Research shows that exercise can delay Alzheimer's, but there's a catch

Research shows that exercise can delay Alzheimer's, but there's a catch

New research finds that activating actives may help slow Alzheimer's-related brain changes—until tau levels reach a tipping point. Could exercise be a key to delaying cognitive decline?

In a study recently published in the journalLancet's healthy longevityResearchers evaluated 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. Aggregation of dysfunctional P-TAU181 in the brain is implicated in the cognitive decline associated with aging and represents a hallmark of Alzheimer's disease (AD) pathology.

Therefore, it is important to determine whether and how these accumulations (of p-tau181) can be prevented through non-pharmaceutical approaches such as physical activity. Cross-sectional analyzes of the associations between TAU levels and physical activity have yielded mixed results, with some studies showing inverse associations and others reporting no association. Previous studies have mostly found no significant effect of MVPA on P-TAU accumulation, making this new research particularly important.

About the study

The present study examined longitudinal and cross-sectional associations between MVPA, P-TAU181 levels, and cognition. They used data from the Multidomain Alzheimer's Prevention (MAPT), which recruited adults without dementia who were ≥70 from memory centers in Monaco and France.

Eligible participants had self-reported complaints, limitations in instrumental activities of daily living, or slow gait speed. However, individuals were excluded if they had a diagnosed dementia disorder, a Mini-Mental State Examination (MMSE) score under 24 years of age, limits on basic activities of daily living, or were already taking omega-3 supplements prior to 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 included cognitive education and counseling about physical activity and nutrition. Blood samples were analyzed in 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 Activities Questionnaire.

Perception was assessed at these time points using the Category Naming Test, the Digit Symbol Substitution Test, the 10 mmse Landmarks, and the Free and Cue Selective Recall Test. A composite cognitive score was calculated from scores on these (four) tests. Mixed effects models were used to examine the associations between MVPA and P-TAU181 levels and to mediate the moderating but not mediating role of P-TAU181 levels between cognition and MVPA.

Results

In total, MAPT enrolled 1,679 people from May 30, 2008 to February 24, 2011. 558 people (33%) had P-TAU 181 measurements, with a median baseline age of 74. 68 percent of subjects were female and 32% were male. Furthermore, MVPA levels were low for 47% of participants and high for 45%. Forty-one subjects (7%) were inactive. At baseline, the mean MVPA was 1,099 metabolic equivalent tasks (MET) minutes per week, and the mean P-TAU181 concentration was 8.9 pg/ml (range 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 values. Nevertheless, there was a significant longitudinal association where high MVPA levels were associated with slower increases in P-TAU181 levels over time. However, this association was only significant when inactive people were compared to active people. No difference was found between those with low and high levels of MVPA.

Furthermore, there was no mediation effect of P-TAU181 levels on the association between MVPA and changes in composite cognitive score. Furthermore, there were no effects of MVPA on changes in composite cognitive score.

In moderation analyses, P-TAU181 levels significantly influenced the associations between MVPA and 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 loads may reduce or eliminate the benefits of exercise.

Conclusions

Results showed that baseline MVPA was not associated with P-TAU181 levels, but higher MVPA levels were associated with a slower increase in P-TAU181 levels over time. However, these results are in contrast to previous studies that found no effect of MVPA on P-TAU accumulation. This suggests that long-term follow-up rather than cross-sectional studies may be required to detect these associations.

Furthermore, the higher baseline P-TAU181 levels abolished the positive association between MVPA and cognition. P-TAU181 levels did not mediate the association between MVPA and cognition.

Limitations of the study include the utility of subjective instruments for assessing physical activity, which are susceptible to response and recall bias. In addition, physical activity and sedentary time in relation to light and intensity were not taken into account, which could influence the results. MAPT subjects received interventions that may have influenced the observed associations. In addition, the researchers analyzed APOE-ε4 status but did not influence the results, indicating that the effects of MVPA on P-TAU181 levels and cognition were independent of genetic Alzheimer's risk factors. Further analysis is required to confirm these results.

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