New research reveals that staying active can help slow Alzheimer’s-related brain changes—until tau levels reach a tipping point. Could exercise be a key to delaying cognitive decline?

Study: Associations between moderate-to-vigorous physical activity, p-tau181, and cognition in healthy older adults with memory complaints: a secondary analysis from the MAPT. Image Credit: Roman Samborskyi / Shutterstock

In a recent study published in the journal The Lancet Healthy Longevity, researchers assessed the associations between phosphorylated (p)-tau181 levels, moderate-to-vigorous physical activity (MVPA), and cognition in older adults.

Tau proteins are abundant in neurons, where they regulate and stabilize microtubule activity in axons and contribute to cell signaling. The aggregation of dysfunctional p-tau181 in the brain is implicated in cognitive decline associated with aging and represents a hallmark of Alzheimer’s disease (AD) pathology.

Therefore, it is critical to determine whether and how these accumulations (of p-tau181) could be prevented via non-pharmaceutical approaches like physical activity. Cross-sectional analyses on the associations between tau levels and physical activity have produced disparate results, with some studies revealing inverse associations and others reporting no association. Previous studies have largely found no significant effect of MVPA on p-tau accumulation, making this new research particularly important.

About the study

The present study investigated longitudinal and cross-sectional associations between MVPA, p-tau181 levels, and cognition. They used data from the Multidomain Alzheimer’s Preventive Trial (MAPT), which recruited adults without dementia who were aged ≥70 from memory centers in Monaco and France.

Eligible participants had self-reported memory complaints, limitations in instrumental activities of daily living, or low gait speed. However, individuals were excluded if they had a diagnosed dementia condition, a Mini-Mental State Examination (MMSE) score below 24, limitations in basic activities of daily living, or were already taking omega-3 supplements before enrollment. This study included MAPT participants with p-tau181 measurements at baseline, three years, or both time points. They were randomized to receive one of four interventions: 1) multidomain intervention plus placebo, 2) multidomain intervention plus omega-3 supplementation, 3) omega-3 supplementation alone, or 4) placebo alone.

The multidomain intervention comprised cognitive training and counseling about physical activity and nutrition. Blood samples were analyzed at the Clinical Neurochemistry Laboratory at Gothenburg University using a Simoa-based in-house method. Physical activity was assessed at baseline, six months, and one, two, and three years, using the Minnesota Leisure Time Activities questionnaire.

Cognition was assessed at these time points using the category naming test, the digit symbol substitution test, the 10 MMSE orientation items, and the free and cued selective reminding test. A composite cognitive score was computed from the scores of these (four) tests. Mixed-effects models were used to explore the associations between MVPA and p-tau181 levels and assess the moderating but not mediating role of p-tau181 levels between cognition and MVPA.

Findings

In total, MAPT enrolled 1,679 individuals from May 30, 2008, to February 24, 2011. Of these, 558 individuals (33%) had p-tau181 measurements, with a median baseline age of 74. Sixty-eight percent of subjects were female, and 32% were male. Further, MVPA levels were low for 47% of participants and high for 45%. Forty-one subjects (7%) were inactive. At baseline, the median level of MVPA was 1,099 metabolic equivalent task (MET)-minutes per week, and the median p-tau181 concentration was 8.9 pg/ml (ranging from 0.4 to 31.7 pg/ml).

The median MMSE score at baseline was 28. There was no association between baseline MVPA and baseline p-tau181 levels. Nevertheless, there was a significant longitudinal association wherein high levels of MVPA were associated with a slower increase in p-tau181 levels over time. However, this association was only significant when comparing inactive individuals to active individuals. No difference was found between those with low versus high levels of MVPA.

Further, there was no mediation effect of p-tau181 levels on the association between MVPA and changes in the composite cognitive score. Moreover, there were no effects of MVPA on changes in the composite cognitive score.

In moderation analyses, p-tau181 levels significantly affected the associations between MVPA and the composite cognitive score. Higher p-tau181 levels attenuated the positive association between MVPA and cognition. Notably, the effect of MVPA was no longer significant when p-tau181 levels exceeded 9.36 pg/ml cross-sectionally and 3.5 pg/ml longitudinally, suggesting that higher tau burdens may reduce or eliminate exercise benefits.

Conclusions

The findings revealed that MVPA was not associated with p-tau181 levels at baseline, but higher MVPA levels were associated with a slower increase in p-tau181 levels over time. However, these findings contrast with earlier studies, which did not find an effect of MVPA on p-tau accumulation. This suggests that long-term tracking, rather than cross-sectional studies, may be necessary to detect these associations.

Besides, higher baseline p-tau181 levels attenuated the positive association between MVPA and cognition. p-tau181 levels did not mediate the association between MVPA and cognition.

The study’s limitations include the utility of subjective tools for physical activity assessment, which are prone to response and recall biases. Additionally, light-intensity physical activity and sedentary time were not considered, which could influence results. MAPT subjects received interventions that may have influenced the observed associations. Additionally, the researchers analyzed APOE-ε4 status, but it did not influence the results, indicating that MVPA’s effects on p-tau181 levels and cognition were independent of genetic Alzheimer’s risk factors. Further analyses are required to corroborate these findings.