Differentiating the influence of sedentary behavior and physical activity on brain health in late adulthood.

Public health messaging calls for individuals to be more physically active and less sedentary, yet these lifestyle behaviors have been historically studied independently. Both physical activity (PA) and sedentary behavior (SB) are linked through time-use in a 24-hour day and are related to health outcomes, such as neurocognition. While the benefits of PA on brain health in late adulthood have been well-documented, the influence of SB remains to be understood. The purpose of this paper was to critically review the evolving work on SB and brain health in late adulthood and emphasize key areas of consideration to inform potential research. Overall, the existing literature studying the impact of SB on the components and mechanisms of brain health are mixed and inconclusive, provided largely by cross-sectional and observational work employing a variety of measurement techniques of SB and brain health outcomes. Further, many studies did not conceptually or statistically account for the role of PA in the proposed relationships. Therefore, our understanding of the way in which SB may influence neurocognition in late adulthood is limited. Future efforts should include more prospective longitudinal and randomized clinical trials with intentional methodological approaches to better understand the relationships between SB and the brain in late adulthood, and how these potential links are differentiated from PA.

Reduced brain activity during a working memory task in middle-aged apolipoprotein E ε4 carriers with overweight/obesity.

Objective: The apolipoprotein E ε4 (APOE ε4) allele and midlife obesity are independent risk factors for Alzheimer's disease (AD). Both of these risk factors are also associated with differences in brain activation, as measured by blood oxygenation level-dependent (BOLD) responses, in the absence of detectable cognitive deficits. Although the presence of these risk factors may influence brain activity during working memory tasks, no study to date has examined whether the presence of the ε4 allele explains variation in working memory brain activity while matching for levels of overweight/obesity. The primary aim of this study was to determine whether the presence of the ε4 allele is associated with differences in task-functional magnetic resonance imaging (fMRI) brain activation in adults with overweight/obesity. We predicted that ε4 carriers would have greater brain activation in regions that support working memory. Methods: This ancillary study included 48 (n = 24 APOE ε4 carriers; n = 24 APOE ε4 non-carriers), sedentary middle-aged adults (Mean age = 44.63 ± 8.36 years) with overweight/obesity (Mean BMI = 32.43 ± 4.12 kg/m2) who were matched on demographic characteristics. Participants were a subsample enrolled in 12-month randomized clinical trial examining the impact of energy-restricted diet and exercise on cardiovascular health outcomes. Participants completed a n-back working memory task with fMRI, which were completed within one month of the start of the intervention. Participants also underwent pseudo-continuous arterial spin labeling scans, a MRI measure of cerebral blood flow (CBF). Results: Compared to non-ε4 carriers with overweight/obesity, ε4 carriers with overweight/obesity had lower fMRI brain activity in the middle frontal gyrus, pre and post central gyrus, supramarginal gyrus, superior temporal gyrus, lateral occipital cortex, and angular gyrus (z range = 2.52-3.56) during the n-back working memory task. Differences persisted even when controlling for CBF in these brain regions. Conclusion: These results indicate that presence of the APOE ε4 allele in middle-aged adults with overweight/obesity is related to altered brain activity during a working memory paradigm, which may confer risk for accelerated neurocognitive decline in late adulthood. Future research is needed to clarify the clinical implications of these findings in the context of risk for AD.

The multi-domain exercise intervention for memory and brain function in late middle-aged and older adults at risk for Alzheimer's disease: A protocol for Western-Eastern Brain Fitness Integration Training trial.

Background: Aging is associated with cognitive decline, increased risk for dementia, and deterioration of brain function. Modifiable lifestyle factors (e.g., exercise, meditation, and social interaction) have been proposed to benefit memory and brain function. However, previous studies have focused on a single exercise modality or a single lifestyle factor. Consequently, the effect of a more comprehensive exercise program that combines multiple exercise modalities and lifestyle factors, as well as examines potential mediators and moderators, on cognitive function and brain health in late middle-aged and older adults remains understudied. This study's primary aim is to examine the effect of a multi-domain exercise intervention on memory and brain function in cognitively healthy late middle-aged and older adults. In addition, we will examine whether apolipoprotein E (ApoE) genotypes, physical fitness (i.e., cardiovascular fitness, body composition, muscular fitness, flexibility, balance, and power), and brain-derived neurotrophic factor (BDNF) moderate and mediate the exercise intervention effects on memory and brain function. Methods: The Western-Eastern Brain Fitness Integration Training (WE-BFit) is a single-blinded, double-arm, 6-month randomized controlled trial. One hundred cognitively healthy adults, aged 45-70 years, with different risks for Alzheimer's disease (i.e., ApoE genotype) will be recruited and randomized into either a multi-domain exercise group or an online educational course control group. The exercise intervention consists of one 90-min on-site and several online sessions up to 60 min per week for 6 months. Working memory, episodic memory, physical fitness, and BDNF will be assessed before and after the 6-month intervention. The effects of the WE-BFit on memory and brain function will be described and analyzed. We will further examine how ApoE genotype and changes in physical fitness and BDNF affect the effects of the intervention. Discussion: WE-BFit is designed to improve memory and brain function using a multi-domain exercise intervention. The results will provide insight into the implementation of an exercise intervention with multiple domains to preserve memory and brain function in adults with genetic risk levels for Alzheimer's disease. Clinical trial registration: ClinicalTrials.gov, identifier: NCT05068271.

Aerobic exercise improves episodic memory in late adulthood: a systematic review and meta-analysis.

Background: Aerobic exercise remains one of the most promising approaches for enhancing cognitive function in late adulthood, yet its potential positive effects on episodic memory remain poorly understood and a matter of intense debate. Prior meta-analyses have reported minimal improvements in episodic memory following aerobic exercise but have been limited by restrictive inclusion criteria and infrequent examination of exercise parameters. Methods: We conducted a meta-analysis of randomized controlled trials to determine if aerobic exercise influences episodic memory in late adulthood (M = 70.82 years) and examine possible moderators. Thirty-six studies met inclusion criteria, representing data from 2750 participants. Results: Here we show that aerobic exercise interventions are effective at improving episodic memory (Hedges'g = 0.28; p = 0.002). Subgroup analyses revealed a moderating effect of age (p = 0.027), with a significant effect for studies with a mean age between 55-68 but not 69-85. Mixed-effects analyses demonstrated a positive effect on episodic memory among studies with a high percentage of females (65-100%), participants with normal cognition, studies reporting intensity, studies with a no-contact or nonaerobic physical activity control group, and studies prescribing >3900 total minutes of activity (range 540-8190 min). Conclusions: Aerobic exercise positively influences episodic memory among adults ≥55 years without dementia, with larger effects observed among various sample and intervention characteristics-the clearest moderator being age. These results could have far-reaching clinical and public health relevance, highlighting aerobic exercise as an accessible, non-pharmaceutical intervention to improve episodic memory in late adulthood.

Aerobic exercise, cardiorespiratory fitness, and the human hippocampus.

The hippocampus is particularly susceptible to neurodegeneration. Physical activity, specifically increasing cardiorespiratory fitness via aerobic exercise, shows promise as a potential method for mitigating hippocampal decline in humans. Numerous studies have now investigated associations between the structure and function of the hippocampus and engagement in physical activity. Still, there remains continued debate and confusion about the relationship between physical activity and the human hippocampus. In this review, we describe the current state of the physical activity and exercise literature as it pertains to the structure and function of the human hippocampus, focusing on four magnetic resonance imaging measures: volume, diffusion tensor imaging, resting-state functional connectivity, and perfusion. We conclude that, despite significant heterogeneity in study methods, populations of interest, and scope, there are consistent positive findings, suggesting a promising role for physical activity in promoting hippocampal structure and function throughout the lifespan.

