Neurobiology of Aging

Alzheimer's disease is associated with both mitochondrial dysfunction and altered neurophysiological signalling. Peripheral measures of mitochondrial respiration have been established as effective predictors of mitochondrial function in the healthy brain, and more recently, of altered brain signalling in clinical groups. Here, we sought to assess whether peripheral mitochondrial energetics are associated with altered neural signalling in Alzheimer's disease. We collected task-free magnetoencephalography (MEG) from individuals on the Alzheimer's disease continuum (69.21 [6.91] years; n = 38) and cognitively normal older adults (72.20 [4.73] years; n = 20). Each participant also provided a blood sample for analysis of mitochondrial respiration using the Seahorse XF96 Analyzer. We used region-wise linear models to test the relationship between ATP-linked mitochondrial respiration and Alzheimer's disease associated neurophysiological changes. We found that mitochondrial respiration linked to ATP production is associated with altered alpha and theta band cortical rhythms in Alzheimer's disease (: pFDR < 0.05, r = -0.7; {theta}: pFDR < 0.05, r = -0.6). We then tested colocalization of mitochondria-neurophysiological relationships with a human brain atlas of respiratory capacity and found that brain regions with lower mitochondrial respiratory capacity exhibit a stronger relationship between aperiodic signalling and peripheral ATP-linked respiration (pFDR = 0.003, r = 0.35). Our findings suggest that peripheral blood measures of mitochondrial function can offer insight into the neurophysiological alterations associated with energetic changes in Alzheimer's disease and warrant further investigation into the translational potential of joint neuronal mitochondrial markers of neurological diseases of aging.

Alzheimers disease (AD) neuropathological changes can be detected with blood-based biomarkers during the long preclinical phase that precedes clinical diagnosis. Tau phosphorylated at threonine 217 (p-tau217) has been found to closely correlate with brain A{beta} burden. A recent large-scale cross-sectional study showed elevated p-tau217 concentrations in older individuals (Aarsland et al., 2025). This increase was higher in those with AD dementia and mild cognitive impairment (MCI), and lower in those with intact cognition and higher educational attainment. Thus, intact cognition and higher education may be associated with lower levels of AD neuropathological changes. Here we tested this hypothesis using longitudinal data from the population-based Betula study (n=1005; 1531 samples). The results revealed increases with increasing age over 10 years in p-tau217, where individuals with accelerated episodic-memory decline had the strongest increase. There were no differences in p-tau217 trajectories between individuals with lower or higher education or with well-maintained or age-typical decline in episodic memory. The lack of association with education was further replicated in the independent BioFINDER-2 cohort. These findings underscore the value of plasma p-tau217 for detecting early pathological changes in population-based settings but provide no support that individuals with well-maintained episodic memory or high educational attainment are spared from neuropathological changes.

Alzheimer's disease (AD) is a major cause of dementia, with polygenic risk scores (PRSs) widely used to capture cumulative genetic risk. While PRSs have been associated with cognitive decline, their relevance to clinically accessible measures in general populations is not yet fully established, particularly in non-European cohorts. In this study, we investigated the association between AD PRSs and cognitive function assessed by the Mini-Mental State Examination (MMSE) in a community-dwelling Japanese older population (N = 1,301). Three PRSs were constructed using genome-wide association study (GWAS) summary statistics derived from European and Japanese populations. Among the PRSs, the score based on Japanese GWAS showed the strongest and most consistent association with MMSE score, whereas those based on European GWAS showed weaker or no associations. Stratification analyses further demonstrated that individuals with higher PRS exhibited lower MMSE scores and a higher prevalence of cognitive impairment. Notably, these associations were attenuated after excluding participants with dementia, suggesting that PRS primarily reflects clinically relevant cognitive decline. No significant associations were observed between PRSs and hippocampal volume in our cohort. These findings highlight the importance of population-specific PRS and suggest its potential utility for stratifying cognitive impairment using simple clinical measures in community-based settings.

