Resting State Electrophysiological Profiles and Their Relationship with Cognitive Performance in Cognitively Unimpaired Older Adults: A Systematic Review.

Background: Aging is a complex and natural process. The physiological decline related to aging is accompanied by a slowdown in cognitive processes, which begins shortly after individuals reach maturity. These changes have been sometimes interpreted as a compensatory sign and others as a fingerprint of deterioration. Objective: In this context, our aim is to uncover the mechanisms that underlie and support normal cognitive functioning in the brain during the later stages of life. Methods: With this purpose, a systematic literature search was conducted using PubMed, Scopus, and Web of Science databases, which identified 781 potential articles. After applying inclusion and exclusion criteria, we selected 12 studies that examined the brain oscillations patterns in resting-state conditions associated with cognitive performance in cognitively unimpaired older adults. Results: Although cognitive healthy aging was characterized differently across studies, and various approaches to analyzing brain activity were employed, our review indicates a relationship between alpha peak frequency (APF) and improved performance in neuropsychological scores among cognitively unimpaired older adults. Conclusions: A higher APF is linked with a higher score in intelligence, executive function, and general cognitive performance, and could be considered an optimal, and easy-to-assess, electrophysiological marker of cognitive health in older adults.

Longitudinal changes in the functional connectivity of individuals at risk of Alzheimer's disease.

First-degree relatives of Alzheimer's disease patients constitute a key population in the search for early markers. Our group identified functional connectivity differences between cognitively unimpaired individuals with and without a family history. In this unprecedented follow-up study, we examine whether family history is associated with a longitudinal increase in the functional connectivity of those regions. Moreover, this is the first work to correlate electrophysiological measures with plasma p-tau231 levels, a known pathology marker, to interpret the nature of the change. We evaluated 69 cognitively unimpaired individuals with a family history of Alzheimer's disease and 28 without, at two different time points, approximately 3 years apart, including resting state magnetoencephalography recordings and plasma p-tau231 determinations. Functional connectivity changes in both precunei and left anterior cingulate cortex in the high-alpha band were studied using non-parametric cluster-based permutation tests. Connectivity values were correlated with p-tau231 levels. Three clusters emerged in individuals with family history, exhibiting a longitudinal increase of connectivity. Notably, the clusters for both precunei bore a striking resemblance to those found in previous cross-sectional studies. The connectivity values at follow-up and the change in connectivity in the left precuneus cluster showed significant positive correlations with p-tau231. This study consolidates the use of electrophysiology, in combination with plasma biomarkers, to monitor healthy individuals at risk of Alzheimer's disease and emphasizes the value of combining noninvasive markers to understand the underlying mechanisms and track disease progression. This could facilitate the design of more effective intervention strategies and accurate progression assessment tools.

How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimer's disease risk? A novel integrative model.

BACKGROUND: Wide evidence suggests that physical activity (PA) confers protection against Alzheimer's disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε4 allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε4. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε4 carriage might be dependent on the specific outcome measure utilised. MAIN BODY: In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model on the interactive effects of PA and APOE ε4 carriage on well-established mechanisms underlying AD. Available literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aß) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response and glucose metabolism. Finally, combining all this information, we have built an integrative model, which includes evidence-based and theoretical synergistic interactions across mechanisms. Moreover, we have identified key knowledge gaps in the literature, providing a list of testable hypotheses that future studies need to address. CONCLUSIONS: We conclude that PA influences a wide array of molecular targets involved in AD neuropathology. A deeper understanding of where, when and, most importantly, how PA decreases AD risk even in the presence of the APOE ε4 allele will enable the creation of new protocols using exercise along pharmaceuticals in combined therapeutic approaches.

Early visual alterations in individuals at-risk of Alzheimer's disease: a multidisciplinary approach.

BACKGROUND: The earliest pathological features of Alzheimer's disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. METHODS: In total, 144 healthy subjects: 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences: 28 high-risk subjects (relatives/APOEɛ4 +) and 16 low-risk (non-relatives/APOEɛ4 -). Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time-frequency power) were calculated for each group. RESULTS: High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time-frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant. CONCLUSIONS: To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions' effectiveness.

Episodic memory dysfunction and hypersynchrony in brain functional networks in cognitively intact subjects and MCI: a study of 379 individuals.