Differences in adolescent cerebral perfusion as a function of obesity: Results from the FLEX-Brain study.

OBJECTIVE: Children and adolescents have greater resting cerebral blood flow (rCBF) during periods of rapid brain growth. Overweight and obesity have a global impact on brain cerebrovascular health in adults, but whether these effects are discernable in adolescents with overweight and obesity remains unknown. This study examined differences in rCBF between adolescents with a healthy weight (HW) and adolescents with overweight or obesity (OW). METHODS: The current study focused on analyzing data from 58 participants (mean age = 15.43 [SD 1.37] years). Participants were classified into OW (n = 38) and HW groups (n = 20) according to the Centers for Disease Control and Prevention's guidelines for children. Voxelwise t tests between the HW and OW groups were conducted to test for regional group differences in rCBF, controlling for age and sex. Mean rCBF was extracted from a gray matter mask to compare global rCBF between the HW and OW groups. RESULTS: The HW group had greater rCBF compared with the OW group in five clusters, with peaks in the cerebellum, precentral gyrus, and supplementary motor area. No clusters survived correction for the OW > HW contrast. Global rCBF did not significantly differ between the groups (p = 0.09). CONCLUSIONS: These results suggest that overweight and obesity in adolescence are associated with discernable reductions in blood flow to specific brain regions rather than having a global impact on rCBF.

The fitness versus body fat hypothesis in relation to hippocampal structure.

The Fitness Versus Body Fat Hypothesis argues that cardiorespiratory fitness (CRF) plays a more important role in cardiovascular health than adiposity. It remains poorly understood whether CRF or adiposity accounts for a greater amount of variation in measures of brain health. We examined the contribution of CRF, adiposity, and their interaction with hippocampal structure. This study included 124 sedentary adults (M = 44.34) with overweight/obesity (Body Mass Index mean = 32.43). FMRIB's Integrated Registration and Segmentation Tool was used to segment the hippocampus. Using hierarchical regression, we examined whether CRF, assessed via a submaximal graded exercise test, or adiposity, assessed as percent body fat using dual-energy x-ray absorptiometry (DXA) was associated with left and right hippocampal volume. Vertex-wise shape analysis was performed to examine regional shape differences associated with CRF and adiposity. Higher CRF was significantly associated with greater left hippocampal volume (p = .031), with outward shape differences along the surface of the subiculum and CA1 regions. Adiposity was not associated with left or right hippocampal volume or shape. The interaction between adiposity and CRF was not significant. Neither CRF nor adiposity were associated with thalamus or caudate nucleus volumes or shapes, two control regions. Higher CRF, but not adiposity, was related to greater left hippocampal volume, with outward shape differences along the surface of the subiculum and CA1 regions in a midlife sample with overweight/obesity. These findings indicate that, within the context of obesity, CRF is an important contributor to hippocampal structure, highlighting the importance of interventions targeting CRF.

Measuring instrumental activities of daily living in non-demented elderly: a comparison of the new performance-based Harvard Automated Phone Task with other functional assessments.

