References
- Yau, W. W., Kirn, D. R., Rabin, J. S., Properzi, M. J., Schultz, A. P., Shirzadi, Z., Palmgren, K., Matos, P., Maa, C., Pruzin, J. J., Schultz, S. A., Buckley, R. F., Rentz, D. M., Johnson, K. A., Sperling, R. A., & Chhatwal, J. P. (2025). Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease. Nature Medicine, 31(12), 4075–4083. https://doi.org/10.1038/s41591-025-03955-6
Frequently asked questions about physical activity and preclinical Alzheimer’s disease
1. What is preclinical Alzheimer’s disease?
Preclinical Alzheimer’s disease is an early stage of the disease in which there are not yet evident cognitive symptoms, but neurobiological changes such as the accumulation of β-amyloid and tau protein can already be detected. This stage may precede clinical cognitive decline by years or decades.
2. Why is physical activity a modifiable risk factor for Alzheimer’s disease?
Physical activity is a modifiable risk factor because it influences neurobiological processes involved in neurodegeneration. Scientific evidence shows that adequate levels of exercise are associated with slower progression of tau pathology and less cognitive decline in the early stages of Alzheimer’s disease.
3. How many steps per day protect the brain in preclinical Alzheimer’s disease?
Neuroprotective benefits are observed starting at approximately 3,000–5,000 steps per day, with a maximum effect between 5,000 and 7,500 steps per day. Substantially exceeding these figures does not appear to provide clear additional benefits for tau accumulation or cognition.
4. Does physical activity reduce β-amyloid accumulation?
No. Current evidence indicates that physical activity is not associated with less brain β-amyloid accumulation. Its protective effect appears to act mainly on the progression of tau pathology, which is more directly related to cognitive and functional decline.
5. How does physical activity affect tau protein?
In people at biological risk for Alzheimer’s disease, greater physical activity is associated with slower tau protein accumulation in temporal brain regions. This reduction in tau progression explains much of the beneficial effect of exercise on slowing cognitive decline.
6. Why is tau protein key to cognitive decline?
Tau protein is closely associated with neurodegeneration and the loss of cognitive functions. Unlike amyloid, tau spread directly correlates with cognitive and functional worsening, making it a key biomarker in the early stages of Alzheimer’s disease.
7. During which stages of Alzheimer’s disease is physical activity most effective?
Physical activity appears to be particularly effective during the preclinical stages of Alzheimer’s disease, when brain pathology is already present but cognitive symptoms have not yet emerged. At this stage, intervention may delay the progression of neurodegeneration and the onset of clinical decline.
8. Can physical activity prevent Alzheimer’s disease?
Physical activity does not guarantee prevention of Alzheimer’s disease, but it may reduce risk and delay the onset of symptoms. It acts as a protective factor that modulates the progression of brain pathology, especially when maintained regularly and consistently over time.
9. How do physical activity and cognitive stimulation complement each other?
Physical activity may slow neurobiological processes such as tau accumulation, while cognitive stimulation helps strengthen cognitive reserve and optimize functional performance. Combining both approaches provides a more comprehensive intervention for Alzheimer’s disease prevention and monitoring.
10. What are the implications of this finding for clinical practice?
These results support including realistic, personalized physical activity recommendations in Alzheimer’s disease prevention programs. Identifying people at risk and promoting moderate increases in activity may delay cognitive decline and improve the effectiveness of early clinical interventions.
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