Neurobiology of Aging

Age-related hearing loss is a leading modifiable risk factor for dementia and is increasingly recognized as a non-motor feature of Parkinson's disease (PD). The apolipoprotein E (APOE) E4 allele is the strongest genetic risk factor for Alzheimer's disease and is associated with cognitive decline in PD, yet its relationship to hearing loss remains unclear. Therefore, we examined the independent and interactive effects of PD status and APOE E4 carrier status on age-related hearing loss using a validated web-based speech-in-noise (SIN) assessment in 239,620 23andMe Research Institute participants without PD and 4,361 PD cases. Generalized additive models for location, scale, and shape (GAMLSS) showed that both PD and APOE E4 independently exacerbated age-related hearing decline, with speech reception thresholds (SRTs) worsening non-linearly with advancing age, but without evidence of synergistic interaction. However, longitudinal analyses in a subcohort completing at least two assessments (1,434 PD cases; 36,242 controls) using GAMLSS mixed models showed a significant three-way interaction between PD status, APOE E4, and age2, such that SIN hearing loss accelerated more steeply with age in APOE E4 carriers with PD. Males and individuals with lower educational attainment also exhibited worse SIN hearing loss. These results identify APOE E4 carriers with PD as a priority population for hearing screening and intervention, and support the integration of SIN assessments into routine PD care to detect hearing decline that may compound cognitive and communicative burden in aging.

Age-related hearing loss (ARHL) is a main acquired risk factor for dementia, including Alzheimer disease (AD), but links are unknown. We are using a mouse model with traits of both aging pathologies to test mechanistic interactions. The "knock-in" AppNL-F mouse reproduces {beta}-amyloid pathology in brain regions homologous to those involved in human AD. Because it was generated from the C57BL/6J mouse, it expresses early signs of ARHL, previously reported in this inbred strain. We found evidence that the early-onset ARHL of the C57BL/6J mouse is accelerated in the AppNL-F mouse. In adult C57BL/6J mice around seven-month-old, there were significant increases in auditory thresholds. In adult age-matched AppNL-F mice, auditory thresholds were significantly more elevated, suggesting acceleration of ARHL. In old mice, past thirteen months of age, hearing thresholds were equally elevated in both strains. Outer hair cell loss was significantly increased in adult AppNL-F relative to age-matched C57BL/6J mice, progressing from basal to apical cochlear turns. Spiral ganglion neuron loss also was larger. In adult AppNL-F mice there was more atrophy and enlarged capillary lumen size in the stria vascularis (SV), supporting accelerated ARHL. These findings suggest that central {beta}-amyloid pathology worsens age-related damage to the auditory receptor, thus accelerating ARHL. Damage to the SV and its capillaries in AppNL-F mice point to exacerbation of strial and vascular pathology in the aging cochlea by central {beta}-amyloid pathology. ARHL acceleration by central {beta}-amyloid pathology may contribute to a vicious circle with implications for prevention and therapies. HighlightsO_LIAge-related hearing loss worsens in a mouse model of Alzheimer {beta}-amyloid pathology. C_LIO_LIHearing thresholds further increase relative to naturally occurring hearing loss. C_LIO_LILoss of outer hair cells and spiral ganglion neurons is larger. C_LIO_LIThe stria vascularis and its microcirculation are more atrophic and damaged. C_LIO_LIAlzheimer disease may potentiate peripheral presbycusis. C_LI

Cognitive impairment is a major source of disability in Parkinsonian disorders, yet biomarkers that distinguish cognitive status from cognitive decline remain limited. DNA methylation-based epigenetic aging measures capture complementary dimensions of biological aging, but it remains unclear whether they primarily reflect stable differences in cognitive vulnerability or longitudinal cognitive change. We examined associations between epigenetic aging measures and global cognition in the Parkinsons Progression Markers Initiative (PPMI) cohort. Seven epigenetic aging measures were derived from peripheral blood DNA methylation data, and cognition was assessed longitudinally using the Montreal Cognitive Assessment (MoCA). Linear mixed-effects models were applied in complementary frameworks, including baseline-plus-change-from-baseline models and within-person versus between-person decomposition models. Secondary analyses included baseline clock-by-time interaction models and a decline-focused sensitivity analysis. Across analyses, higher epigenetic aging was consistently associated with lower overall MoCA scores. In the baseline-plus-change-from-baseline models, the analytic baseline component showed the dominant signal, whereas the change-from-baseline terms were not significant after false discovery rate correction. In the within-person versus between-person decomposition models, associations were concentrated in the between-person component, while within-person deviation terms were not significant. Secondary analyses were consistent with this pattern. Together, these findings suggest that blood-based epigenetic aging measures may be more informative as biomarkers of cognitive status or vulnerability than as markers of short-term cognitive progression. Larger studies with longer follow-up and more detailed cognitive phenotyping are needed to clarify their longitudinal relevance.