Delayed recall (DR) impairment is one of the most significant predictive factors in defining the progression to Alzheimer's disease (AD). Changes in brain functional connectivity (FC) could accompany this decline in the DR performance even in a resting state condition from the preclinical stages to the diagnosis of AD itself, so the characterization of the relationship between the two phenomena has attracted increasing interest. Another aspect to contemplate is the potential moderator role of the APOE genotype in this association, considering the evidence about their implication for the disease. 379 subjects (118 mild cognitive impairment (MCI) and 261 cognitively intact (CI) individuals) underwent an extensive evaluation, including MEG recording. Applying cluster-based permutation test, we identified a cluster of differences in FC and studied which connections drove such an effect in DR. The moderation effect of APOE genotype between FC results and delayed recall was evaluated too. Higher FC in beta band in the right occipital region is associated with lower DR scores in both groups. A significant anteroposterior link emerged in the seed-based analysis with higher values in MCI. Moreover, APOE genotype appeared as a moderator between beta FC and DR performance only in the CI group. An increased beta FC in the anteroposterior brain region appears to be associated with lower memory performance in MCI. This finding could help discriminate the pattern of the progression of healthy aging to MCI and the relation between resting state and memory performance.

Impact of Sociodemographic Features and Lifestyle on Cognitive Performance of Peruvian Adults.

BACKGROUND: Cognitive impairment and dementia may result from a combination of modifiable and nonmodifiable risk and protective factors, such as the environment, educational attainment, time devoted to cognitively stimulating activities, and physical activity. OBJECTIVE: This study aimed to investigate the mediating role of sociodemographic characteristics and lifestyle factors in the years of education and cognitive performance in Peruvian adults. METHODS: This cross-sectional study included 1,478 subjects assessed by Addenbrooke's Cognitive Examination Revised (ACE-R). Using mediation models, we evaluated the mediation role of parents' educational level, reading time (RT), and physical activity time (PAT) in the years of education (IYE) and cognitive performance. RESULTS: People who reported having lived in an urban area during their childhood are estimated to have, on average, 2.085 years more formal education than those who lived in rural areas. In addition, 49% of cognitive performance scores are explained by the mediation effect of reading and physical activity time in the IYE. This implies that higher levels of education, mediated by RT and PAT per week, are 1.596 units associated with higher scores on the ACE-R. CONCLUSION: Despite the fact that nonmodifiable factors (i.e., childhood residence area, parents' educational level) seem to exert an effect on older adults' cognition, their influence is mediated by other factors that are indeed modifiable (i.e., reading time, physical activity engagement). In this sense, lifestyle changes could help prevent or decrease the risk of cognitive impairment and reduce the disease's impact on vulnerable environments in Latin American and Caribbean countries.

Non-Modifiable Factors as Moderators of the Relationship Between Physical Activity and Brain Volume: A Cross-Sectional UK Biobank Study.

BACKGROUND: Previous research suggests physical activity attenuates grey and white matter loss; however, there appears to be individual variability in this effect. Understanding factors that can influence the relationship between physical activity and brain volume may enable prediction of individual response. OBJECTIVE: The current study examined the relationship between objectively-measured physical activity and brain volume; and whether this relationship is moderated by age, sex, or a priori candidate genetic factors, brain-derived neurotrophic factor (BDNF) Val66Met, or apolipoprotein (APOE) ɛ4 allele carriage. METHODS: Data from 10,083 men and women (50 years and over) of the UK Biobank were used to examine the study objectives. All participants underwent a magnetic resonance imaging scan to quantify grey and white matter volumes, physical activity monitoring via actigraphy, and genotyping. RESULTS: Physical activity was associated with total grey matter volume, total white matter volume, and right hippocampal volume. Only males had an association between higher physical activity levels and greater cortical grey matter volume, total grey matter volume, and right hippocampal volume. Age moderated the relationship between physical activity and white matter volume. CONCLUSION: Our results indicate that in males, but not females, an association exists between objectively-measured physical activity and grey matter volume. Age may also play a role in impacting the relationship between physical activity and brain volume. Future research should evaluate longitudinal brain volumetrics to better understand the nature of age and sex-effects on the physical activity and brain volume relationship.

Characterization of Retinal Drusen in Subjects at High Genetic Risk of Developing Sporadic Alzheimer's Disease: An Exploratory Analysis.

