Resistance training enhances delayed memory in healthy middle-aged and older adults: A randomised controlled trial

Objectives High-intensity exercise is a potential therapeutic tool to postpone or prevent the onset of cognitive decline. However, there is a lack of sufficient evidence regarding the longitudinal effects of structured resistance training on cognitive function in healthy adults. The purpose of this study was to investigate the effect of two ecologically valid, intense 12-week resistance training programs on cognitive function in late middle-aged adults. Design Single-site parallel randomised controlled trial at the Department of Exercise Science strength and conditioning laboratory. Groups allocated by minimisation randomisation. Methods Forty-five healthy adults (age range = 41-69 years) were enrolled and randomised into A.) high-load, long rest resistance training (n = 14), or B.) moderate-load, short rest resistance training (n = 15) twice per week for 12 weeks, or a non-exercising control (n = 16). Follow-up within 7 days. Data were collected September 2016-December 2017. Cognitive function assessed using the CogState computerised battery. Assessors were blinded to participant group allocation. Secondary outcomes were maximal muscle strength and body composition. Results Forty-four participants were analysed in 2018. Delayed verbal memory performance was improved (p = 0.02) in resistance training groups (g = 0.67-0.79) when compared to the control group, with no differences between training groups. Likewise, increases in maximal muscle strength were observed (p < 0.01) in resistance training groups when compared to the control group, with no differences between training groups. No differences in body composition were observed. There were no adverse events or side-effects of the intervention. Conclusions 12 weeks of intense resistance training improves delayed verbal memory irrespective of training design (i.e., high-load vs. moderate-load)

The peripheral hearing and central auditory processing skills of individuals with subjective memory complaints

Purpose: This study examined the central auditory processing (CAP) assessment results of adults between 45 and 85 years of age with probable pre-clinical Alzheimer’s disease – i.e., individuals with subjective memory complaints (SMCs) as compared to those who were not reporting significant levels of memory complaints (non-SMCs). It was hypothesized that the SMC group would perform significantly poorer on tests of central auditory skills compared to participants with non-SMCs (control group). Methods: A total of 95 participants were recruited from the larger Western Australia Memory Study and were classified as SMCs (N = 61; 20 males and 41 females, mean age 71.47 ±7.18 years) and non-SMCs (N = 34; 10 males, 24 females, mean age 68.85 ±7.69 years). All participants completed a peripheral hearing assessment, a CAP assessment battery including Dichotic Digits, Duration Pattern Test, Dichotic Sentence Identification, Synthetic Sentence Identification with Ipsilateral Competing Message (SSI-ICM) and the Quick-Speech-in-Noise, and a cognitive screening assessment. Results: The SMCs group performed significantly poorer than the control group on SSI-ICM −10 and −20 dB signal-to-noise conditions. No significant differences were found between the two groups on the peripheral hearing threshold measurements and other CAP assessments. Conclusions: The results suggest that individuals with SMCs perform poorly on specific CAP assessments in comparison to the controls. The poor CAP in SMC individuals may result in a higher cost to their finite pool of cognitive resources. The CAP results provide yet another biomarker that supports the hypothesis that SMCs may be a primary indication of neuropathological changes in the brain. Longitudinal follow up of individuals with SMCs, and decreased CAP abilities should inform whether this group is at higher risk of developing dementia as compared to non-SMCs and those SMC individuals without CAP difficulties

Amyloid-Related memory decline in preclinical Alzheimer’s Disease is dependent on APOE ε4 and is detectable over 18-Months

High levels of β-amyloid (Aβ) in the brain and carriage of the APOE ε4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. However, the relationship between these two biomarkers and cognitive decline is unclear. The aim of this study was to investigate the relationship between cerebral Aβ level, APOE ε4 carrier status, and cognitive decline over 18 months, in 317 cognitively healthy (CN) older adults (47.6% males, 52.4% females) aged between 60 and 89 years (Mean = 69.9, SD = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Aβ who were also APOE ε4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE ε4 non-carriers, high Aβ was unrelated to cognitive decline in learning and working memory. Carriage of APOE ε4 in CN older adults with low Aβ was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Aβ and APOE ε4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Aβ and APOE ε4 as biomarkers of early Alzheimer’s disease

A randomized controlled trial of high-intensity exercise and executive functioning in cognitively normal older adults

