Outrunning Alzheimer´s diseaseDoes physical activity preserve brain health even in the presence of genetic risk factors?

Resumen

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with progressive accumulation of plaques of amyloid- and neurofibrillary tangles of hyperphosphorylated tau in the brain parenchyma, resulting in synaptic toxicity, brain atrophy and cognitive decline. In the majority of cases AD is a complex disease, where both environmental and genetic factors interact contributing to the risk of developing this pathology. The most important genetic risk factor associated with AD is the carriage of the apolipoprotein E (APOE) ε4 allele. As for environmental factors, it has been well-established that physical activity (PA) has beneficial effects on the brain as exerted through multiple mechanisms, including upregulation of neurotrophic factors, regulation of the immune response and enhancement of the cardiovascular system. In the specific case of AD, PA has become associated with better preserved cognitive function, lower levels of brain amyloid and tau burden and attenuated neurodegeneration. Given that, as indicated above, APOE ε4 carriage is considered the greatest genetic risk factor for AD, a question arises as to whether these beneficial effects can also be achieved by individuals at genetic risk. Several studies have been developed to answer this question, although available evidence is inconclusive. For this reason, with the purpose of contributing to this field and better understanding the relationship between PA, APOE ε4 carriage and brain health, I have conducted three empirical studies and one systematic review. In the three empirical studies I included healthy older adults, both carrying and not carrying the ε4 allele, presenting with different kinds of PA measures (subjective and objective). I used magnetoencephalography, a functional neuroimaging technique, to study the moderator role of APOE ε4 in the relationship between PA and several electrophysiological markers of synaptic function, which is impaired early along in the AD continuum. In particular, in Study 1 I investigated individual alpha peak frequencies, in Study 2 I focused on functional connectivity patterns, and in Study 3 I analyzed power within the alpha band. In Study 1, I determined that individual alpha peak frequency was higher in individuals who indicated being more physically active. However, following stratification, only non-carriers showed a positive relationship with individual alpha peak frequency. In Study 2, applying network-based statistics, I found that both ε4 carriers and non-carriers showed lower temporal hypersynchrony at higher PA (objectively measured). In Study 3, following the same statistical approach, I detected that objectively measured PA was associated with greater power in the alpha band in posterior regions. However, following stratification by genetic risk and age, only middle-aged non-carriers and older carriers showed this effect. In both studies (2 and 3) I observed that the APOE genotype influenced the relationship between these functional outcomes, brain structure and cognition. Given that the results obtained in these three empirical studies in addition to other research studies, did not unequivocally point in the same direction, I decided to conclude this work with a systematic review (Study 4). The objective of this review was to elucidate sources of variability that could explain differing results in the varied studies available exploring the moderator role of APOE ε4 in the relationship between PA and several indicators of brain health. I included studies examining dementia incidence, functional and structural neuroimaging outcomes, and cerebrospinal fluid alterations. The most relevant conclusion that I extracted from this systematic review is that both genotype groups appear to benefit with reduced dementia risk. In particular, physically active carriers seem to benefit more from lower amyloid burden and healthier neurofunctional profiles. Nevertheless, there is a high degree of heterogeneity in the experimental designs with considerable limitations; for example, in most of the studies where only non-carriers benefited from higher PA, statistical power was insufficient. During these four studies I have been able to verify a positive relationship between PA and brain function, which is also present, at least to some extent, in APOE ε4 carriers. Grouped together, these studies suggest that PA could delay AD pathology not only for APOE ε4 non-carriers, but also for carriers. However, further research is required to elucidate the specific outcomes that can be ameliorated, the most beneficial PA regimes, as well as age-dependent and ε4 carriage dose-dependent effects. Overall, PA clearly improves brain health, where strategies to increase PA in the general population should be pursued.