Having a family history (FH+) of Alzheimer's disease (AD) and being a carrier of at least one ɛ4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aß plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH- or FH+) and their allelic characterization of ApoE ɛ4 (ApoE ɛ4- or ApoE ɛ4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen.

Foveal Avascular Zone and Choroidal Thickness Are Decreased in Subjects with Hard Drusen and without High Genetic Risk of Developing Alzheimer's Disease.

A family history (FH+) of Alzheimer's disease (AD) and ɛ4 allele of the ApoE gene are the main genetic risk factors for developing AD, whereas ɛ4 allele plays a protective role in age-related macular degeneration. Ocular vascular changes have been reported in both pathologies. We analyzed the choroidal thickness using optical coherence tomography (OCT) and the foveal avascular zone (FAZ) using OCT-angiography and compared the results with ApoE gene expression, AD FH+, and the presence or absence of hard drusen (HD) in 184 cognitively healthy subjects. Choroidal thickness was statistically significantly different in the (FH-, ɛ4-, HD+) group compared with (i) both the (FH-, ɛ4-, HD-) and the (FH+, ɛ4+, HD+) groups in the superior and inferior points at 1500 µm, and (ii) the (FH+, ɛ4-, HD+) group in the superior point at 1500 µm. There were statistically significant differences in the superficial FAZ between the (FH+, ɛ4-, HD+) group and (i) the (FH+, ɛ4-, HD-) group and (ii) the (FH+, ɛ4+, HD-) group. In conclusion, ocular vascular changes are not yet evident in participants with a genetic risk of developing AD.

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

Does APOE genotype moderate the relationship between physical activity, brain health and dementia risk? A systematic review.

INTRODUCTION: For decades, researchers have tried to understand the moderating effect of APOE ε4 carriage on the relationship between physical activity (PA), brain health and dementia risk. However, this field has produced inconsistent findings. METHOD: We conducted a systematic review of the literature, searching for observational and interventional studies examining the effect of APOE ε4 carriage on the relationships between PA, dementia risk and different markers of brain health. RESULTS: Observational studies using dementia risk as a primary outcome measure generally found that in shorter follow-up periods (up to 10 years) both APOE ε4 carriers and non-carriers benefit from PA, although longer follow-ups showed mixed results. In neuroimaging studies, mainly carriers or both groups showed benefits. Additionally, the association between PA and amyloid burden was more evident among carriers. Overall, studies with greater samples of active APOE ε4 carriers are more likely to report benefits within this group in terms of lower dementia risk and reduced brain pathology. DISCUSSION: Although we have identified some patterns for the modulating effect of APOE ε4 on PA and dementia or brain pathology, the available data is, overall, inconclusive. Heterogeneity in study design, methodology, and outcomes blur the ability to detect clear associations.

Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease.

BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer's disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.

The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health.

BACKGROUND: Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer's disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ε4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. METHOD: The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ε4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. RESULTS: A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ε4 carriers, and in ε4 non-carriers), but its effects manifest differently according to genetic risk. In ε4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ε4 non-carriers, this profile is associated with improved cognition (working and episodic memory). CONCLUSIONS: PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ε4 carriers.

Magnetoencephalography applied to the study of Alzheimer's disease.

Magnetoencephalography (MEG) is a relatively modern neuroimaging technique able to study normal and pathological brain functioning with temporal resolution in the order of milliseconds and adequate spatial resolution. Although its clinical applications are still relatively limited, great advances have been made in recent years in the field of dementia and Alzheimer's disease (AD) in particular. In this chapter, we briefly describe the physiological phenomena underlying MEG brain signals and the different metrics that can be computed from these data in order to study the alterations disrupting brain activity not only in demented patients, but also in the preclinical and prodromal stages of the disease. Changes in non-linear brain dynamics, power spectral properties, functional connectivity and network topological changes observed in AD are narratively summarized in the context of the pathophysiology of the disease. Furthermore, the potential of MEG as a potential biomarker to identify AD pathology before dementia onset is discussed in the light of current knowledge and the relationship between potential MEG biomarkers and current established hallmarks of the disease is also reviewed. To this aim, findings from different approaches such as resting state or during the performance of different cognitive paradigms are discussed.Lastly, there is an increasing interest in current scientific literature in promoting interventions aimed at modifying certain lifestyles, such as nutrition or physical activity among others, thought to reduce or delay AD risk. We discuss the utility of MEG as a potential marker of the success of such interventions from the available literature.

BDNF Val66Met Polymorphism and Gamma Band Disruption in Resting State Brain Functional Connectivity: A Magnetoencephalography Study in Cognitively Intact Older Females.

The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor (BDNF) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females. All of them were ε3ε3 homozygotes for the apolipoprotein E (APOE) gene and were divided into two subgroups according to the presence of the Met allele: Val/Met group (n = 16) and Val/Val group (n = 20). They did not differ in age, years of education, Mini-Mental State Examination scores, or normalized hippocampal volumes. Our results showed reduced antero-posterior gamma band FC within the Val/Met genetic risk group, which may be caused by a GABAergic network impairment. Despite the lack of cognitive decline, these results might suggest a selective brain network vulnerability due to the carriage of the BDNF Met allele, which is linked to a potential progression to dementia. This neurophysiological signature, as tracked with MEG FC, indicates that age-related brain functioning changes could be mediated by the influence of particular genetic risk factors.

Factors Explaining Language Performance After Training in Elders With and Without Subjective Cognitive Decline.

The present study explores if cognitive reserve, executive functions, and working memory capacity are predictive of performance in the language domain (specifically in sentence comprehension and naming) after a cognitive training intervention. Sixty-six Spanish older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline according to Jessen et al.'s (2014) criteria (n = 35; 70.94 ± 4.16 years old) or cognitively intact (n = 31; 71.34 ± 4.96 years old). Written sentence comprehension and visual confrontation naming were assessed both immediately after recruitment (at the baseline), and then 6 months later, once each participant had completed his/her cognitive training (a well-known program in Spain, called UMAM; English translation: Madrid City Council Memory Unit Program). Cognitive reserve, executive functions (cognitive flexibility and controlled interference efficiency), and working memory capacity were measured for all participants at the baseline. Results pointed out that the subjective cognitive decline group presented greater benefits in the language domain than cognitively intact participants. We also observed that lower executive functioning and working memory capacity at the baseline predicted larger benefits in language performance after training, but only in the group of cognitively intact older adults. However, selected predictors hardly explained subjective cognitive decline participants' results in language performance after training.

Physical activity effects on the individual alpha peak frequency of older adults with and without genetic risk factors for Alzheimer's Disease: A MEG study.

OBJECTIVE: Since a cure for Alzheimer's Disease (AD) is yet to be discovered, attention has shifted towards prevention. Physical activity (PA) emerged as a notorious lifestyle factor that could influence brain structure and function. The individual alpha peak frequency (IAPF) is a measure that summarizes the spectral content of brain signals and has been proven to be sensitive to both AD pathology and PA interventions. Therefore, our goal was to unravel whether chronic PA modulates IAPF and if APOE ɛ4 carriage moderates this relationship. METHODS: We analyzed 4-minutes of resting-state magnetoencephalographic recordings from 100 healthy elders that provided self-reported measures of PA, and the IAPF was calculated. RESULTS: We found that IAPF was negatively influenced by age and APOE and positively influenced by PA. The effect of PA on IAPF only remained significant for the ɛ4 non-carriers group. CONCLUSIONS: PA is positively associated to higher IAPF in healthy older adults and could potentially act as a protective factor against cognitive decline. Nevertheless, such effect is non-significant among elders who are more vulnerable to developing AD due to their genetic carriage. SIGNIFICANCE: This investigation offers the first neurophysiological evidences on the combined effects of APOE genotype and PA in healthy elders.

Efficacy of Cognitive Training in Older Adults with and without Subjective Cognitive Decline Is Associated with Inhibition Efficiency and Working Memory Span, Not with Cognitive Reserve.

The present study explores the role of cognitive reserve, executive functions, and working memory (WM) span, as factors that might explain training outcomes in cognitive status. Eighty-one older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline or cognitively intact. Each participant underwent a neuropsychological assessment that was conducted both at baseline (entailing cognitive reserve, executive functions, WM span and depressive symptomatology measures, as well as the Mini-Mental State Exam regarding initial cognitive status), and then 6 months later, once each participant had completed the training program (Mini-Mental State Exam at the endpoint). With respect to cognitive status the training program was most beneficial for subjective cognitive decline participants with low efficiency in inhibition at baseline (explaining a 33% of Mini-Mental State Exam total variance), whereas for cognitively intact participants training gains were observed for those who presented lower WM span.