Background There is a paucity of interventional research that systematically assesses the role of exercise intensity and cardiorespiratory fitness, and their relationship with executive function in older adults. To address this limitation, we have examined the effect of a systematically manipulated exercise intervention on executive function. Methods Ninety-nine cognitively normal participants (age = 69.10 ± 5.2 years; n = 54 female) were randomized into either a high-intensity cycle-based exercise, moderate-intensity cycle-based exercise, or no-intervention control group. All participants underwent neuropsychological testing and fitness assessment at baseline (preintervention), 6-month follow-up (postintervention), and 12-month postintervention. Executive function was measured comprehensively, including measures of each subdomain: Shifting, Updating/ Working Memory, Inhibition, Verbal Generativity, and Nonverbal Reasoning. Cardiorespiratory fitness was measured by analysis of peak aerobic capacity; VO2peak. Results First, the exercise intervention was found to increase cardiorespiratory fitness (VO2peak) in the intervention groups, in comparison to the control group (F =10.40, p≤0.01). However, the authors failed to find mean differences in executive function scores between the high-intensity, moderate intensity, or inactive control group. On the basis of change scores, cardiorespiratory fitness was found to associate positively with the executive function (EF) subdomains of Updating/Working Memory (β = 0.37, p = 0.01, r = 0.34) and Verbal Generativity (β = 0.30, p = 0.03, r = 0.28) for intervention, but not control participants. Conclusion At the aggregate level, the authors failed to find evidence that 6-months of high-intensity aerobic exercise improves EF in older adults. However, it remains possible that individual differences in experimentally induced changes in cardiorespiratory fitness may be associated with changes in Updating/ Working Memory and Verbal Generativity

Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort

Introduction: Alzheimer's disease (AD) is a growing socioeconomic problem worldwide. Early diagnosis and prevention of this devastating disease have become a research priority. Consequently, the identification of clinically significant and sensitive blood biomarkers for its early detection is very important. Apolipoprotein E (APOE) is a well-known and established genetic risk factor for late-onset AD; however, the impact of the protein level on AD risk is unclear. We assessed the utility of plasma ApoE protein as a potential biomarker of AD in the large, well-characterised Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) cohort. Methods: Total plasma ApoE levels were measured at 18-month follow-up using a commercial bead-based enzyme-linked immunosorbent assay: the Luminex xMAP human apolipoprotein kit. ApoE levels were then analysed between clinical classifications (healthy controls, mild cognitive impairment (MCI) and AD) and correlated with the data available from the AIBL cohort, including but not limited to APOE genotype and cerebral amyloid burden. Results: A significant decrease in ApoE levels was found in the AD group compared with the healthy controls. These results validate previously published ApoE protein levels at baseline obtained using different methodology. ApoE protein levels were also significantly affected, depending on APOE genotypes, with ε2/ε2 having the highest protein levels and ε4/ε4 having the lowest. Plasma ApoE levels were significantly negatively correlated with cerebral amyloid burden as measured by neuroimaging. Conclusions: ApoE is decreased in individuals with AD compared with healthy controls at 18-month follow-up, and this trend is consistent with our results published at baseline. The influence of APOE genotype and sex on the protein levels are also explored. It is clear that ApoE is a strong player in the aetiology of this disease at both the protein and genetic levels

Alzheimer’s disease cerebrospinal fluid biomarkers are not influenced by gravity drip or aspiration extraction methodology

Introduction: Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. Methods: Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. Results: For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Aβ42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Aβ42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. Conclusions: Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Oestrogen replacement therapy may improve memory functioning in the absence of APOE e4

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an ε4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 ± 6.34); ERT non-users (n = 80, mean age 67.03 ± 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE ε4 allele. APOEε4 carriers receiving ERT performed no better on episodic memory testing than APOE ε4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE ε4 allele

BDNF Val66Met moderates the relationship between cardiorespiratory fitness and memory in cognitively normal older adults

Higher cardiorespiratory fitness has been associated with enhanced cognitive function in older adults; yet, this relationship demonstrates a degree of variability. Thus, it is hypothesised that variation in genetic factors may influence the relationship between fitness and cognitive health. In this study we evaluate whether the BDNF Val66Met polymorphism moderates the relationship between cardiorespiratory fitness and verbal and visuospatial memory. Data from ninety-nine cognitively normal men and women aged 60 – 80 years were used. Fitness was assessed by peak oxygen consumption, and verbal and visuospatial memory were evaluated using well-validated measures. Participants were categorised into: lower-fit Met carriers, higher-fit Met carriers, lower-fit Val/Val, or higher-fit Val/Val. A significant interaction was observed between BDNF Val66Met and fitness on visuospatial memory performance; whereby lower-fit Met carriers performed 1SD lower than higher-fit Met carriers (p=0.04). We observed higher levels of fitness mitigated the deleterious effect of BDNF Met allele carriage on visuospatial memory. Future intervention studies should evaluate the effect of structured exercise on cognitive health between BDNF Val66Met carriers and Val/Val homozygotes

Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts