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Exercise training is among the main strategies that have been proposed to promote cognitive and brain health outcomes in older individuals with and without cognitive impairment. The effects of exercise on cognition are mediated, in part, by structural and functional adaptations in the brain, including changes in gray matter volumes and white matter microstructural integrity. Muscular contractions during exercise produce a category of cytokines referred to as myokines, which represent a potential molecular pathway mediating neuroplastic adaptations and associated cognitive improvements in response to exercise. Understanding the ideal combination of exercise training parameters across populations and life stages could lead to interventions that promote greater effects on cognitive and brain health outcomes. Exercise training is an important strategy to counteract cognitive and brain health decline during aging. Evidence from systematic reviews and meta-analyses supports the notion of beneficial effects of exercise in cognitively unimpaired and impaired older individuals. However, the effects are often modest, and likely influenced by moderators such as exercise training parameters, sample characteristics, outcome assessments, and control conditions. Here, we discuss evidence on the impact of exercise on cognitive and brain health outcomes in healthy aging and in individuals with or at risk for cognitive impairment and neurodegeneration. We also review neuroplastic adaptations in response to exercise and their potential neurobiological mechanisms. We conclude by highlighting goals for future studies, including addressing unexplored neurobiological mechanisms and the inclusion of under-represented populations. [ABSTRACT FROM AUTHOR]

Abstract Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F [1,1599] = 7.4, p < 0.01) and 9-year change (F [1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, −1.7; 95% CI, −3.2 to −0.3) and female Val/Val carriers (difference, −5.6; 95% CI, −6.8 to −4.3). White female Met carriers showed a slower rate of change (annual rate of change = −0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, −0.2; 95% CI, −0.4 to −0.02) and male Met carriers (difference, −0.3; 95% CI, −0.5 to −0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders. Highlights • BDNF Val66Met polymorphism effect on cognitive decline is controversial and may be due to an interaction with biological sex. • There was an interaction such that the Met allele was protective against declines in executive functioning for females, but in white participants only. • Interaction between sex and BDNF Val66Met polymorphism was not seen in black participants. [ABSTRACT FROM AUTHOR]

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women. [ABSTRACT FROM AUTHOR]

Abstract: Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer''s disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons. [Copyright &y& Elsevier]

Objectives: Physical activity (PA) and total sleep time (TST) are each associated with cognition; however, whether these relationships vary by age and biological sex is unclear. We examined the relationships of PA or TST with cognition, and whether age and sex moderated these relationships, using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015).Study Design: A cross-sectional analysis of participants from the Comprehensive cohort of the CLSA with complete PA and sleep data (n = 20,307; age range 45-86 years).Main Outcome Measures: PA and TST were measured using the Physical Activity Scale for the Elderly (PASE) and self-reported TST over the past month. Cognition was indexed using a three-factor structural equation model (i.e., memory, executive function, and verbal fluency).Results: Non-linear restricted cubic spline models indicated that PA and TST explained statistically significant (p < 0.01) but modest variance of each cognitive domain (<1 % of 23-24 % variance). Age and sex did not moderate associations of PA with any cognitive domain. However, age and sex moderated relationships of TST with cognition, whereby: 1) associations of TST with memory decreased with age for males and females; and 2) males and females had different age-associated relationships of TST with executive function and verbal fluency.Conclusions: PA and TST modestly contribute to multiple domains of cognition across middle and older adulthood. Importantly, the association of PA with cognition does not appear to vary across middle or older adulthood, nor does it vary by biological sex; however, TST appears to have a complex relationship with multiple domains of cognition which is both age- and sex-dependent. [ABSTRACT FROM AUTHOR]

Abstract: Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women. [Copyright &y& Elsevier]

Abstract: Background: Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain. Scope of review: This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats. Major conclusions: Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning. General significance: Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females. [ABSTRACT FROM AUTHOR]

Abstract: Variations in maternal care affect the development of individual differences in learning and memory and neuroendocrine responses to stress in adult male offspring, but it is not known how variations in maternal care affect adult female offspring. The present study investigated the performance of adult Sprague–Dawley male and female offspring exposed to either low or high levels of maternal licking/grooming on a spatial memory task (Experiment 1) and the effects of acute stress on corticosterone levels and spatial memory performance (Experiment 2). In Experiment 1 rats were trained for 24 days on the spatial working/reference memory version of the radial arm maze (RAM). In Experiment 2, rats were trained on the same RAM task, exposed to an acute stress, and the effect of stress on corticosterone levels and subsequent spatial memory was examined. In Experiment 1, adult female offspring of low licking/grooming dams had enhanced working memory compared to all other groups. In Experiment 2, all groups of male and female offspring had enhanced working memory 24 h after exposure to acute 2 h restraint stress while reference memory was enhanced after stress in male and female offspring of low licking/grooming dams. Furthermore, female offspring of low licking/grooming dams showed the largest corticosterone response to the acute restraint stress compared to all other groups. Male offspring of low licking/grooming dams showed a flattened corticosterone response to stress. Thus variations in maternal care differentially affect working memory and stress reactivity in male and female offspring. [Copyright &y& Elsevier]

• Exercise helps maintain executive functions during prolonged bed rest in adults aged 55–65 years. • Exercise mitigates the effects of bed rest on the intraindividual variability in cognition. • The benefits of exercise for executive functions are more robust in women. Prolonged bed rest is prevalent among middle-aged and older adults and is associated with multiple negative health outcomes. Therefore, it is important that we better understand the utility of exercise training as a countermeasure to the adverse effects of bed rest. We examined the effect of exercise training on intraindividual variability in cognitive performance among adults aged 55–65 exposed to 14 days of physical inactivity modelled via 6° head-down tilt bed rest. The study is a non-blinded, parallel-group, proof-of-concept randomized controlled trial. Twenty-three healthy middle-aged and older adults (12 males, 11 females) aged 55–65 were randomized to: (1) 14 days of 6° head-down tilt bed rest (Control) or (2) 14 days of 6° head-down tilt bed rest with daily exercise (Exercise). The National Institutes of Health Toolbox Cognitive Battery assessed executive functions (Flanker incongruent/congruent and Dimensional Change Card Sort) and processing speed (Pattern Comparison). We assessed cognitive function at baseline, 6° head-down tilt bed rest midpoint, completion, and seven days following completion. We indexed intraindividual variability with two metrics: (1) residual intraindividual standard deviation and (2) intraindividual coefficient of variation. Flanker congruent and incongruent residual intraindividual standard deviations were the primary outcomes. Linear mixed models assessed between-group differences and the moderating effect of biological sex. At bed rest completion, Exercise had significantly lower (better) Flanker incongruent residual intraindividual standard deviation (estimated mean difference = −3.63, 95%CI -6.10;-1.17, p = 0.005) and intraindividual coefficient of variation (estimated mean difference = −0.10, 95%CI -0.19;-0.003, p = 0.022) vs. Control. Sex moderated the effect of exercise on Flanker incongruent intraindividual coefficient of variation. Exercise females had significantly lower intraindividual coefficient of variation vs. Control (estimated mean difference = −0.23; 95%CI -0.34;-0.12, p < 0.001). There were no significant between-group differences in processing speed intraindividual variability and summary scores of executive functions and processing speed (p s > 0.05). Exercise training during bed rest preserved intraindividual variability of executive functions but not processing speed. ClinicalTrials.gov NCT04964999 [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by severe cognitive decline and pathological changes in the brain (brain atrophy, hyperphosphorylation of tau, and deposition of amyloid-beta protein). Females have greater neuropathology (AD biomarkers and brain atrophy rates) and cognitive decline than males, however these effects can depend on diagnosis (amnestic mild cognitive impairment (aMCI) or AD) and APOE genotype (presence of ε4 alleles). Using the ADNI database (N = 630 females, N = 830 males), we analyzed the effect of sex, APOE genotype (non-carriers or carriers of APOEε4 alleles), and diagnosis (cognitively normal (CN), early aMCI (EMCI), late aMCI (LMCI), probable AD) on cognition (memory and executive function), hippocampal volume, and AD biomarkers (CSF levels of amyloid beta, tau, and ptau). Regardless of APOE genotype, memory scores were higher in CN, EMCI, and LMCI females compared to males but this sex difference was absent in probable AD, which may suggest a delay in the onset of cognitive decline or diagnosis and/or a faster trajectory of cognitive decline in females. We found that, regardless of diagnosis, CSF tau-pathology was disproportionately elevated in female carriers of APOEε4 alleles compared to males. In contrast, male carriers of APOEε4 alleles had reduced levels of CSF amyloid beta compared to females, irrespective of diagnosis. We also detected sex differences in hippocampal volume but the direction was dependent on the method of correction. Altogether results suggest that across diagnosis females show greater memory decline compared to males and APOE genotype affects AD neuropathology differently in males and females which may influence sex differences in incidence and progression of aMCI and AD. • CSF tau pathology was elevated in female APOEε4 carriers compared to male carriers. • CSF amyloid beta levels were reduced in male APOEε4 carriers relative to female carriers. • Severity of diagnosis decreased memory scores to a greater extent in females. [ABSTRACT FROM AUTHOR]

Sex differences are well-established in Alzheimer's disease (AD) frequency and pathogenesis, but are not mechanistically understood. Accelerated epigenetic age has been associated with both cognitive aging and AD pathophysiology, but has not been studied by sex in AD or related cognitive impairment. Using the ADNI cohort, we found that none of sex, cognitive impairment diagnosis, nor load of APOEε4 alleles (strongest genetic AD risk factor) were associated with epigenetic age acceleration (DNAmAge, Intrinsic DNAmAge, PhenoAge, or GrimAge), although females exhibit more accelerated epigenetic aging using the Skin & Blood clock in the transition from normal cognition to cognitive impairment than males. [ABSTRACT FROM AUTHOR]

Summary: Adult hippocampal neurogenesis is often associated with hippocampus-dependent learning and memory. Throughout a new neuron's development, it is differentially sensitive to factors that can influence its survival and functionality. Previous research shows that spatial training that occurred 6–10 days after an injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), increased cell survival in male rats. Because sex differences in spatial cognition and hippocampal neurogenesis have been reported, it is unclear whether spatial training would influence hippocampal neurogenesis in the same way in males and females. Therefore, this study examined sex differences in hippocampal neurogenesis following training in a spatial task. Male and female rats were trained in the spatial or cued version of the Morris water maze 6–10 days after one injection of BrdU (200mg/kg). Twenty days following BrdU injection, all animals were given a probe trial and perfused. Males performed better in the spatial, but not cue, task than females. Spatial training increased BrdU-labeled cells relative to cue training only in males, but both males and females showed greater activation of new cells (BrdU co-labeled with immediate early gene product zif268) after spatial training compared to cue training. Furthermore, performance during spatial training was positively correlated with cell activation in females but not males. This study shows that while spatial training differentially regulates hippocampal neurogenesis in males and females, the activity of new neurons in response to spatial memory retrieval is similar. These findings highlight the importance of sex on neural plasticity and cognition. [ABSTRACT FROM AUTHOR]