Multiscale entropy (MSE) changes in relation to age, whereby aging is associated with an increasing bias towards fine scale entropy. This change is thought to represent a shift toward localized information processing in the brain as we age. However, this relationship has not been tested in large sample sizes alongside other demographic factors and cognitive behaviours. This study aimed to validate previously reported effects of aging on MSE in a large open access database (Cambridge Centre for Ageing and Neuroscience, N=587) and expand the findings to include an investigation of the effects of sex and a variety of cognitive behaviours. MSE curves and power spectrum densities (PSD) were calculated for each region of interest from the magnetoencephalography data. Multivariate partial least squares analyses were used to assess the relationship between MSE or PSD and 5 behavioural / demographic factors including: age, sex, fluid intelligence, visual short-term memory and a generalized measure of cognitive function. Age was associated with increased fine scale and decreased coarse scale entropy, as well as complementary spectral changes, including slowing of peak alpha rhythms, increased beta-band activity, and reduced gamma-band activity, which replicates prior MSE and PSD findings. In both domains, these age-related patterns differentiated based on sex with advancing age. Importantly, the unique effects of sex diverged between MSE and PSD. This result indicates that entropy-based measures can isolate aspects of temporal organization that are not clearly summarized by spectral structure alone.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimers disease (AD). It has, however, been challenging to develop measurements of brain structure directly linked to peripheral measures of neuroinflammation. This cross-sectional study examined whether plasma levels of markers related to inflammation are associated with diffusion magnetic resonance imaging (dMRI) measures of white matter microstructure: mean diffusivity (MD) and Neurite Orientation Dispersion and Density Imaging (NODDI) free water fraction (FWF) and orientation dispersion index (ODI). Participants included 457 dementia-free individuals (mean age=63.82, SD=7.63). Blood plasma markers related to inflammation included two measures of systemic inflammation, (1) high-sensitivity C-reactive protein (CRP), and (2) a composite of pro-inflammatory cytokines (IL-1, IL-1{beta}, IL-2, IL-6, IL-8, TNF-, TNF-{beta}), as well as (3) glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher values of all three measures (FWF, ODI, MD) in cerebral white matter, and with higher ODI in the cerebellar peduncles. Higher CRP levels were associated with higher ODI in cerebral and cerebellar white matter. Associations with GFAP were not significant after adjusting for multiple comparisons. Results were consistent after accounting for plasma biomarkers of AD pathology (p-tau181/A{beta}42). Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (higher FWF, ODI, and MD), supporting the view that these dMRI-based metrics are sensitive to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types.

Twice as many women develop Alzheimers disease (AD) compared to men. Several key aspects, such as genetic risk factors, hormonal vulnerability, social responsibilities, and differences in longevity, contribute to the strong female bias in AD. To assess whether sex differences can be detected during the onset of AD, we examined the amyloid-{beta} (A{beta}) plaque burden--one of the hallmarks of AD--and microglial states in young 5XFAD mouse models of amyloid pathology. We hypothesized that an increase in microglial cell number and phagocytic activity will directly correlate with an elevated A{beta} burden and shape the appearance of compact dense-core plaques in the cortex from 2 to 6 months of age. As expected, no change in microglial density and phenotype was found in A{beta} plaque-free hypothalamus of 5XFAD male and female mice when compared to age-matched wildtype controls. By quantifying the number and coverage of diffuse and dense-core plaques in the cortex, we discovered a pronounced increase in A{beta} plaques and microglial clustering in 4-month-old female 5XFAD compared to male mice. By 6 months, no sex difference in plaque load and microglial density was observed. Our spatiotemporal characterization of microglial Clec7a/Dectin-1 and CD68 expression revealed sex differences in the upregulation of these phagocytic markers in plaque-proximal microglia. In 2-months-old males, greater phagolysosomal activity around diffuse plaques may benefit A{beta} clearance. However, in females, the lower initial microglial reactivity and subsequent rise in Dectin-1-driven phagocytic activity may have led to the increase in dense-core plaques at 4 months. Our results suggest that during early amyloidosis, sex differences in CD68-associated lysosomal activity and microglia-driven plaque compaction may cause disproportionate AD risk and severity that is compounded by other exacerbating factors during aging. Taken together, sex-specific targeting of microglial proliferation and phagocytic activity may be a promising intervention in presymptomatic patients with known AD risks.

Memory performance typically declines with age, but the underlying neurobiological mechanisms remain unclear. Superagers, people over 80 years of age with episodic memory performance comparable to individuals 30 years younger, appear to resist this decline. Novelty and expectation violations are known to engage the hippocampus-midbrain system to enhance memory formation. Here, we examined whether superagers superior memory performance is supported by preserved hippocampal-midbrain function during novelty and expectation processing. We manipulated item and contextual novelty (i.e., expectation violations) during encoding to test whether superagers show greater mnemonic benefits than their age-matched peers, whether these benefits reflect enhanced hippocampal and midbrain functioning as measured by fMRI, and whether they are associated with preserved dopaminergic integrity measured with neuromelanin-sensitive MRI. Our results show that, although superagers demonstrated overall superior memory performance, both groups exhibited superior recognition of contextually unexpected items. Nevertheless, differences emerged in the processing of expectation during encoding. Superagers exhibited stronger hippocampal responses to expectation violations and habituation to expected events, irrespective of item novelty. Conversely, typical older adults exhibited reduced midbrain response when expected novelty was absent. Neuromelanin accumulation did not account for group differences in midbrain activity or memory performance. Taken together, these findings suggest superagers benefit from adaptive responses to expectation and its violation, which is therefore a candidate mechanism distinguishing exceptional from typical cognitive ageing. SIGNIFICANCE STATEMENTAlthough memory typically declines with age, superagers are individuals aged over 80 who maintain memory performance comparable to people 30 years younger. We examined whether preserved hippocampal-midbrain function during novelty and expectation processing could underlie their superior memory. Superagers exhibited adaptive hippocampal responses to expectation and its violation, with higher activation for unexpected events and habituation to expected events. In contrast, typical older adults showed hippocampal and midbrain responses oriented towards anticipated novel content, despite not showing differences in neuromelanin accumulation. These findings underscore the critical role of hippocampal function in supporting memory preservation in late life and advance our understanding of the neural mechanisms underlying healthy cognitive ageing.

Klotho KL is an aging factor that has been associated with Alzheimers Disease (AD) risk. Two common alleles circulate in human populations: the major allele FC and the minor allele VS, which is defined by two SNPs that cause two amino acid substitutions (F352V and C370S) in KLs second exon. To investigate the possibility that human KL variants influence brain aging and cognition, we developed a novel mouse model with humanized KL alleles. We used RNA-Seq to measure the whole brain transcriptome in four-and 12-month-old male and female C57Bl/6J mice carrying either the FC or the VS KL allele. We found that FC and VS carriers had widespread differences in gene expression in the brain at 12 months old, but not at four months old. The largest differences were in genes annotated to mitochondrial, ribosomal, and synaptic functions. Differential exon usage analysis identified differential splicing of synaptic genes, further supporting a role for KL on neuronal function. A more focused analysis of differential expression identified variation in glutamate receptors and amyloid precursor (APP) processing in particular, thereby linking human KL haplotypes to biological processes integral to AD pathogenesis. These results provide evidence that the human FC and VS KL haplotypes affect the function of the KL protein product in a manner that has widespread effects on gene expression in the brain and supports the hypothesis that these haplotypes may influence AD risk and pathogenesis.

Animals rely on associative spatial memory to navigate toward previously learned, reward-associated goals. This reward-guided navigation is supported by the hippocampus and its interactions with cortical and subcortical regions: processes which are vital for integrating sensory cues and forming experience-dependent associations. In adulthood, hippocampal-dependent information processing is shaped by aging, reflecting changes in synaptic plasticity and neuromodulatory support. In parallel, mice with distinct genetic backgrounds show systematic differences in behavior, sensory function, and hippocampal plasticity. How mouse strain and age interact to affect spatial appetitive memories has not been well defined. Here, we trained CBA/CaOlaHsd and C57BL/6 mice in early (2-3 months) or late adulthood (7-8 months), in daily training events, to perform a T-maze task with rewards available at a fixed location and decreasing probability in one maze arm. The task consisted of an initial deterministic phase in which a correct response was always rewarded, followed by a probabilistic phase during which reward omissions became increasingly prevalent. We measured correct choices, as well as latencies across training blocks, and combined trial-by-trial metrics with reinforcement learning modeling to assess decision strategies. We observed that CBA/CaOlaHsd mice displayed lower choice latencies than C57BL/6 mice, reached high performance earlier, and maintained better performance when the reward probability decreased. Age was associated with higher latencies and modulated both performance and decision policies in a strain-dependent manner. Moreover, CBA/CaOlaHsd mice displayed higher learning rates from positive outcomes and adopted strategies consistent with more robust context exploitation under uncertainty. C57BL/6 mice, by contrast, exhibited stronger omission-driven strategy switching. Together, these findings reveal robust strain- and age-dependent differences in trial-by-trial decision policies and spatial learning performance.

Hippocampal volume is a key biomarker for Alzheimers disease and brain aging, yet reported sex differences vary substantially depending on head-size adjustment methods. We examined whether the hippocampal-to-ventricle ratio (HVR), a self-normalizing measure, provides more consistent sex difference estimates than conventional adjustment approaches. Using a subset of UK Biobank structural MRI data (N = 27,680; 56% female; ages 45-82), we compared sex differences across four adjustment methods (unadjusted, proportions, stereotaxic, residualized) and in samples matched on age and on intracranial volume (ICV). Hippocampal sex differences reversed direction across methods, ranging from d = -0.89 (males larger, unadjusted) to d = 0.58 (females larger, proportions), with a range of 1.5 standard deviations across analytical choices. In contrast, HVR showed a consistent female advantage (d = 0.52) that persisted in the ICV-matched subsample (d = 0.19), confirming this effect is not a head-size artifact. Males exhibited steeper cross-sectional age-related HVR differences (1.7x female rate, p < 10-50), consistent with males showing ventricular expansion at younger ages. Structural equation modeling revealed that HVR predicted general cognition comparably to hippocampal volume ({beta} = 0.04, overlapping CIs), and unlike residualized hippocampal volume, HVR maintained significant brain-cognition associations in both sexes. We provide sex-specific normative centile curves for clinical application. These findings indicate that apparent hippocampal sex differences largely reflect methodological choices rather than biology, while HVR captures consistent morphological variation related to brain aging that may have clinical utility.

Healthy aging is associated with progressive structural brain decline, yet the loss of functional abilities varies across individuals, which has been linked to reserve mechanisms. Within the framework of complex systems theory, reserve is thought to manifest as resilience when the system is challenged by stressors, such as increases in task difficulty. The cerebellum has been proposed as a potential source of motor reserve, but empirical evidence linking cerebellar structure, function, and resilience remains limited. We conducted a cross-sectional study including 50 young, 80 older, and 30 older-old adults to examine resilience to increasing task demands across cerebellar-specific and general outcomes. Participants completed three motor tasks (pure elbow motion, motor timing, postural stability) and two cognitive tasks (mental rotation, spatial working memory). Structural MRI was acquired to quantify cerebellar grey matter volume within functionally defined regions. Cerebellar-specific motor measures (anticipatory muscle activation and timing variability) were preserved across age groups and remained resilient under increased task demands, including in adults over 80 years of age. In contrast, general sensorimotor performance (postural sway) declined with age and showed reduced resilience. Within the cognitive domain, both cerebellar-specific and general measures showed comparable age-related declines and reduced resilience. Resilience measures were not correlated across tasks, indicating that resilience is task- and domain-specific. Furthermore, cerebellar grey matter volume did not predict resilience in motor or cognitive outcomes. These findings support the cerebellar motor reserve hypothesis, suggesting that cerebellar-dependent motor processes remain resilient despite age-related structural decline. However, resilience appears to be function-specific rather than a generalized individual trait. Overall, the results highlight dissociations between brain structure, function, and resilience, underscoring the selective contribution of the cerebellum to motor preservation in healthy aging.

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

Background and Aims: Plasma phosphorylated tau 217 (p-tau217), including %p-tau217, has emerged as a robust biomarker of Alzheimer's disease (AD) pathology, with increasing interest in its longitudinal behavior. In "Predicting onset of symptomatic Alzheimer's disease with plasma p-tau217 clocks," Petersen et al. applied disease clock models, Sampled Iterative Local Approximation (SILA) and Temporal Integration of Rate Accumulation (TIRA), to estimate age at plasma %p-tau217 positivity and reported that this measure predicts age at onset of symptomatic AD. We aimed to determine whether this apparent predictive performance reflects biomarker information or arises from structural artifacts in the analysis. Methods: We analyzed digitized data from published figures and decomposed the clock-derived predictor into baseline age and estimated time from %p-tau217 positivity. We quantified shared and unique explained variance between baseline age and the clock-derived predictor using commonality analysis. To further disentangle structural and biomarker contributions, we evaluated a null scenario in which the biomarker-derived timing component was replaced with randomly generated values drawn over the observed range, preserving the predictor distribution while removing biomarker information. Results: The reported predictive performance was largely driven by structural artifacts arising from bounded follow up and constraints among the variables. Restriction to individuals who progressed during limited follow up, together with constraints on the allowable timing of events, induced a strong association between baseline age and age at symptom onset. In ADNI, baseline age alone explained substantially more variance in age at onset than the clock-derived predictors (R2=0.78 vs. 0.337 and 0.470 for TIRA and SILA). The estimated time from %p-tau217 positivity contributed minimal additional information, and randomized predictors yielded comparable performance to baseline age alone (R2=0.79). Conclusion: The apparent predictive ability of plasma %p-tau217 disease clocks is driven largely by structural age relationships rather than independent biomarker signal. The plasma %p-tau217 timing component provided minimal predictive value, and its combination with age obscured these structural dependencies. These findings underscore the need for careful evaluation of constructed predictors and outcomes in longitudinal analyses of disease progression.

We present a novel integrative analysis of transposable elements (TEs) in 4 single cell RNA-seq (scRNA-seq) datasets of postmortem substantia nigra pars compacta samples of Parkinson Disease (PD) patients matched healthy controls, with the objective of building a cell-type specific trustworthy atlas of TEs that may clarify the role of TEs in sex differences in PD. We have used the soloTE tool to evaluate the TEs expression changes across all snRNA-seq studies identified in our previous systematic review, and then integrated the results using meta-analysis techniques. Finally, we evaluated the possible associations between TEs and protein coding genes by integrating our previous results in this matter with the information of TEs obtained, in order to propose the possible action mechanism by which some of the TEs contribute to PD.

Age-related cognitive decline and depressive symptoms are prevalent in later life, yet the genetic determinants of vulnerability remain unclear. Here, we investigated how genetic and epigenetic regulation of the serotonin transporter gene SLC6A4 contributes to susceptibility to these age-related conditions in later life. In community-dwelling older adults in Japan (N = 1,317), functional stratification of the serotonin transporter-linked polymorphic region (5-HTTLPR) revealed that participants with low-activity genotypes showed a robust co-occurrence of cognitive decline and depressive symptoms, whereas this comorbid pattern was not observed in those with the high-activity genotype. The genotype-dependent co-occurrence was consistently replicated across seven independent population-based cohorts (total N = 7,889). DNA methylation at a functional promoter CpG site increased with age and partially mediated age-related cognitive decline specifically among low-activity genotypes. In contrast, the high-activity genotype was associated with relative resistance to these functional declines, partly mediated by a protective effect on hippocampal volume during aging. Notably, genotype-dependent effects on hippocampal volume were absent in adolescence, indicating that the influence of SLC6A4 emerges in an aging-specific manner. Together, these findings identify SLC6A4 promoter activity as a key genetic factor modulating vulnerability and resilience in later life.

Spatial navigation could theoretically serve as an early neurobehavioral marker of Alzheimers disease risk, yet technological limitations have hindered its widespread adoption. We leveraged breakthroughs in technology to create a custom smartphone application to compare real-world spatial memory with lab-based measures. Specifically, we compared performance across two established lab-based tasks, judgments of relative direction (JRD) and map drawing, and our novel app-based, in situ pointing task administered in a familiar large-scale, real-world environment. Young adults completed both laboratory and mobile navigation tasks, allowing within-subject comparisons across modalities. JRD performance strongly correlated with map drawing performance. In contrast, App-based pointing showed lower error and reduced inter-individual variability relative to JRD performance, but weak correlations with lab-based measures. We also developed a novel analytical technique in which we transformed the app-based pointing into a relational, JRD-like metric, and we observed strong correlations and correlated patterns of errors across all tasks. Thus, real-world, app-based pointing captures stable directional performance (e.g., as indexed by the lower errors and lower variability relative to the JRD Task) and, when expressed in a common framework, correlates with laboratory measures of spatial memory, thus suggesting that these tasks tap into partially overlapping cognitive representations. These results provide a pivotal advancement to our understanding of both shared and unique variance across spatial memory paradigms, and support the use and further development of mobile navigation tools as scalable complements to lab-based assessments for studying spatial cognition and its decline in preclinical and clinical stages of Alzheimers disease. HighlightsO_LISpatial memory is a core cognitive function and is impaired in Alzheimers disease C_LIO_LITesting memory in large-scale, real-world environments enhances ecological validity C_LIO_LIWe compared performance of our novel real-world measure with lab measures C_LIO_LIWe observed strong correlations between the lab-based measures C_LIO_LIWe observed shared and unique variance between lab- and real-world measures C_LI

ABSTRACT BACKGROUND: Recent studies consisting primarily of white participants have found lowered plasmalogen levels to be associated with lower cognitive function. We explore the association of blood plasmalogen levels with global cognition and brain imaging metrics in older African Americans. METHODS: Included in these cross-sectional analyses were participants in the Minority Aging Research Study (MARS) and the Rush Clinical Core without dementia, available serum lipid levels, and a concurrent cognitive function assessment. A plasmalogen biosynthesis value (PBV) was calculated for each participant utilizing five ratios of four key glycerophospholipids. A linear regression model of global cognition was constructed with PBV, adjusted for sex, age, education, total cholesterol, and body mass index. In participants with 3T MRI brain imaging, the association between PBV and white matter hyperintensities (WMH) was explored. RESULTS: Of the 298 participants, the mean age was 74.6 years, mean education was 15.6 years, and 84% were women. The median PBV was 0.42 (interquartile range: 0.22 to 1.14). A unit higher in PBV was suggestively associated with a 0.17 {beta}-unit higher cognitive z-score (SE =0.09, p = 0.06). In 254 participants with MRI data, an increase in log10 SD of PBV suggested the less white matter hyperintensities (estimate = -0.20, SE = 0.12, p = 0.08). DISCUSSION: In older African Americans, higher PBV was associated with higher level of global cognition, and potentially lower levels of brain white matter hyperintensities. Larger studies are needed in additional cohorts to determine if PBV is associated with annual rate of change in cognitive function.

Meningeal lymphatic vessels (mLV) play essential roles in draining cerebrospinal fluid (CSF) into peripheral blood. The mLVs are hypothesized to be supportive structures to the glymphatic system, which is thought to remove metabolic byproducts from brain parenchyma and has been most directly studied in rodent models. Previous rodent studies have indicated a correlation between mLV function and cognitive performance, but this relationship in humans remains unexplored. Age-related declines in glymphatic system efficiency in humans and cognitive performance have been observed separately. This study investigates age- and sex-related differences in CSF production via choroid plexus volumes, mLV characteristics, and glymphatic system efficiency, overall elucidating the implication of cerebral lymphatic function on cognition. We recruited 26 healthy adults from Dallas-Fort Worth and acquired magnetic resonance images. mLVs along the sagittal sinus were visualized and segmented from T2-FLAIR images. The glymphatic system was evaluated by measuring diffusivity along the perivascular space. Choroid plexus volume and brain volume were estimated from T1-MPRAGE. Neuropsychological tests were conducted to assess cognitive function. Our findings indicate that glymphatic function diminishes with age, while mLV and choroid plexus volumes increase. Males displayed greater mLV volume than females, yet no sex differences were found in glymphatic function or choroid plexus volume. Notably, mLV volume increased as glymphatic function declined, independent of age. Moreover, a glymphatic-mLV latent variable significantly predicted processing speed, underscoring the influence of cerebral lymphatics on cognition. In conclusion, this study highlights a decline in glymphatic function with age, accompanied by increased mLV volumes and altered processing speed. These lymphatic system changes may underlie or contribute to the cognitive declines observed in healthy and pathological aging. Significance StatementThe glymphatic system and meningeal lymphatic vessels play crucial roles in removing brain cell waste. The relationship between these systems and their effect on human cognition, particularly processing speed, is unknown. We demonstrate that these systems change with advancing age. Variations in cerebral lymphatic function contribute to differences in processing speed independent of age, ultimately affecting higher-order cognitive function. The findings presented have implications for cognitive function in both healthy and diseased states.

Biological aging is accelerated in people with multiple sclerosis, but whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age (3.2 years, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.

This study addresses key gaps in our understanding of the cognitive changes associated with normal brain aging and their underlying structural and functional correlates. Declining levels of brain endocannabinoids (eCB), particularly 2-arachidonoylglycerol (2-AG), are thought to contribute to age-related cognitive impairment, but the mechanisms involved remain poorly understood. Here, we show that levels of 2-AG and its synthesizing enzyme, diacylglycerol lipase- (DAGL-), are significantly reduced in the medial prefrontal cortex (mPFC) of aged mice. This decline is associated with impairments in mood and memory, as demonstrated by behavioral analyses. Immunofluorescence studies further revealed reduced expression of cannabinoid receptors CB1 and CB2 on microglia in aged brains, suggesting that diminished eCB signaling may contribute to enhanced neuroinflammation. Consistent with this idea, microglia from aged mice exhibited increased HMGB1-TLR4-NF-{kappa}B signaling, indicative of a pro-inflammatory state. LC-HR-MS analysis also showed elevated glutamate levels and reduced glutamine and GABA levels in the mPFC, linking impaired eCB signaling to excitotoxic imbalance during aging. Importantly, intraperitoneal administration of cannabidiol (CBD) to aged mice reversed mood and memory deficits, restored CB1 and CB2 receptor expression, attenuated HMGB1-TLR4-NF-{kappa}B signaling, and normalized the glutamate-glutamine/GABA balance in the mPFC. Collectively, these findings identify eCB signaling as a critical regulator of age-associated cognitive decline and support CBD as a potential therapeutic strategy to promote healthy brain aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/711942v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@e9c9ddorg.highwire.dtl.DTLVardef@c3fbd2org.highwire.dtl.DTLVardef@c9d5eforg.highwire.dtl.DTLVardef@fc4371_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIReduction of 2-AG in the brains medial prefrontal cortex (mPFC) over time is a hallmark of cognitive decline. C_LIO_LIPro-inflammatory signalling such as HMGB1 (High Mobility Group Box 1)-TLR4 (Toll-like receptor 4)-NF-kB (Nuclear Factor kappa B) signalling are elevated in aged brain. C_LIO_LIAltered glutamine-glutamate/GABA cycle associated with reduced 2-AG levels. C_LIO_LICBD administration mitigates cognitive decline associated with aging and diminishes neuroinflammation. C_LI