Veterans experience mild traumatic brain injury (mTBI) at significantly higher rates than civilians, alongside high rates of comorbid conditions such as PTSD, mood disorders, and alcohol abuse. These conditions have documented impacts on brain health that compound with age. Prior work has demonstrated reduced white matter (WM) integrity and greater age-related trends in WM deterioration in Veterans with mTBI compared to Veterans without mTBI. These studies provide important insights, yet were limited in their ability to differentiate mTBI effects from those of common comorbid conditions. It remains unclear whether specific WM tracts are more vulnerable to mTBI overall or if effects are limited to specific portions of tracts. This study assessed the impact of cumulative mTBI burden on WM aging in U.S. Veterans [n = 710, ages = 19-80, mean age = 37]. Associations between age, mTBI burden, and WM integrity measured via fractional anisotropy, and mean, axial, and radial diffusivity were analyzed using multivariate regression of whole-tract means and along-tract effect clustering via Freesurfer's TRACULA package. Whole-tract interactions by mTBI on age-related deterioration were found in the ventral cingulate bundle and optic radiation. Along-tract analysis identified interactions clusters along these and five additional tracts. In all cases, higher mTBI burden was associated with steeper cross-sectional relationships between age and microstructural integrity. mTBI differentially impacted specific sections of affected WM tracts. These results suggest greater age-related WM deterioration with higher mTBI burden after acute injury recovery extending into later age.

Mineralized blood vessels (MBV) are a form of vascular pathology associated with cerebrovascular aging and neurodegeneration; however, their regional distribution and clinicopathological correlates in Alzheimer disease (AD) remain poorly characterized. We examined 265 decedents with intermediate/high AD neuropathologic change from three Alzheimer's Disease Research Centers (Columbia University, University of California San Diego, and University of California Davis). Hematoxylin and eosin-stained sections from the posterior hippocampus, putamen, and globus pallidus were evaluated for MBV. Associations with demographic, clinical, genetic, and neuropathological variables were assessed using bivariate tests and multivariable logistic regression adjusting for age at death, sex, ethnicity, and center. MBV frequency differed across regions, with highest involvement in the globus pallidus (58.3%), followed by the posterior hippocampus (28.6%), and putamen (13.8%) (all pairwise p < 0.001). After covariate adjustment, MBV presence was not associated with sex, ethnicity, education, APOE ε4 carrier status, or cerebral amyloid angiopathy (CAA). After correction for multiple comparisons, MBV remained associated with état criblé in the putamen and globus pallidus (both FDR-adjusted p < 0.01), and concomitant Lewy body disease remained associated with reduced MBV presence in the posterior hippocampus and globus pallidus (both FDR-adjusted p < 0.05). Nominal associations with a history of transient ischemic attack (TIA) did not remain significant after correction for multiple comparisons. This study identified MBV as a regionally selective feature of cerebrovascular aging in AD, enriched in deep gray matter. MBV may contribute to regional vulnerability and pathological heterogeneity in the aging AD brain.

Although cortical thinning and atrophy are well documented in aging and neurodegenerative disease, the cortical structural features associated with preserved or superior cognition across typical adulthood remain incompletely characterized. We examined associations between cortical thickness and cognitive performance in a large, typically aging cohort and tested whether they vary by age and cognitive domain. We analyzed cross-sectional data from cognitively healthy adults in the Human Connectome Project-Aging/Aging Adult Brain Connectome, spanning middle (36-59 years), early older (60-79), and late older (80 +) adulthood. Sex-stratified, age-residualized factor scores for memory, fluid, and crystallized abilities classified participants as high, middle, and low performers. Whole-brain cortical thickness was compared across groups. Descriptively, the largest and most consistent effects were observed for fluid abilities in midlife, with higher performance associated with greater thickness in bilateral somatomotor, visual, and auditory cortices. These effects spanned multiple sensory and motor regions and were replicated in stringent subsamples, including longitudinally stable and cross-domain high-performance groups. The observed patterns appear to be driven primarily by reduced thickness in low performers rather than by a distinct structural signature of high performers. Differences in cortical thickness between performance groups diminished with advancing age. These findings are consistent with the possibility that greater cortical thickness in sensory and motor cortices reflects a developmental structural advantage associated with higher fluid intelligence during middle adulthood. However, this advantage may not be sufficient to sustain high cognitive performance in later life, when other neural mechanisms may become increasingly important.

Studies of centenarians and supercentenarians provide insight into aging and substrates of cognitive impairment at the extreme limits of age. In this study, we examined pathologic findings in 15 centenarians (99-109 years) and 7 supercentenarians (111-115 years) who underwent autopsy at our institution during a 25-year period between 2000 and 2025 and compared them with a cohort of 24 older adults (70-90 years) who underwent autopsy during 2024-2025. Of the 22 centenarians and supercentenarians, 15 underwent full autopsies and 7 had brain only examinations. The average age at death of the centenarians/supercentenarians was 105 ± 5.8 years (5 males and 17 females). Of those who underwent a complete autopsy, the most common cause of death was pneumonia in 10 individuals followed by cardiac amyloidosis in 5. There was a wide spectrum of Alzheimer disease (AD) neuropathologic change with some individuals showing modest AD changes despite their advanced age. Amyloid plaque burden did not differ between older adults, centenarians and supercentenarians, but centenarians/supercentenarians had a higher burden of neurofibrillary tangles. Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was seen in 59% of centenarian/supercentenarian participants compared with 29% of older adults while hippocampal sclerosis (HS) was seen in nearly half of centenarians and supercentenarians but not in older adults. Centenarians and supercentenarians had a higher frequency of aging-related tau astrogliopathy (ARTAG) in the frontal lobe compared with older adults (36% vs 4%). Furthermore, a higher proportion of centenarian and supercentenarian individuals demonstrated more severe cerebrovascular disease, including atherosclerosis of the basal vasculature, moderate to severe arteriolosclerosis and lacunar infarcts and microinfarcts. Thus, although our findings are based on a convenience sample and may not be generalizable to all centenarians and supercentenarians, individuals at the extreme limits of age had a high frequency of ARTAG, LATE-NC, HS, and cerebrovascular disease.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimer's disease (AD). Diffusion magnetic resonance imaging (dMRI) metrics of white matter microstructure are hypothesized to be sensitive to inflammation, though few studies have assessed this relationship in non-clinical populations. This cross-sectional study of 457 dementia-free older adults (Mage=63.82) examined associations of plasma markers related to inflammation with white matter microstructure metrics from multi-shell dMRI Neurite Orientation Dispersion and Density Imaging (NODDI) and conventional, single-shell dMRI metrics. Plasma inflammatory markers included high-sensitivity C-reactive protein (CRP), a composite of pro-inflammatory cytokines, and glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher cerebral free water fraction (FWF) and higher cerebellar peduncle orientation dispersion index (ODI). Higher CRP was associated with higher cerebral and cerebellar ODI, which was non-significant after adjusting for additional demographics and vascular risk factors. Higher GFAP was associated with lower cerebral FWF and lower cerebral and cerebellar neurite density index (NDI). The only significant association with conventional DTI metrics was between higher cytokine composite levels and higher cerebral mean diffusivity (MD). Results were consistent after accounting for plasma AD biomarkers. Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (FWF, ODI, NDI, and MD), supporting the sensitivity of these dMRI-based metrics to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types, with multi-shell approaches like NODDI providing information beyond conventional, single-shell dMRI.

Bilingualism has been proposed to confer advantages in cognitive aging, yet the neural mechanisms underlying any such advantages remain debated. In a pre-registered analysis of cross-sectional and longitudinal data from elders in the HABS-HD cohort, we asked whether bilingualism is associated with three measures of brain structure (total brain volume, hippocampal volume and white-matter lesions) and/or moderates the relationship between brain structure and two measures of cognition (executive function and episodic memory). Overall, we found no significant differences between bilinguals and monolinguals in their baseline brain structure or subsequent change in brain structure, suggesting that a life of bilingualism was not clearly associated with Brain Reserve or Brain Maintenance in old age. In baseline analyses, bilingualism moderated the relationship between total brain volume and executive function, and between hippocampal volume and episodic memory, such that these cognitive functions were less dependent on these brain measures in bilinguals, consistent with the concept of Cognitive Reserve. However, any effect of bilingualism on longitudinal associations between brain-change slopes and cognitive-change slopes did not reach significance, suggesting that bilingualism-related Cognitive Reserve may be limited to baseline differences. Further, exploratory analyses showed that the effects of bilingualism on hippocampal volume, and on its relationship with episodic memory, might differ according to clinical dementia status. In summary, our findings suggest that bilingualism is associated with altered baseline brain-cognition relationships, rather than with preservation of brain structure.

Neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Frontotemporal Degeneration, significantly impair communication abilities in humans. Animal models, particularly rats and mice, are widely used to study the underlying mechanisms of these disorders. Ultrasonic vocalisations (USVs) play a crucial role in signalling emotional states during social interaction, mating, and distress and may reflect low versus high arousal and/or a positive versus negative affective state of the animal, making them valuable behavioural biomarkers for neurological dysfunction. This systematic review synthesises the existing literature on USVs in rodent models of neurodegeneration. Specifically, it compares USV alterations across disease models, summarises the experimental paradigms used to elicit USVs, and reviews the neurobiological findings reported alongside these vocal changes. By integrating findings across studies, this review highlights consistent patterns, methodological differences, and current knowledge gaps to guide future research. Studying USV impairments in animal models may help to neurobiologically validate biomarkers based on the detection of acoustic changes in the vocal output of patients with neurodegenerative diseases. By bridging the gap between preclinical and clinical research, this review aims to contribute to the growing field of neurobehavioral biomarkers, which could ultimately improve early diagnosis and intervention in human neurodegenerative conditions.

Pigeons (Columba livia) rely heavily on spatial cognition for navigation. As such, this species is commonly used to investigate the neural correlates of spatial behaviours in birds, particularly the hippocampus and septum. As this species can live for decades when housed in the laboratory, several studies have recently used pigeons to examine long-term effects of aging on the brain, a concept that is less well-understood in birds compared to mammals. Studies assessing age-related structural plasticity in the pigeon brain have yielded mixed findings, possibly due to methodological differences. Here, we used Nissl-stained brain sections collected from homing (racing) pigeons (N = 29) ranging in age from 2 to 22 years old (divided into "adult", "old", and "very old" groups), and a standard histological volume reconstruction method, to assess brain-wide age effects (volume of the overall telencephalon) as well as effects specifically on spatial (hippocampus, septum) and non-spatial (entopallium) structures. Overall, we found that telencephalon and entopallium volumes declined with age, whereas hippocampus and septum volumes remained stable across the lifespan. We also detected a modest positive correlation between age and hippocampus volume, suggesting hippocampus volume increases as pigeons age, although this finding should be interpreted cautiously. Overall, our results suggest that in pigeons, neural structures and circuits supporting spatial cognition appear to be selectively preserved relative to other brain regions during aging, and more broadly, that age-related structural changes in the avian brain are not shaped only by generalized senescence, but by functional and behavioural demands placed on specific structures and circuits across the lifespan.

Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains unclear. Here, we used an inducible APOE "switch" model to selectively replace microglial E4 with E2 in older adult mice while maintaining E4 expression in other CNS and peripheral cells. Following a Western diet, microglial E2 replacement was associated with fewer phago-lysosomal microglia and decreased apoE localization within these phago-lysosomal microglia. Following a peripheral inflammatory stimulus (LPS), microglial E2 replacement was linked with increased expression of metabolic and immune-related pathways. Together, these findings indicate that microglial E2 expression is associated with selective cellular and transcriptional changes while E4 continues to be expressed by other cell types.

Resilience has become an integral component of theory and research in brain aging. Recent frameworks have provided guidelines for identifying and investigating resilience in the context of diversity (e.g., sex and risk exposure differences). We leverage a multi-factorial longitudinal approach to operationalize and predict pathways of resilience, stability and vulnerability as a function of differential within-person trajectory patterns of hippocampal volume and cognitive change. Participants included cognitively unimpaired (at baseline) older adults (n = 415; M age = 74.9; 59.9% Female) from the Alzheimer's Disease Neuroimaging Initiative with longitudinal imaging and cognition data, plus multimodal risk indicators. We used latent class growth analyses to identify hippocampal and cognitive trajectory classes. Machine learning applications identified risk indicators associated separately by pathway in the entire sample and disaggregated by sex. Based on differential combined class membership, we identified three subgroups: resilience (declining hippocampal/stable cognitive trajectories), stable (stable hippocampal/stable cognitive trajectories), vulnerable (stable hippocampal/declining cognitive trajectories). Leading risk indicators of resilience (e.g., lower plasma Aβ1-42) and vulnerability (e.g., lower education) originated from the biological and demographic domains. Leading risk indicators of stability originated from the biological and genetic domains (e.g., higher CSF Aβ1-42, lower polygenic hazard score). Sex-disaggregated results highlighted indicators unique to the females, such as higher body mass index (stability) and lower geriatric depression score (stability, vulnerability). Pathway patterns of resilience, stability and vulnerability were characterized objectively in initially cognitively unimpaired older adults based on specified hippocampal and cognitive trajectory combinations. Risk factors from a broad range of modalities should be considered in future research.

Understanding cognitive aging requires approaches that capture individual variability while enabling integration across studies. In rodent models, behavioral data are central to this effort, yet cross-laboratory differences in experimental design limit comparability and constrain secondary analysis. To address this gap, we developed the Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD), a first-of-its-kind collaborative repository aggregating trial-level Morris water maze data from multiple laboratories. ID-CARD is designed to support large-scale, integrative analyses and to facilitate secondary use of existing behavioral data in alignment with emerging data-sharing and transparency initiatives. Rather than imposing retrospective harmonization of experimental protocols, we implemented a normalization and modeling framework that enables comparison of learning trajectories while preserving meaningful variation across studies. Behavioral data from > 5000 rats spanning common strains, both sexes, and multiple ages were normalized in training and performance domains and fit with a logarithmic function to derive an error accumulation rate coefficient (EARC) as a measure of spatial learning. Age was strongly associated with increased EARC, indicating attenuated learning, even after adjusting for non-spatial cue performance. Analyses of goodness of fit revealed systematic structure in learning dynamics, where age was associated with reduced learning-curve conformity after accounting for overall performance. Inter-individual variability in spatial learning also increased with age, with strain-specific interactions. These findings demonstrate that integrated analysis of heterogeneous behavioral datasets can yield robust, individual-level insights into cognitive aging. ID-CARD provides a scalable resource and analytic framework to advance discovery in behavioral neuroscience by enabling reuse, integration, and comparative analysis of existing data.

Working memory is one of the core cognitive functions that declines in older adulthood. Brain reserve (BR) refers to neurobiological status of the brain that supports cognition, offering a valuable neurostructural framework for understanding working memory decline among older adults. However, most existing studies rely on gross, whole-brain measures of BR which may lack sensitivity to specific cognitive functions, and few studies have examined their sex differences. Based on 131 healthy older adults (aged 52-86) from Australia, this study used multimodal imaging data, including grey matter volume, cortical thickness, and white matter tract integrity, to identify BR proxies for older adults' working memory, and to test for sex differences and their interaction effects with age. Results indicate that BR proxies for older adults' working memory were primarily concentrated in white matter tracts related to sensory processing and hemispheric integration, including the acoustic, optic, and thalamic radiations, as well as the corpus callosum, while whole-brain BR proxies showed no significant correlations with working memory performance. Meanwhile, BR proxies significantly mediated the negative correlation between age and working memory performance. No sex differences were observed in behavioral measures of working memory; however, women exhibited higher structural integrity and smaller age-related differences in multiple critical white matter pathways compared to men during late adulthood. These findings suggest that older women have better preserved working memory-related BR, supporting the theory that BR acts as "neurobiological capital" to buffer supposed age-related cognitive decline. Our study provides new empirical evidence for understanding sex differences in BR, which shows a female advantage in later life, as well as the protective mechanisms during working memory aging.

Navigating uneven terrain poses a significant challenge for older adults, often resulting in falls. Identifying the neural correlates of walking on uneven terrain might help understand the mechanisms of age-related mobility decline. We examined age and physical function group differences in white matter microstructure and tested whether associations between white matter measures and uneven-terrain walking behavior differed between these groups. Twenty-two young adults (22.45 ± 2.58 years) and 86 older adults (75.47 ± 6.77 years) completed structural and diffusion-weighted MRI and treadmill walking across flat, low, medium, and high uneven terrain conditions. Older adults were classified as higher- or lower-functioning based on Short Physical Performance Battery scores. Free water (FW) and free water corrected fractional anisotropy (FAt) were primary outcomes. Walking behavior was quantified using step-duration coefficient of variation (COV) and perceived stability. Lower-functioning older adults showed greater baseline gait variability and steeper increases in variability with increasing terrain unevenness than both young adults and higher-functioning older adults. Older adults showed widespread higher FW and lower tissue integrity than young adults, particularly in frontal and motor-related white matter. Secondary analyses showed that higher-functioning older adults had higher axial diffusivity (ADt) than lower-functioning older adults in frontal and interhemispheric regions. A significant group-by-behavior interaction showed that higher FW was more strongly associated with greater baseline gait variability in lower-functioning than higher-functioning older adults, particularly in the body of corpus callosum. Extracellular free water and tissue-specific white matter measures showed distinct associations with baseline versus uneven-terrain walking in older adults.

Recent studies suggest that cortical hyperexcitability in Alzheimer's disease (AD) may accelerate disease progression. However, the field lacks validated non-invasive methods to assay excitability in humans. In this study we used transcranial magnetic stimulation with electromyography to investigate mechanisms of motor cortical excitability in 63 biomarker-positive early-AD (ranging from mild cognitive impairment to mild dementia) participants and 72 cognitively unimpaired age-matched adults (CU). Single-pulse stimulation was applied to motor cortex to record resting motor thresholds (rMT) and motor-evoked potentials. An Input-Output curve was generated by delivering 10 pulses each at eight different intensities of maximum stimulator output (%MSO). Linear models or equivalent non-parametric tests 1) compared excitability metrics between groups, 2) tested correlations with cognition (mini-mental state exam, MMSE; Alzheimer's disease assessment scale-cognitive, ADAS-Cog), and 3) tested the impact of APOE4. Results show that early-AD participants have increased motor cortical excitability than CU, with lower rMT (p < 0.001), lower Input-Output curve Inflection Point (p = 0.007), and higher Dynamic Range (p = 0.035). An analysis of the Input-Output curve adjusting for rMT showed larger responses in AD specifically in the 135-150% rMT range (p = 0.023). In AD, higher excitability was related to worse cognition (rMT: MMSE p = 0.008, Inflection Point: MMSE p = 0.030 and ADAS-Cog p = 0.041). There was no relationship between APOE4 and excitability. In conclusion, AD participants have increased motor cortical excitability, related to cognition. This is evident both at lower and higher stimulation intensities. TMS may provide a useful measure of target engagement for therapies aimed at preserving cognition or slowing decline in early-AD.

Ocular measures are increasingly used as non-invasive proxies of cognitive processes such as attention and listening effort. However, their interpretation in aging populations is complicated by concurrent changes in ocular physiology and oculomotor control, raising a critical question: to what extent do age-related differences in these measures reflect cognitive rather than other physiological factors? Here, we dissociate these contributions by characterizing ocular dynamics (resting and event-evoked) during passive fixation in younger (N = 98, 18-35 years) and older adults (N = 71, 60 + years). Aging is associated with pronounced alterations in pupil dynamics, including reduced baseline variability and slower, attenuated responses to both auditory and visual events. In contrast, microsaccade dynamics did not correlate with aging. Across measures, ocular responses showed moderate-to-high within-subject stability across blocks, and factor analysis in the older cohort revealed separable components reflecting instantaneous pupil responsivity, sustained pupil responsivity, and microsaccade dynamics, with additional variance associated with sensory decline and age-related pupil dynamics. Together, these findings demonstrate a clear dissociation: pupil-based metrics are strongly influenced by aging, whereas microsaccades remain comparatively stable across age groups. This dissociation provides a principled basis for interpreting ocular indices in aging research and highlights the need to account for baseline physiological differences when inferring cognitive processes from eye-based measures.