Frontiers in Aging Neuroscience

BackgroundAn increase in pulse pressure, the difference between systolic and diastolic blood pressure, has emerged as a predictor of cognitive impairment in older adults. However, its predictive utility relative to blood pressure status and potential differential effects based on blood pressure status remain unclear. MethodsThis study used data from the ACTIVE trial (N = 2,802 adults aged 65+) to examine the association between pulse pressure and cognitive decline over 10 years. Linear mixed-effects models assessed the relationship between pulse pressure, blood pressure, and decline in global cognition, memory, reasoning, and processing speed. ResultsHigher pulse pressure was associated with faster global cognitive decline (b= -0.003, 95% CI [-0.004, -0.001]) after controlling for demographics, cognitive training status, and attrition. This effect was consistent for the memory and reasoning domains. The effects remained significant after adjusting for blood pressure status, with pulse pressure demonstrating complementary predictive utility to blood pressure. Specifically, the negative effect of pulse pressure on global cognitive decline was observed only among participants with elevated blood pressure (b = -0.005, 95% CI [-0.005, -0.002]), not in those with normal blood pressure. This pattern was consistent across the three cognitive domains. ConclusionsPulse pressure is associated with accelerated cognitive decline among older adults, but this relationship is moderated by blood pressure status. Pulse pressure monitoring could improve cognitive risk assessment in older adults with elevated blood pressure. This underscores the importance of managing blood pressure to mitigate the risk of cognitive decline associated with increased pulse pressure.

PurposeAtrophy of the hippocampus is an early biomarker of Alzheimers disease (AD) and a main contributor to the patients mnemonic degeneration. While previous research has mostly focused on how hippocampal atrophy impaired long-term memory performance, its relation to short-term memory impairment, which was also found among patients with AD, remains largely uninvestigated. Filling this gap, the current study examined how atrophy in the hippocampus and its subfields may have influenced visual short-term memory (VSTM) in patients with amnestic mild cognitive impairment (aMCI), a common precursor of AD. MethodsFifty-eight aMCI patients and 69 healthy controls (HC) matched in age were included in the current study. VSTM was assessed using an adapted change detection task with a memory load of 2 or 4 items. Hippocampal subfields were automatically segmented in T1-weighted image using FreeSurfer and were manually inspected for errors. Volumes of the subfields were extracted and compared between aMCI and HC subjects using ANCOVA with age, gender and education as covariates. Furthermore, we also examined the partial correlation between VSTM performances and hippocampal subfield volumes with age, gender and education as covariates. ResultsCompared to HC subjects, aMCI subjects had lower response accuracy (ACC) and lower memory capacity under both load conditions and had longer reaction time (RT) in the 2-load condition. Left hippocampus volume was significantly smaller in aMCI and was positively correlated with ACC and capacity in HC but not in aMCI. Among the hippocampal subfields, left hippocampal tail, left molecular layer, left dentate gyrus (DG), left CA4, bilateral subiculum, bilateral presubiculum, bilateral fimbria, were significantly smaller while right hippocampal fissure was significantly widened in aMCI compared to HC. Volumes of the left subiculum, left molecular layer, left DG and left CA4 were positively correlated with ACC and capacity in HC but not in aMCI. Bilateral fimbria volume was negatively correlated with RT under the 2-load condition in HC but not in aMCI. ConclusionThe results of this study suggested that hippocampal deterioration, especially in subfields related to information input and output (e.g. molecular layer, DG, subiculum), may have contributed to VSTM impairment in aMCI by disrupting hippocampal-cortical communications. This finding adds to increasing evidence of hippocampal engagement in short-term memory processes and points to VSTM impairment as a potential neuropsychological indicator for MCI and AD.

Alzheimers disease (AD) is correlated with brain atrophy, neuronal loss, neurotransmitter imbalance, and cognitive decline, which also occur in normal aging. Thus, comparing the differences between normal aging and AD is of interest in order to test the accelerated aging hypothesis of AD. An imbalance between excitatory/inhibitory (E/I) neurotransmission, especially in gamma-aminobutyric acid (GABA) inhibition dysfunction, is involved in both AD and normal aging. In the present study, we performed correlation analyses between electroencephalograms (EEGs) and memory in middle-aged ([~]12 months old) wild-type mice (WT) and AD model mice (APP/PS1) after E/I balance adjustment via GABAA agonist muscimol and antagonist bicuculline administration (0.1 mg/kg intraperitoneally). Specifically, EEGs of the hippocampus and prefrontal cortex were recorded during Y-maze performance. Overall, WT and AD mice showed different correlation patterns between EEG activity and behavioral memory performance. Significant correlations were observed in EEG activity across a wider range of frequency bands (2-100 Hz, except 4-8 Hz) in WT mice, but were mainly observed in low frequency bands (delta-theta, 2-8 Hz) in AD mice. In addition, muscimol and bicuculline treatment contributed to better brain function in AD mice; in contrast, bicuculline administration resulted in poorer brain function in WT mice. Thus, our study suggests that AD shows a distinct pattern of disrupted brain function, rather than accelerated aging. Importantly, this work reveals new insights into future AD treatment by influencing low-frequency EEG activity through E/I balance adjustment, thereby aiding cognitive recovery.

BackgroundCognition may be influenced by health-related factors such as blood pressure (BP). However, variations in BP may differentially affect cognition as a function of race. This study investigates the relationship between normal, high, and variable BP and cognitive decline in older Black and White adults. Methods2284 participants (1139 Blacks, 1145 Whites, MAge=73.4, SD=6.6) from 3 harmonized cohorts of older adults from the Rush Alzheimers Disease Center, were divided into 3 groups (normal, high, variable) based on systolic BP mean and standard deviation. Cognitive scores were computed from multiple assessments in 5 domains (i.e., episodic memory, semantic memory, working memory, processing speed, visuospatial ability). Performance across 19 tests were averaged to create a measure of global cognition. Linear mixed-effects models examined racial differences between BP and cognitive change over an average of 6.7 years. ResultsWhite adults with high or variable BP had faster rates of decline in global cognition compared to Black adults. White adults with high BP declined faster in perceptual speed, semantic memory, and working memory compared to Black adults with high BP, whereas White adults with variable BP had faster rates of decline in all cognitive domains compared to Black adults with variable BP. No racial differences were observed in individuals with normal BP. ConclusionsWhite older adults with elevated or fluctuating BP show faster rates of cognitive decline compared to older Black adults. Findings highlight the complex interplay between BP and cognitive health, emphasizing the need for targeted interventions to address racial disparities in cognitive well-being.

Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to interrogate the functional integrity of the hippocampal trisynaptic circuit (HTC), which is known to participate in memory, to determine whether age-associated increases in MAP contributes to circuitry dysfunction that may lead to mild-cognitive impairment (MCR). Ripples, and specifically sharp-wave ripple oscillations, play a role in memory replay and consolidation during awake immobility among other behaviors. These synchronous high frequency local field potentials (LFPs) in the ripple band (140 to 200 Hz) serve as an HTC level surrogate marker for circuitry function in rodents, non-human primates, and humans. Thus, we asked whether age-associated increased MAP might alter ripple dynamics. Recognizing that each patient responds in a unique way to hypertension we used a within subject design wherein each animal served as its own control in the investigative model. We surgically implanted high density silicon probe electrodes in HTC CA1 of young and aged SD males to determine whether a nootropic drug, 5IA, a negative allosteric modulator of 5 subunit containing type-A GABA receptors, could detect aberrant modulation of ripples within each subject. Here we report that acute oral administration of 5IA selectively modulated ripple amplitude, but not its duration or frequency during epochs of awake immobility. The response of peak ripple amplitude to 5IA is substantially diminished when chronic MAP exceeds 160 mmHg, corresponding to significant hypertension. The results are consistent with a model in which age-associated increases in MAP is associated with dysfunctional 5 GABA-A receptor modulation of ripple amplitude, but not duration or frequency, as a potential precision biomarker for memory dysfunction. SummaryAge-related neurogenic hypertension disrupts memory and ripple band neural circuitry function in the hippocampal trisynaptic circuit involved in memory consolidation.

Connectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity and balance. Our results show that greater S1-M1 and cerebellar-M1 connectivity was related to greater postural sway during standing. This may be indicative of an increase in functional recruitment of additional brain networks to maintain upright balance despite differences in network connectivity. Also, cognition moderated the relationship between S1-M1 connectivity and balance, such that those with lower cognition had a stronger relationship between connectivity and balance performance. It may be that individuals with poor cognition need increased recruitment of brain regions (compensation for cognitive declines) and in turn, higher wiring costs, which would be associated with increased functional connectivity.

Neural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Age-dependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22- to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuN-positive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

The discovery that metabolic alterations often coexist with neurodegenerative conditions has sparked interest in the examination of gastrointestinal factors as potential modulators of brain health. Here, we examined the role of adipokines (leptin, adiponectin, resistin, and IL6) and insulin on different markers of brain atrophy in participants on the spectrum of Alzheimers Disease. We included 566 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset with 1063 follow-up time points (average follow-up: one year); and examined the association between gastrointestinal factors and volumetric MRI values, white matter hyperintensities, and measures of cognitive impairment. Higher leptin, resistin, IL6, and insulin were associated with markers of cerebral atrophy, such as lower total brain volume, or higher ventricular volume. Higher leptin and resistin were also associated with greater impairment in daily life activities. Higher adiponectin was associated with lower ventricle volume. There was no association between adipokines or insulin with white matter hyperintensities. Our findings indicate a co-occurrence between alterations in gastrointestinal factors and in brain volume along the preclinical to clinical spectrum of Alzheimers Disease. These results suggest that strategies aimed at promoting metabolic health may positively impact brain health.

The rostral ventrolateral medulla (RVLM), a part of the medullary reticular formation, plays a major role in several physiological responses, including cardiovascular and sympathetic nervous system functions. Although aging causes disturbances in the responses of these physiological systems, RVLM involvement in these age-related changes is not clear. Previous work using high-throughput gene expression analysis of the RVLM in aged animals suggested that chemical neurotransmission-related genes might be downregulated with advancing age. Since RVLM function involves a balance of signals from inhibitory and excitatory inputs, which is largely mediated by gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission, we hypothesized that aging is associated with altered excitatory and/or inhibitory neurotransmission-related gene expression in the RVLM. To test this hypothesis, we micropunched an RVLM-containing area from young (3-5 months), middle-aged (12-14 months), and aged (22- 26 months) Fischer 344 male rats. RNA purified from these micropunches was analyzed using GABA and Glutamate RT2 Profiler PCR arrays (n= 8-10). Each profiler array has primers for 84 GABA and glutamate neurotransmission related genes. In addition, the expression of selected genes was validated at the RNA level using TaqMan(R) based-qPCR and at the protein level using western blotting. All the genes that displayed significant differential expression (1.5-fold, p < .05, FDR < .05) were identified to be downregulated in the RVLM of aged and middle-aged rats compared to young rats. This downregulation did not appear to be a result of RVLM tissue sampling differences among the age groups, since a separate validation of our sampling method, which involved careful mapping of micropunched regions to a standardized brain atlas, revealed no spatial differences in sampled sites among age groups. Among the downregulated genes, the percentage of glutamate neurotransmission-related genes was higher than GABA neurotransmission-related genes. The Solute carrier family 1 member 6 (Slc1a6) gene showed the highest fold downregulation at the RNA level in the RVLM of aged compared to young rats, and its protein product, Excitatory amino acid transporter 4 (EAAT4), showed a downregulatory trend in the RVLM of aged and middle-aged rats. These results suggest that molecular constituents of both GABA and glutamate neurotransmission might be altered in the RVLM of aged and middle-aged rats, and the changes in glutamate neurotransmission might be more prominent. Investigating age-associated anatomical and functional changes in RVLM GABA and glutamate neurotransmission might provide a foundation for understanding the effects of aging on physiological function.

BackgroundCognitive slowing accompanies normal aging, yet understanding of the mechanisms of slowing is limited at the network and neuronal level. Relating the pathophysiological factors responsible for cognitive slowing, and interpreting its relationship to working memory, requires multiscale computer modeling. ObjectiveThe aim of this research is to explore multiple mechanisms of cognitive slowing using computational modeling of the cortex to link neuronal activity with cognitive content. MethodWe developed multiscale computer models of a simple cognitive task - Condition 1 of the Stroop recognition task - using the Nengo system, a cognitive simulation environment with a semantic pointer architecture developed to model cognitive tasks using spiking neural networks. We explored how changes associated with aging such as increased input noise, axonal loss, neuronal loss, and feedback would affect the function of the models. ResultsAxonal loss and increased input noise produced profound slowing. High levels of neuronal loss severely impaired memory and paradoxically decreased slowing via the ability to respond more quickly by "releasing" a prior memory. Increased feedback improved memory at the cost of increased slowing. ConclusionOur simulations suggest that significant slowing could be caused by white matter loss (axonal loss) or input signal degradation (which could be caused by visual or other afferent system worsening). As neuronal loss markedly decreased the duration of working memory, we propose that physiological feedback is increased to preserve working memory at the cost of further cognitive slowing.

Normal aging in humans and non-human primates is associated with a decline in cognitive functions. Subject-wise differences in cognitive decline can be attributed to different degrees of damage to cortical white matter (WM) which is largely affected by neuroinflammation during aging. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have recently been identified as a potential immunomodulatory therapeutic for brain damage and Alzheimers disease (AD) and related dementias by suppressing neuroinflammation. Here, we evaluated the efficacy of MSC-EVs for slowing or ameliorating cognitive decline during aging in rhesus monkeys, a well-studied model of normal aging that is free of extensive AD pathology. We report that late middle-aged monkeys treated with MSC-EVs every two weeks for 18 months showed improved performance on a task of spatial working memory relative to vehicle control monkeys. In addition, we used diffusion magnetic resonance imaging (MRI) and resting state functional MRI to evaluate structural white matter and functional network changes in vivo. Imaging data revealed that MSC-EV treatment preserved prefrontal and temporal WM structural integrity and large-scale functional network connectivity that are correlated with early, increased CSF levels of amyloid beta protein. Amyloid beta levels at 12 months are also correlated with improved cognitive performance at the end of the 18 months of treatment. These findings suggest that MSC-EVs can mitigate age-related cognitive decline by potentially enhancing the CSF clearance of neurodegenerative proteins, which correlates with greater WM integrity and functional brain connectivity.

ObjectiveThe human brain is influenced by different biological rhythms, including the daily 24-hour (diurnal) cycle. Past studies have reported evidence of variation in cognitive performance over the course of the day, and of differences in the peak time for cognition in older age. Here, we investigated these questions using two existing longitudinal studies of healthy adults. MethodsTime of neuropsychological battery testing was extracted from study records, and we analyzed cognitive performance measures from 4 domains (Vocabulary, Processing Speed, Fluid Reasoning, and Episodic Memory) in 543 healthy adults between the ages of 20 and 80. Time of day was dichotomized as morning (281 tested before noon), and afternoon (242 tested after noon). ResultsMultivariate analyses controlling for both gender and years of education revealed no significant effect of time of testing (or its interaction with participant age) on cognitive performance. These results suggest that diurnal effects during time periods typically used to test human subjects are unlikely to have a meaningful effect on performance on the neuropsychological tests that are used for standard cognitive assessment. ConclusionThis suggests that the effect of time of day on cognition in the context of aging may not be as ubiquitous as previously suggested, and thus is unlikely to represent a large confound in existing studies of cognition across the adult lifespan.

Astrocytes are glial cells that participate in multiple physiological functions, such as protecting neurons against all types of damage. However, astrocytes develop morphological alterations during aging, such as decreased length, volume, and branch points of their processes, also known as astrocytic atrophy. Until now, the exact mechanism associated with the onset of atrophy is unknown. Tree shrew (Tupaia belangeri) is a long-lived animal from the Scadentia order that develops several age-dependent brain alterations. In this study, we analyzed the morphology of GFAP+ astrocytes in the hippocampal region of adult, old, and aged male tree shrews. Aged animals presented more GFAP+ astrocytes in the proximal subiculum, CA3, and CA2-CA1 subregions than younger animals, being significantly higher only in CA3. However, in aged subjects, the number of atrophic astrocytes was significantly higher in the dentate gyrus and CA2 subregion compared to old animals. Interestingly, in the proximal subiculum, astrocytes had a reduced arborization at all ages evaluated. S100A10, a protein overexpressed by neuroprotective-type astrocytes, was mainly found in the nucleus of astrocytes of adult and old subjects. However, in old and aged animals, S100A10 was located in the cytoplasmic compartment of atrophic astrocytes. Furthermore, in astrocytes of aged tree shrews, cytoplasmic inclusions of S100A10 colocalized with the nuclear export protein, Crm-1. These results suggest that the transport of S100A10 from the nucleus to the cytoplasmic compartment of astrocytes could be a process related to astroglial atrophy during the aging process in the hippocampus of three shrews.

ObjectivesTo explore the cognitive profile in urban Indian older adults and observe the prevalence of cognitive impairment associated with age, glycated hemoglobin (HbA1c) levels, vitamin B12, and other psychosocial factors MethodsUrban community dwelling older adults (55-85years, n=123) underwent a detailed demographic and cognitive assessment comprising of tests from different cognitive domains - memory, executive function, visuospatial abilities, and verbal fluency. Serum samples were collected from a subset of participants (n=60) to determine HbA1c and vitamin B12 levels. ResultsPerformance in all cognitive domains declined with age. The decline became prominent around age 70. HbA1c correlated inversely with processing speed and executive function. Vitamin B12 did not correlate with performance on any cognitive test. Geriatric depression correlated inversely with visuospatial abilities. Surprisingly, stepwise multiple regression revealed that HbA1c and geriatric depression contributed to 28% variance on Montreal Cognitive Assessment whereas participant age did not contribute significantly. Mild Cognitive Impairment (MCI) was observed in 17% of participants. Participants classified as MCI had higher levels of HbA1c and geriatric depression, and lower performance in all cognitive domains compared to non-MCI participants. ConclusionAlthough cognitive performance declined with age, HbA1c and geriatric depression played a greater role than age in predicting cognitive decline. This study highlights the prevalence of metabolism linked changes in cognition in community dwelling Indian older adults.

BackgroundThe brainstem and its different sub-systems control essential functions such as motor agility etc. that worsen with age. The purpose of this study was: 1. To assess the impact of age-related volume loss within three brainstem sub-systems on functions supported by them. 2. To use data-driven machine learning to identify different volume loss patterns or subtypes and investigate how they are associated with function. MethodsStructural MRI and behavioral data from 674 Human Connectome Project Aging (HCA) participants was used in this project. The brainstem was extracted, internal brainstem structures segmented and the segmentations warped onto a probabilistic population atlas on which the nuclei of interest had been labeled. Jacobian deformation maps were calculated, each rois mean Jacobians extracted and converted into z-scores with and without correction for age. Linear regression analyses were used to assess volume - function (cognition, motor agility, autonomic control) associations for each roi belonging to the sub-system supporting these functions. Subtype and Stage Inference (SuStaIn) was used to identify different volume loss patterns in each sub-system. ResultsAge explained larger percentage of the variation of the behavioral variables than brainstem volumes. SuStaIn identified up to 4 subtypes, one representing typical aging and the remainder atypical aging. The subtypes did not significantly differ behaviorally with the exception of grip strength and diastolic blood pressure. ConclusionAging affects brainstem systems which contributes to the worsening of these functions with increasing age. SuStaIn detected different patterns of volume loss or subtypes within each of the brainstem systems.

It is now acknowledged that Alzheimers Disease (AD) processes are present decades before the onset of clinical symptoms, but whether lifestyle activities can protect against these early AD processes in mid-life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies [Deng et al. (2022) and Heneghan et al. (2022)] on the contribution of mid-life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort of the PREVENT-Dementia research program (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance. Participants (40-59 years; N = 461) completed cognitive and clinical assessments cross-sectionally. Mid-life activities were measured with the Lifetime of Experiences Questionnaire. Known risk factors for sporadic late-onset AD (Apolipoprotein E [E]4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were investigated. Replicating our key previous findings (Deng et al., 2022 and Heneghan et al., 2022), we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score, (b) positively associated with stimulating lifestyle activities, and (c) that females performed significantly better than males in episodic and relational memory. The key novel finding of this study was that inherited dementia risk (i.e., APOE [E]4 genotype) modulated the association between sex, lifestyle and cognition. Only for APOE [E]4+ females, not APOE [E]4-, higher occupational attainment was associated with better episodic and relational memory. Conversely, only for APOE [E]4+ males, not APOE [E]4-, higher occupational attainment was associated with worse episodic and relational memory. These findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of Alzheimers disease. Furthermore, these findings suggest an urgent need for targeted research on female-specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health.

Sporadic or late onset Alzheimers disease (LOAD) is a multifactorial neurodegenerative disease with aging the most known risk factor. Non-human primates (NHPs) may serve as an excellent model to study LOAD because of their close similarity to humans in many aspects including neuroanatomy and neurodevelopment. Recent studies reveal AD-like pathology in old NHPs. In this pilot study, we took advantage of brain samples from 6 Cynomolgus macaques that were divided into two groups: middle aged (average age 14.81 years) and older (average age 19.33 years). We found multiple AD-like pathological alteration in the prefrontal cortex (but not in the hippocampus) of the older NHPs including tau hyperphosphorylation, increased activity of AMP-activated protein kinase (AMPK), decreased expression of protein phosphatase 2A (PP2A), impairments in mitochondrial morphology and postsynaptic densities (PSDs) formation. These findings may provide insights into the factors contributing to the development of LOAD, particularly during the early stage transitioning from middle to old age. Future endeavors are warranted to elucidate mechanisms underlying the regional (and perhaps cellular) vulnerability with aging and the functional correlation of such pathological changes in NHPs.

It is now acknowledged that Alzheimers disease (AD) neuropathology starts decades before the onset of clinical symptoms, but it remains unknown whether modifiable lifestyle factors can protect against these incipient AD processes, early, in mid-life. Cognitive reserve can explain cognitive preservation in some older adults despite ageing or dementia symptoms, but it is not known whether it can protect against neurodegeneration in mid-life. We asked whether modifiable lifestyle activities contribute to cognitive reserve in mid-life, and whether it can offset the risk of AD in individuals who are cognitively healthy. Cognition, structural, and functional brain health measures were assessed at baseline and two years follow-up, in a cohort of middle-aged participants (N = 210; 40-59 years). Mid-life activities were measured using the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities and known risk factors for sporadic late-onset AD (i.e., the Cardiovascular Risk Factors Aging and Dementia [CAIDE] score) on measures of cognition and brain health. Multivariable linear regression found that mid-life activities made a unique contribution to cognition, independent of education and occupation. Crucially, mid-life activities moderated the relationship between cognitive ability (verbal and visuospatial functions, and conjunctive short-term memory binding) and brain health. Cognitive ability of people with higher mid-life activities, particularly those with high dementia risk scores, was less dependent on their brain functional architecture. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously been associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. These findings suggest that modifiable activities contribute uniquely to cognitive reserve in midlife, and may offset the risk of AD. The modifiability of these activities supports their targeting by public health initiatives aimed at dementia prevention.

Post-stroke cognitive decline (PSCD) poses a significant challenge to long-term recovery and quality of life following stroke, influenced by both fixed biological factors and modifiable health behaviors such as oral and dental care. In this data-driven exploratory analysis of the PREMIERS Phase II randomized trial (ClinicalTrials.gov NCT#02541032), we examined the moderating effects of clinical, biological, and demographic characteristics on the relationship between dental care and PSCD over a 12-month period. The study included 280 stroke/transient ischemic attack (TIA) survivors who received either intensive or standard dental care. Cognitive outcomes were assessed using the Montreal Cognitive Assessment (MoCA) at baseline and follow-up, with change in MoCA score as the primary outcome. Lasso regression was applied for empirically based feature selection of moderators, and bootstrapped multiple linear regression demonstrated that increased dental visits predicted relatively better cognitive outcomes in older adults (age interaction-term {beta} = -0.664, p < 0.001), Black participants (race interaction-term {beta} = -0.475, p < 0.05), and those with low-intermediate education levels (education interaction-term {beta} = 0.413, p < 0.05). Exploratory graphs revealed that older adults, Black adults, and adults with low-intermediate education showed greater cognitive improvement with higher dental visit frequency, with the final model (including selected moderators) significantly predicting PSCD (F(11, 268) = 10.51, p = 5.17 x 10-16). These findings highlight the potential of equity-focused, precision-medicine interventions that incorporate dental care to mitigate PSCD in vulnerable stroke populations.

Healthy aging brings widespread shifts in aperiodic (non-oscillatory) electroencephalographic (EEG) components, which may underlie physiological changes in cognitive performance. Education, a known protective factor against age-related decline in cognitive performance, has been largely overlooked in studies linking aperiodic EEG components to cognition. This study addresses this gap, hypothesizing that education moderates the interplay between age, aperiodic components, and cognitive performance, as measured by Mini-Mental State Examination (MMSE) scores. We reanalyzed an open-source EEG dataset of 714 healthy individuals aged 18-91 years using Generalized Additive Mixed Models. Aperiodic exponent and offset both declined with age, but higher education levels mitigated these declines. Notably, exponent and offset interacted with age and education in predicting MMSE performance in the bilateral cingulate, left hippocampus, bilateral parietal, right occipital, and left temporal regions. Among older adults, the relationship between the aperiodic components and cognitive performance diverged by education: those with lower education showed worse cognitive outcomes with lower exponents and offsets, whereas higher-educated individuals after 60 years showed a reverse pattern, with lower exponents and offsets predicting better MMSE performance. Our findings suggest that the link between aperiodic components and cognitive aging is not straightforward but depends on moderating factors such as education. These results underscore the importance of accounting for individual differences, like educational background, when exploring age-related changes in EEG aperiodic components and cognition.