BACKGROUND: Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer's disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants. METHODS: Twenty-nine CN and 17 MCI participants were administered the Harvard APT, the computer performance-based Czaja Functional Assessment Battery (CFAB), and the AD Cooperative Study ADL prevention instrument (ADCS ADL-PI) participant and study partner versions; in addition, 52 different CN and 7 MCI participants were administered the Harvard APT and the Subjective Study Partner and Participant-reported (SSPP) IADL scale. The Harvard APT was compared with the three other IADL assessments. RESULTS: In both CN and MCI, better performance on the Harvard APT was associated with better performance on the CFAB. In CN, better performance on the Harvard APT was associated with better ADCS ADL-PI participant-reported IADL, while in MCI better performance on the Harvard APT was associated with better ADCS ADL-PI study partner-reported IADL. Furthermore, in CN better performance on the Harvard APT was associated with better SSPP-IADL participant and study partner-reported IADL. CONCLUSIONS: In this small pilot study, the Harvard APT, a brief, self-administered, objective measure of IADL performance, appears to correlate well with other sensitive measures of everyday functioning, providing good preliminary convergent validity for this new measure. Moreover, it appears to perform well across both CN and MCI participants, which suggests that it is a promising measure of early, clinically meaningful functional change. This may not be the case as suggested in our small sample for subjective IADL scales that may perform differentially depending on the reporter (self vs. study partner) across the clinical spectrum possibly due to diminishing awareness of IADL difficulties in individuals who become cognitively impaired. Secondary prevention trials in AD have a great need for such ecologically valid and reliable measures of early IADL changes.

Subjective cognitive concerns are associated with objective memory performance in Caucasian but not African-American persons.

Objective: subjective cognitive concerns (SCC) have been proposed as a means of identifying individuals at risk for Alzheimer's disease (AD). However, the utility of SCCs has not been well-explored for African-Americans, who are twice as likely to develop AD dementia as Caucasians. We investigated whether race affects the association between SCCs and objective memory performance. Methods: we used a composite of three SCC questionnaires, and three challenging episodic memory tests. We studied 289 (61% female; African-American n = 47) clinically normal older individuals. Two hierarchical linear regressions assessed the modifying role of race on the association between SCC and objective memory performance. The first regression was conducted on the full sample, while the second matched the racial groups on age, estimated verbal IQ and socioeconomic status. Results: in the full sample, both groups reported similar levels of SCCs, P = 0.10, although African-Americans performed worse on the memory tasks, P < 0.001. No group differences were observed in the matched sample. The SCC × race interaction term was nonsignificant in the full sample, ß = 0.109, P = 0.09, but was significant in the matched sample, ß = 0.422, P = 0.037. While a significant correlation was observed between SCCs and memory among Caucasians, r = -0.401, the correlation was not found among African-Americans, r = -0.052. Conclusions: results suggest that the dissociation between SCCs and memory performance in African-Americans may indicate qualitative differences in how diverse groups endorse cognitive concerns, even after considering socioeconomic and educational factors.

Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly.

BACKGROUND: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. OBJECTIVE: To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. DESIGN: In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task's ability to discriminate across diagnostic groups at baseline was also assessed. SETTING: Academic clinical research center. PARTICIPANTS: Two hundred and seven participants (45 young normal, 141 clinically normal elderly, and 21 mild cognitive impairment) were recruited from the community and the memory disorders clinics at Brigham and Women's Hospital and Massachusetts General Hospital. MEASUREMENTS: Participants performed the three tasks of the Harvard Automated Phone Task, which consist of navigating an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, repetitions, and correct completion of the task. The primary outcome measure used for each of the tasks was total time adjusted for correct completion. RESULTS: The Harvard Automated Phone Task discriminated well between young normal, clinically normal elderly, and mild cognitive impairment participants (APT-Script: p<0.001; APT-PCP: p<0.001; APT-Bank: p=0.04). Worse baseline Harvard Automated Phone Task performance or worsening Harvard Automated Phone Task performance over time tracked with overall worse performance or worsening performance over time in global cognition, processing speed, executive function, and episodic memory. CONCLUSIONS: Prior cross-sectional and current longitudinal analyses have demonstrated the utility of the Harvard Automated Phone Task, a new performance-based activities of daily living instrument, in the assessment of early changes in complex activities of daily living in non-demented elderly at risk for Alzheimer's disease. Future studies will focus on cross-validation with other sensitive activities of daily living tests and Alzheimer's disease biomarkers.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global ß-Amyloid Burden.

Importance: The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical ß-amyloid [Aß] and tau) provides an important opportunity to understand the basis of SCD and AD risk. Objective: To examine associations between SCD and global Aß and tau burdens in regions of interest in clinically healthy older adults. Design, Setting, and Participants: This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11-labeled PET (PiB-PET) imaging for Aß. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016. Main Outcomes and Measures: Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The Aß level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of Aß, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score. Results: Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high Aß burden. Greater SCD was associated with increasing entorhinal cortical tau burden (ß = 0.35; 95% CI, 0.19-.52; P < .001) and Aß burden (ß = 0.24; 95% CI, 0.08-.40; P = .005), but not inferior temporal tau burden (ß = 0.10; 95% CI, -0.08 to 0.28; P = .27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for Aß burden (ß = 0.36; 95% CI, 0.15-.58; P = .001), and no interaction influenced SCD (ß = -0.36; 95% CI, -0.34 to 0.09; P = .25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex. Conclusions and Relevance: Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of Aß. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

The influence of demographic factors on subjective cognitive concerns and beta-amyloid.

BACKGROUND: Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aß) burden. METHODS: In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63-90 years (mean 73.7±6) with 6-20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aß burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aß burden and SCC. A post-hoc mediation model was implemented to further understand the relationship between Aß burden and SCC via their relationship with education. RESULTS: Age (ß = -0.84, p = 0.36) and sex (ß = -0.55, p = 0.22) did not modify the relationship between SCC and Aß burden. Fewer years of education was correlated with greater SCC (r = -0.12, p = 0.05), but the relationship between Aß burden and SCC was stronger in those with more education (ß = 1.16, p < 0.05). A partial mediation effect was found of Aß burden on SCC via education (b = -0.12, 95% CI [-0.31, -0.02]). CONCLUSIONS: These findings suggest that the association between SCC and Aß burden becomes stronger with greater educational attainment. Thus, SCC may be of particular importance in highly educated CN individuals harboring amyloid pathology.

The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials.

BACKGROUND: Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. OBJECTIVES: We used a Computerized Cognitive Composite for Preclinical Alzheimer's Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. DESIGN SETTING PARTICIPANTS: Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women's Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at-home measuring episodic memory, reaction time and working memory. MEASUREMENTS: A reliability analysis explored equivalence of the six alternate C3-PAD test versions. A feasibility assessment calculated the percentage of individuals who completed all at-home tests correctly, in contrast to incomplete assessments. Correlational analyses examined the association between C3-PAD-clinic compared to C3-PAD-home assessments and between C3-PAD performance and standardized paper and pencil tests. RESULTS: Excellent reliability was observed among the 6 C3-PAD alternate versions (Cronbach alpha coefficient=0.93). A total of 28 of 49 participants completed all at-home sessions correctly and 48 of 49 completed four out of five correctly. There were no significant differences in participant age, sex or education between complete and incomplete at-home assessments. A single in-clinic C3-PAD assessment and the at-home C3-PAD assessments were highly associated with each other (r2=0.508, p<0.0001), suggesting that at-home tests provide reliable data as in-clinic assessments. There was also a moderate association between the at-home C3-PAD assessments and the in-clinic standardized paper and pencil tests covering similar cognitive domains (r2= 0.168, p< 0.003). CONCLUSIONS: Reliable and valid cognitive data can be obtained from the C3-PAD assessments in the home environment. With initial in-clinic training, a high percentage of older individuals completed at-home assessments correctly. At-home cognitive testing shows promise for inclusion into clinical trial designs.

The Apathy Evaluation Scale: A Comparison of Subject, Informant, and Clinician Report in Cognitively Normal Elderly and Mild Cognitive Impairment.

BACKGROUND: Apathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and possibly preclinical AD. OBJECTIVE: To compare the three AES sub-scales - subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C) - over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). METHODS: Mixed effects longitudinal models were used to assess predictors of score for each AES sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. RESULTS: Fifty-seven MCI and 18 CN subjects (ages 53-86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. CONCLUSION: In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia.