Frontiers in Aging Neuroscience

Introduction: Cognitive intraindividual variability (IIV), a measure of fluctuation in performance across time or tasks, is an emerging marker of cognitive decline. However, little is known about within-domain IIV in Latino adults. To address this gap, we examined memory IIV and hippocampal integrity in older Latino individuals. Methods: Sixty-seven participants from the Boston Latino Aging Study underwent cognitive testing and MRI. Linear regressions assessed whether memory IIV was associated with hippocampal volume and hippocampus-cingulum tract fractional anisotropy. Additional analyses evaluated associations using mean memory performance as the outcome. Results: Higher mean performance was associated with greater hippocampal volume (=0.24, p=.03), while memory IIV was not (=0.028, p=.84). Higher memory IIV was associated with lower fractional anisotropy in the hippocampus-cingulum tract (=-0.34, p<.01), while mean performance was not (=-0.07, p=.52). Discussion: Memory IIV may be more closely linked to hippocampal white matter, while mean memory performance may better reflect hippocampal volume.

Ageing is often associated with a decline in cardiovascular and cerebrovascular health. This study examines the relationship between cerebral arterial elasticity and measures of cardiovascular health, as well as longitudinal changes in cerebral arterial elasticity over a 1.5 year interval. The pulse relaxation function (PReFx) is a measure of regional cerebral arterial elasticity derived using diffuse optical tomography (pulse-DOT). PReFx was measured over the anterior brain, including the frontal lobes and anterior sections of temporal and parietal regions that are especially vulnerable to vascular and cognitive ageing. We examined relationships between PReFx and measures of four cardiovascular risk factors (CVRF; i.e., hypertension, cholesterol, diabetes, obesity), as well as CVRF burden (i.e., number of CVRFs) in the highly active and cognitively healthy ACTIVate cohort (60-70 years). We replicated the well-established relationship between PReFx and both age and cardiorespiratory fitness, and examined associations between PReFx, measures of cardiovascular health and CVRF burden. Higher CVRF burden was linearly associated with lower cerebral arterial elasticity. The relationship between age and cerebral arterial elasticity was partially mediated by pulse pressure, an index of hypertension. PReFx declined significantly in as little as 1.5 years, and the effect did not vary with baseline level of any of the four CVRFs. We conclude that PReFx shows promise as a putative biomarker for monitoring cerebrovascular ageing in healthy older adults.

INTRODUCTION: Tau pathology in Alzheimers disease preferentially afflicts excitatory neurons in the limbic and association cortices that utilize high levels of calcium signaling to perform cognitive operations. This includes the layer III pyramidal cells in the dorsolateral prefrontal cortex (dlPFC) that subserve higher cognition, which express the calcium-binding protein, calbindin, when young and healthy, but lose calbindin and develop tangles and degenerate in Alzheimers disease (AD). These data suggest that loss of calbindin may be associated with the emergence of tau pathology. However, the relationship between calbindin and early-stage, soluble tau pathology is challenging to study in human brains, as soluble pTau dephosphorylates within 15min postmortem. In contrast, the relationship between calbindin and soluble pT217-tau expression can be studied in aging macaques with naturally-occurring tau pathology, where perfusion fixation is possible to capture phosphorylation state in situ. METHODS: The current study used multiple-label-immunofluorescence to label MAP2-positive dlPFC layer III pyramidal cells for calbindin and pT217-tau in macaque brains across the adult age span (8-34.5yrs). The study employed a semi-automated CellProfiler workflow to identify labeled pyramidal cell dendrites the cellular compartment where tau pathology begins in AD. RESULTS: Calbindin expression decreased with age, while pT217Tau increased with age. Specifically, the ratio of calbindin/pT217-tau within a dendrite decreased with age, and was especially prominent in the aged macaques with long-term inflammatory disorders. DISCUSSION: These data suggest that the loss of calbindin in dendrites with advancing age, and especially with inflammation, contributes to the rise of tau pathology and the risk of AD.

INTRODUCTION: Alzheimer's disease (AD) involves early sensory and perceptual changes that can precede memory decline. We developed a two-layer rate-based neural model of early and higher visual areas with feedforward, feedback, and recurrent connections to examine how excitatory/inhibitory (E/I) balance shapes visual motion perception in AD. METHODS: Using Motion-Induced Position Shift and Altered Motion Repulsion stimuli, we factorially manipulated excitatory (E) and inhibitory (I) subfield power and connectivity to examine their effects on illusion representation across visual layers. RESULTS: Increased E, decreased I, and increased E/I reduced illusion representation, consistent with reduced illusion susceptibility in AD, whereas the converse increased illusion representation, reflecting neurotypical processing. Higher-level layer 2 representations were more resistant to E/I perturbations than lower-level layer 1. Illusion representation was less affected by E/I increases in intra-areal (recurrent) connectivity than in inter-areal (feedforward/feedback) connectivity. DISCUSSION: This mechanistic framework links E/I balance and connectivity to altered visual motion illusion representations in AD and suggests that E/I and connectivity measures may provide probes of early AD neurobiology. The framework may also generalize beyond vision.

BACKGROUND: Accumulations of AD and LATE-NC both contribute to changes in hippocampal volume, possibly via distinct and/or overlapping mechanisms. Microglia-driven inflammation is a shared pathway associated with both AD and LATE-NC. However, the extent to which microglia inflammation is associated with hippocampal volume is less understood. OBJECTIVE: Examine the relationship between AD and LATE-NC with hippocampal volume in persons with differing levels of microglia inflammation. METHODS: Cerebral hemispheres from 441 older adults who came to autopsy were studied. All hemispheres underwent ex-vivo MRI and detailed neuropathologic examination for neurodegenerative and cerebrovascular pathologies. Microglia were quantified in the hippocampal CA1/subiculum region using machine learning-based classifiers trained on digitized CR3-43-stained images via the HALO digital pathology platform. First, linear regression models examined the association of microglia with hippocampal volume, adjusting for demographics, postmortem interval (PMI), and common age-related pathologies. Second, linear regression models were employed to examine whether microglia density modified associations of {beta}-amyloid, tangle, or LATE-NC on hippocampal volume. RESULTS: Participants had a mean age of 90 years at death with 75% being women. Intermediate or high likelihood ADNC was present in 64% and LATE-NC (stage 2/3) was present in 52%. In linear regression models, adjusting for demographics and PMI, higher microglia density was associated with a lower hippocampal volume to hemisphere ratio (estimate = -0.021 SE=0.01, p=0.002); however, after adjusting for common age-related pathologies the association was attenuated (p=0.70). {beta}-amyloid, tangles, and LATE-NC remained independently associated with a lower hippocampal volume. The association of LATE-NC with hippocampal volume was stronger in brains with greater microglia burden (estimate for the interaction term = -0.016; SE=0.01, p=0.002). No interactions were seen between {beta}-amyloid or tangles with microglia on hippocampal volume. In stratified analyses, microglial density modified the association between LATE-NC and hippocampal volume, independent of AD neuropathologic status. CONCLUSION: Microglia-driven inflammation strengthens the association of LATE-NC, but not AD pathology, on hippocampal volume loss. These findings emphasize the importance of inflammatory pathways [when interpreting MRI-based neurodegeneration markers] in aging and mixed pathology.

Apolipoprotein E (APOE) genotype is theorised to influence dementia risk partly through effects on blood-brain barrier (BBB) function, but clinical studies examining APOE effects on BBB biomarkers report inconsistent results. Therefore, this systematic review and meta-analysis quantified associations between APOE genotype and two commonly used fluid biomarkers of CNS barrier function: cerebrospinal fluid (CSF)/serum albumin quotient (Q-Alb), and soluble platelet-derived growth factor receptor beta (sPDGFRB). Ovid MEDLINE, Embase, and Web of Science were searched on 30th June, 2026. Eligible peer-reviewed human studies reported Q-Alb or blood or CSF sPDGFRB; by APOE genotype. Risk of bias was assessed using the Joanna Briggs Institute checklist. Twenty-eight studies involving 5,375 participants were included: 17 assessed Q-Alb and 11 assessed sPDGFRB. Random-effects meta-analyses determined that APOE e2 carriage was associated with higher Q-Alb (g = 0.29, 95% CI 0.11 to 0.46). APOE e4 carriage was not associated with Q-Alb overall (g = .13, 95% CI -.17 to .43) or sPDGFRB overall (g = .10, 95% CI -.21 to .40). Genotype-specific Q-Alb analyses suggested medium positive but non-significant effects among e4/e4 and e2/e4 carrier subgroups. For sPDGFRB, exploratory subgroup analysis revealed effect estimates near zero in cognitively unimpaired participants, and a small positive non-significant effect in cognitively impaired participants. Larger effects were also observed in samples with an older mean age, although this was not statistically significant. Overall, evidence for APOE e4-associated alterations in Q-Alb and sPDGFRB remained inconclusive, highlighting the need for further study across the spectrum of cognitive ageing and dementia. In contrast, APOE e2 carriage was associated with greater barrier dysfunction as indexed by Q-Alb, broadening the predominant focus on APOE e4 and identifying e2 as a potentially important but understudied contributor to altered neurovascular function.

Background: Alzheimer's Disease and Related Dementias (ADRD) is a growing global public health challenge, and caregivers experience high rates of burden, unmet needs, and system failures. These challenges vary by caregiver role and relationship to the care recipient, reflecting the heterogeneous nature of caregiving. Yet prior work has largely studied burden, unmet needs, and system failures as separate domains rather than examining how they co-occur within individual caregivers. Methods: We applied an LLM-based classification framework (Claude 3.5 Sonnet) to 7,198 posts from three ALZConnected caregiver forums (general, spouse/partner, and adult child caregivers), coding each post for burden, unmet needs, and system failures across 9, 12, and 10 categories respectively. We compared expression rates by caregiver role (primary vs. secondary) and relationship to the care recipient (spousal vs. child) and used post-level co-occurrence networks to map how categories cluster within and across domains. Results: Burden was expressed in 89.0% of posts and unmet needs in 93.3%, while system failures appeared in 34.8%. Primary caregivers reported burden more often than secondary caregivers (91.6% vs. 84.7%), while secondary caregivers reported more unmet needs (94.6% vs. 92.5%) and more system failures (37.2% vs. 33.4%). Child caregivers reported higher rates than spousal caregivers across all three domains. Co-occurrence networks showed dense within-domain clustering (density 0.61-0.65) and 84 significant cross-domain connections, with the strongest links between behavioral/safety burden and safety-management needs (21.7% of posts) and between emotional burden and emotional-support needs (20.9%). Conclusion: Burden, unmet needs, and system failures are not independent problems but form interconnected challenge ecosystems that vary by caregiver role and relationship. This suggests caregiver support should be designed around these connected patterns rather than treated as separate, single-domain interventions.

Background: Aging-related changes in motor performance are associated with a widespread reorganization of the motor network. Despite extensive research on altered brain activity patterns in aging, the underlying neurophysiological mechanisms driving these reorganizational changes remain incompletely understood, particularly regarding the role of inhibitory control. Methods: We here combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to examine aging-related alterations in local excitability, oscillatory dynamics, and neural coupling in the motor system. Brain responsivity was probed by applying single-pulse TMS to the primary motor cortex (M1) in younger and older subjects at rest. Results: Our findings indicated reduced cortical excitability in the stimulated M1 of older participants, consistent with an age-related reduction of GABAergic inhibitory control. Phase-locking analyses revealed reduced intra- and interhemispheric coupling in lower frequency bands, suggesting decreased inhibitory output from the stimulated M1. Moreover, older individuals demonstrated less localized event-related desynchronization (ERD) with greater power decreases in the prefrontal cortex contralateral to the stimulation site, indicating enhanced prefrontal involvement in the aging motor system. Conclusions: Together, these findings underline the relevance of alterations in inhibitory processes in the motor network in aging and point to a shift from an automatic, locally driven towards a broader, putatively more cognitively controlled sensorimotor processing in older adults.

Alzheimers Disease (AD) and related dementias (AD/RDs) impact cortical motor and sensory biology whereas the precise changes to these systems, and their clinical relevance, remain under debate. We hypothesized that cortical representations of complex and simple movements are differently altered during disease progression in 5XFAD mice, a well-established model of AD. Motor cortex somatotopy was determined in 5XFAD and Wild-Type Control (WT Control) mice at 6 and 12 months (mos.) of age using long-duration intracortical microstimulation (LD-ICMS) to systematically identify cortical sites evoking complex and simple forelimb movements. At 6 mos. of age, 5XFAD mice exhibited a significant expansion of motor cortical sites representing simple movements, specifically Elbow Flexion (p=0.0004) and Wrist Flexion (p=0.024). The over-sized territory for Elbow Flexion significantly distinguished 5XFAD from WT mice (Receiver Operating Characteristic [ROC] area under the curve [AUC]= 0.94, p= 0.0009) whereas discriminative performance of Wrist Flexion was a non-significant trend (AUC=0.75, p=0.059). By 12 mos. of age, motor cortex organization was markedly reorganized in 5XFAD mice, with significantly fewer cortical sites evoking complex Advance movement (p<0.0001) as well as simple Shoulder (p=0.0001), Elbow Extension (p=0.024), and Wrist Extension (p=0.003) movements. The number of sites for simple Wrist Flexion was significantly increased (p=0.011) in 12 mo. old 5XFAD mice. At 12 mos., territory size of several of these movement zones highly distinguished 5XFAD from WT mice, including Advance (AUC= 0.96, p= 0.0005), Shoulder (AUC= 0.97, p= 0.0004), Elbow Extension (AUC=0.78, p=0.034), Wrist Extension (AUC=0.85, p= 0.0082), and Wrist Flexion (AUC=0.80, p= 0.023). These findings demonstrate progressive, age-dependent remodeling of motor cortex somatotopy in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances. Motor cortex somatotopic remodeling may provide a sensitive biomarker of AD/RDs progression.

Introduction: Individuals diagnosed with mild cognitive impairment (MCI) have an increased risk of developing dementia. Since there are currently no curative pharmacological therapies for MCI, nonpharmacological and exercise-related medical therapies represent a promising approach. This study aims to evaluate the effects of nonpharmacological interventions on cognitive performance in individuals with MCI. Methods and analysis: The study will be a prospective, randomized, sham-controlled, single-centre superiority trial with a parallel-group design. A total of 100 patients aged 60 years with MCI will be randomly assigned to one of the three intervention groups or the control group. The three intervention arms comprise high-intensity interval training (HIIT), yoga, and intermittent hypoxia-hyperoxia exposure (IHHE), whereas participants in the control group will receive a sham application of IHHE (IHHE-S). The primary outcome is the cognitive function after 3-month intervention period assessed by Montreal Cognitive Assessment. The secondary outcomes and the evaluation of modifiable risk factors for dementia include quality of life, laboratory data, physical activity, anthropometric data, and cardiorespiratory fitness. All harms and (serious) adverse events will be assessed systematically at each study visit. Ethics and dissemination: This study has been approved by the Ethics committee of the Medical Faculty of the University of Tuebingen (494/2025BO1). Research findings will be published in peer-reviewed journals and presented to stakeholders and at scientific conferences.

Importance: Lower relative amplitude of the rest-activity pattern has been associated with cognitive decline and incident dementia in older adults, but its relationship with domain-specific cognitive performance during midlife is less well characterized. Objective: To examine cross-sectional associations between accelerometer-derived relative amplitude and fluid and crystallized cognitive performance among midlife adults. Design, Setting, and Participants: Cross-sectional analysis of 851 adults aged 35-64 years enrolled in the MidCog Study and recruited from 13 primary care clinics, including academic practices and federally qualified health centers. Participants completed a 14-day wrist accelerometer recording and the NIH Toolbox Cognition Battery. Exposure: Accelerometer-derived relative amplitude, calculated from the contrast between activity during the most active consecutive 10-hour period and the least active consecutive 5-hour period. Main Outcomes and Measures: Age- and education-adjusted NIH Toolbox T-scores (normative mean = 50, SD = 10) for the Fluid Cognition Composite; attention, executive function, episodic memory, working memory, and processing speed; the Crystallized Cognition Composite; receptive language and expressive language. Multivariable linear regression models sequentially adjusted for sociodemographic characteristics, other rest-activity rhythm metrics, established dementia risk factors, average activity, time in bed, and sleep efficiency. Results: In the final adjusted model, each 1-SD lower relative amplitude was associated with a 2.27-point lower Fluid Cognition Composite T-score (95% CI, 1.15-3.40). Lower relative amplitude was also associated with lower attention by 2.74 points (95% CI, 1.49-4.00), executive function by 1.49 points (95% CI, 0.51-2.47), episodic memory by 2.03 points (95% CI, 0.81-3.25), and processing speed by 1.56 points (95% CI, 0.49-2.64). Relative amplitude was not associated with working memory or crystallized cognitive outcomes. Conclusions and Relevance: Among midlife adults recruited from primary care practices, lower relative amplitude was associated with modestly poorer fluid cognitive performance after adjustment for established dementia risk factors and sleep characteristics. Relative amplitude may represent a scalable behavioral correlate of cognitive variability within the normative range. Longitudinal studies beginning in midlife are needed to establish temporality, predictive value, or modifiability.

Cross-sectional studies suggest associations between physical exercise and white matter in older adults, but evidence from randomized controlled trials is scarce. Neurite orientation dispersion and density imaging indices are biophysically informed metrics of white matter microstructure. Here, we tested whether a remotely delivered, 8-week multicomponent physical exercise intervention impacts neurite density (NDI) and orientation dispersion (ODI) across major white matter tracts in older adults. This secondary analysis of a randomized controlled trial included participants with available diffusion MRI data (n = 66; age: 66.4 {+/-} 3.6 y; 43 females). Participants were randomized to a multicomponent exercise (PAG, n = 34) or an active control (CON, n = 32) intervention. Intervention effects on NDI/ODI were tested using linear mixed-effects and Bayesian multilevel models adjusted for age and sex. A significant Timepoint x Group interaction was observed for NDI (p = 0.003) but not for ODI (p = 0.785), further confirmed in Bayesian analyses for 22 white matter tracts, indicating a greater increase in NDI in the PAG. The standardized composite VO2max score increased from pre- to post-intervention within the PAG, although the Timepoint x Group interaction was not significant (p = 0.079). Across all participants, pre-to-post changes in mean NDI were positively correlated with changes in VO2max, but this association did not differ between groups. Our results indicate that white matter microstructure remains responsive to short-term, multicomponent physical exercise in older adults.

In populations with well-preserved cognitive function, cognitive screening total scores tend to cluster near the ceiling, making it difficult to characterize age-group differences from total scores alone. We compared the temporal structure of word production, acoustic features, and the magnitude and timing of forehead total-hemoglobin (total-Hb) responses during a phonemic verbal fluency task in adults in their 40s and 70s. A total of 254 healthy participants (115 in their 40s, 139 in their 70s) completed a 60-s phonemic verbal fluency task requiring words beginning with the Japanese syllable /ka/, administered as part of the Japanese version of the Montreal Cognitive Assessment (MoCA-J). We derived the total word count, word counts in 10-s bins, mean inter-word pause duration, speech offset time, smoothed cepstral peak prominence (CPPS), jitter, and shimmer. Area under the curve (AUC) and time-to-peak (TTP) were computed from forehead total-Hb signals recorded with a wearable single-wavelength near-infrared spectroscopy device. MoCA-J scores clustered near the ceiling in both groups, although the age-group difference was significant. The 70s group produced fewer words (14.00 vs 17.09) and showed longer inter-word pauses (1.60 vs 0.72 s). CPPS was lower, AUC was higher, and TTP was longer (32.97 vs 15.63 s) in the 70s group, whereas jitter did not differ. Word counts across 10-s bins showed an age group time-bin interaction. Within each age group, participants who produced more words showed longer TTP. Age-group differences in TTP and AUC persisted after adjustment for speech offset time (proportions mediated, 6.7% and 0.5%) and in a subsample matched on speech offset time. Even when screening scores clustered at the ceiling, the temporal structure of word production and forehead total-Hb responses differed between age groups, and these two classes of measures dissociated. Because the sample was selectively recruited and single-wavelength total-Hb signals do not index localized neural activity, the findings are descriptive and motivate longitudinal, multi-axis characterization of speech in aging.

Signal peptide peptidase-like 2b (SPPL2b) is a brain-enriched intramembrane protease implicated in synaptic function, immune signaling, and neuronal development, but its physiological role in brain and neuronal homeostasis remains poorly understood. We investigated the impact of constitutive Sppl2b deletion on the brain proteome and neuronal function using quantitative shotgun proteomics in cortex and hippocampus from wild-type and SPPL2b-deficient mice at 3 and 12 months, combined with western blot, immunofluorescence, dendritic spine analysis, and behavioral testing. SPPL2b deficiency was associated with alterations in biological processes linked to axonal transport and synaptic vesicle trafficking, including consistent upregulation of the kinesin motor protein KIF1A and vesicle-associated membrane protein 2 (VAMP2). SPPL2b deletion also attenuated age-associated proteomic changes in synaptic pathways and was accompanied by increased dendritic spine density, morphological remodeling of pyramidal neurons, increased locomotor activity, and reduced anxiety-like behavior. These findings reveal a previously unrecognized association between SPPL2b and synaptic proteome remodeling during aging and nominate SPPL2b-dependent pathways as candidates for further mechanistic and functional investigation in neurodegenerative disease.

Early detection of mild cognitive impairment (MCI) can be reliably achieved using measures of executive functions, however executive compensation can mask these changes in the earliest stages. Gaze behavior, specifically during visual search, has been hypothesized to measure executive functions and attention within MCI, but prior study has been inconclusive. This study characterized naturalistic visual search in MCI across distractor conditions and evaluated multivariate gaze-based classification of MCI from cognitively normal aging. In a cross-sectional, propensity-matched cohort of 62 CN and 62 MCI participants, participants completed a naturalistic scene-viewing search task under five distractor conditions (none, dissimilar, similar, background, and unexpected). Significant interactions were observed including in target dwell ratio and scanpath entropy, with trial-to-trial variability in area-of-interest coverage found to be higher in MCI. Repeated 10x5-fold cross-validation with feature selection discriminated CN from MCI with an area under the curve of 0.732 (95% CI [0.645, 0.818]); an expert-curated 14-feature panel reached 0.898 (95% CI [0.840, 0.949]). MCI-associated search disruption is displayed across qualitatively distinct distractor contexts, including in the absence of distractors, suggesting that naturalistic visual search merits evaluation as a candidate early-detection measure.

The discrepancy between chronological age and predicted brain age, derived from neuroimaging data, serves as a biomarker for neurological health. However, the exact electroencephalography (EEG) mechanisms contributing to the variation of brain age are yet to be understood. This paper comprehensively investigated the relationship between brain age estimated from EEG-based functional connectivity and cognitive or mental manifestations of healthy adults. A mean absolute error (MAE) of 5.97 and R-squared (R2) of 0.85 were reported for training data, while an MAE of 10.73 and R2 of 0.56 were reported for the prediction data. Increased brain age was found to be negatively related to the scores of memory and attention tasks. Most young adults (19 of 26) suffering from mental symptoms such as addictions, depression, phobia, and anorexia nervosa demonstrated higher brain age than their chronological age. Alcohol consumption was also significantly correlated to the difference between brain and chronological ages. The functional connectivity of frontal and central motor regions was found to be most distinguishing between individuals with high and low brain ages. These brain regions were significantly correlated with brain age but not chronological age, suggesting a relatively stronger relationship with biological age. Ablation studies further confirmed the importance of the frontal brain and all bands EEG in the prediction of brain age. This work advances the understanding of EEG mechanisms contributing to brain age and could provide an interpretation for physiological or psychological conditions associated with brain age.

Background Understanding the mechanisms underlying brain aging and age-related pathological changes is essential for advancing brain health research. Our group previously developed a mechanistic mathematical model of healthy brain, Chamberland et al. (2024) that integrates key biological processes involved in normal aging, from which Alzheimer's disease (AD) related changes may emerge naturally. Objectives To characterize and validate this brain model by evaluating its sensitivity, calibrating its parameters, and assessing generalizability in independent populations. Methods The model represents the evolution of key biological processes associated with brain aging, including amyloid beta (A{beta}), tau pathologies, neuroinflammation, and neuronal death. After identifying the 30 most influential parameters, we calibrated the model using cognitively normal (CN) participants from the AD Neuroimaging Initiative (ADNI) database (n = 211) by minimizing a loss function composed of three outcomes (AB) plaques, tau tangles, and neuronal density). The calibrated model was then applied to the UK Biobank cohort (n = 35,899) of normal controls (aged 44-82 years). The effects of sex and APOE were evaluated using stratified simulations. Results Parameter calibration significantly reduced the prediction errors for A{beta} and tau. Neuronal density predictions showed strong agreement in the UK Biobank cohort. The variance decomposition identified APOE status as a major contributor to variability in A{beta}. Conclusion Our validated brain health model links mechanistic pathways with population data and reproduces neuronal density patterns in an independent cohort. These findings support its use as a framework for studying brain aging and investigating how Alzheimer's disease related pathological changes may emerge with aging.

Reduced visibility is a common contributor to falls in older adults, but the neural processes that support safe locomotion under low lighting are not well established. In this study, 22 young (mean age = 22.5) and 20 older (mean age = 70.9) adults walked along a pathway under bright, ambient and dark lighting conditions while stepping over expected and unexpected obstacles projected on the floor. Mobile electroencephalography (EEG), combined with motion capture, was used to quantify spectral power changes during obstacle crossing preparation and the post-crossing phases, relative to a standing baseline. We identified that reduced lighting conditions elicited a widespread increase in cortical engagement, predominantly in the alpha band, during both preparation and reset phases. Obstacle negotiation recruited a distributed sensorimotor network, with reduced theta-alpha-beta desynchronisation during preparation and a robust post-movement beta rebound during the post-crossing reset phase. Expectation effects were modest, with unexpected obstacles inducing greater transient alpha-beta desynchronisation relative to expected obstacles, suggesting additional cortical resources are recruited under uncertainty. Age effects were minimal and limited to reduced frontal alpha desynchronisation in older adults compared to young adults during the preparation phase, possibly reflecting differences in walking speed rather than differences in neural control. In conclusion, environmental features such as low lighting and obstacle presence exert a stronger influence on cortical dynamics during walking than age and expectation effects alone. This provides a foundation for future work examining how these processes may differ in older adults at increased risk of falls.

Chimpanzees share a number of age-related brain changes with humans, such as reductions in neurons and increases in neuropathology. To date, there are no published studies of peripheral biomarkers related to Alzheimers pathology and their associations with age and cortical atrophy in chimpanzees. Here we examined cross-sectional differences and longitudinal changes in biomarkers of pathological protein aggregation, neuroinflammation, and microglial function measured in serum. We examined the relationships between biomarkers and clinically relevant biomarker ratios with both age and cortical atrophy. We found linear and quadratic relationships between age and several biomarkers and ratios. Most biomarkers increased with age. While controlling for sex, we found significant negative associations between age and sulci surface area, mean depth, and gray matter thickness and a positive association with fold opening. A{beta}42 and A{beta}40 showed higher biomarker values associated with lower surface area, mean depth, and gray matter thickness and higher fold opening values. The clinically relevant biomarker ratios were also associated with cortical atrophy - A{beta}42/A{beta}40 was negatively associated with gray matter thickness, and pTau217/A{beta}42 (both total and brain-derived) was positively associated with surface area and gray matter thickness and negatively associated with fold opening. Consistent with our hypotheses and previous findings in humans, many peripheral biomarkers associated with neurodegeneration and Alzheimers disease increase as chimpanzees age. We believe this is the first evidence demonstrating an association between these clinically relevant biomarkers of Alzheimers disease and phenotypes of brain aging in nonhuman primates, underscoring their importance as models of aging and neurodegenerative disease.

Sex-steroid hormones influence brain structure across aging, but their relationship to the cerebellum, a region implicated in cognition and vulnerable to age-related decline, remains poorly characterized, particularly longitudinally and across both sexes. We examined whether 17{beta}-estradiol, progesterone, and testosterone relate to cerebellar volume across two timepoints, and whether these relationships differ by sex. In a mixed-sex sample of aging adults (Baseline N = 137; Year 1 N = 93), free salivary hormones and cerebellar lobular volumes were quantified. Linear regression tested cross-sectional, predictive, and change-score hormone-volume associations, and formal hormone-by-sex interactions, in a priori primary and secondary cerebellar lobules of interest. Hormone-cerebellum relationships were consistently sex-differentiated. Estradiol change related to Crus I volume change in opposite directions in males and females, a dissociation extending across bilateral Crus I and Lobule VI, and Right Crus II. In females, greater increases in testosterone were associated with greater decline in Left Crus I and Right Lobule V volumes. In males, testosterone showed no significant associations in primary analyses, however, increases in estradiol were associated with larger volumes. Progesterone showed a male-specific cross-sectional association with Crus II. Several relationships ran opposite to the direction predicted by estradiols established neurotrophic role. Sex-steroid influences on the aging cerebellum are sex-differentiated, regionally specific, and may not be predicted exclusively by cortical or female-focused models. These findings establish the cerebellum as a potential site of sex-specific hormonal influence on brain aging and also further highlight the complexity of the impact of sex-steroid hormones on the aging brain.