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.

Relational memory, the ability to encode and retrieve associations among multiple elements of an experience, is a core component of episodic memory that shows disproportionate age-related decline. Despite a substantial neuroimaging literature examining relational memory in aging, findings remain heterogeneous, and no quantitative synthesis has been conducted. The present study addressed this gap using Activation Likelihood Estimation (ALE) meta-analyses to characterize the neural correlates of relational memory success during encoding and retrieval in younger and older adults. Separate within-age-group, conjunction, and subtraction analyses were conducted, along with an exploratory analysis examining a general relational memory network across 70 independent studies. During encoding, younger adults showed robust convergence across medial temporal and prefrontal regions, whereas older adults showed more limited convergence. Shared convergence across age groups was observed in the left hippocampus and right inferior temporal gyrus, and direct age-group contrasts revealed greater prefrontal convergence in younger relative to older adults. During retrieval, younger adults showed convergence in posterior default mode and subcortical regions, whereas older adults showed convergence in the left angular gyrus, with no shared convergence observed across age groups. Across all studies, the hippocampus showed the most robust bilateral convergence across age groups and memory phases, underscoring its critical role in relational binding. Together, these findings provide the first quantitative characterization of the neural correlates of relational memory success in aging and highlight stable hippocampal involvement alongside age-related variability in prefrontal and posterior retrieval-related recruitment.

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.

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 changes in 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.

Despite several age-related processes impacting motor performance, older adults often retain the ability to implicitly adapt to sensory prediction errors. Here, we leverage the fact that implicit adaptation is not attenuated by aging to study the impact of aging on responses to motor errors. In other domains, such as reinforcement learning, aging has been shown to influence how task outcomes or rewards are processed and used to guide subsequent actions, with some studies emphasizing that older adults react more strongly to a miss than to a hit. We aimed to extend these reinforcement learning findings to the motor domain with two preregistered experiments testing whether missing the target leads to larger implicit adaptation in young and older adults to the same extent. In addition, we compared these results to one reinforcement learning task in the motor domain (Boolean feedback after reaching in the absence of visual feedback) and one in the cognitive domain (reward-based decision making). While we found age-related effects in the cognitive domain, we did not observe a consistent effect of age on the modulation of reaching direction or motor adaptation by task outcomes. These results suggest a domain-specific nature of age-related changes in sensitivity to task outcomes.

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.

INTRODUCTIONAge, Apolipoprotein E4 (APOE4) genotype, and biological sex are major risk factors for late-onset Alzheimers disease (LOAD). Neuroimaging is central to its characterization, and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE4 has not recapitulated LOAD-relevant brain phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (hAPOE) may therefore improve translational modeling of structural brain changes. METHODSAged mice (mean age = 23.25 months) carrying murine (m) or humanized (h) APP and either murine Apoe or hAPOE3/3, hAPOE3/4, or hAPOE4/4 underwent in-skull ex vivo volumetric MRI. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with FDR correction applied within contrasts. RESULTSBrain volumes were primarily determined by APP background, with hAPP globally reducing total and regional volumes relative to mAPP mice. Across hAPP models, hAPOE4/4 exhibited the greatest brain-wide reductions, which was mitigated by a single hAPOE3 allele. In contrast, mouse APP exerted modest effect in hAPOE, with hAPOE4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, hAPP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independent of APP or APOE genotype. DISCUSSIONThese findings demonstrate that APP background is a primary driver of mouse brain volume, with hAPP producing global reductions amplified by the hAPOE4/4 genotype. In contrast, hAPOE4 effects in the mAPP background were modest and nonspecific, consistent with normative aging. Together, these results suggest that hAPP and hAPOE4 act synergistically, and that hAPOE4 alone is insufficient to recapitulate AD-relevant brain changes in mice. The hAPP/hAPOE4/4 model yields a brain-wide phenotype consistent with LOAD-associated volumetric patterns, whereas mAPP/hAPOE models may better reflect non-pathological aging.

The slowing of executive function and memory impairment are the leading hallmarks of cognitive decline with age. The exact cause of this change is unknown and is the focus of aging research. Expression levels of Vesicle Associated Membrane Protein 2 (VAMP2)/Synaptobrevin-2 (syb2) are decreased with age. Here we report results from a novel transgenic mouse model (TgV2) that overexpresses syb2. We hypothesized that overexpression of syb2 improves synaptic function during aging, thus it delays dementia. Aged TgV2 mice, which maintained syb2 levels, performed better in spatial memory tests than 2-year-old WT control mice, which had lost half of syb2 due aging. In hippocampal CA1 synapses of aged TgV2 mice, long-term potentiation was increased. These effects of maintained syb2 levels were beneficial for both males and females providing improved synaptic plasticity. These results indicate that overexpression of syb2 supports cognitive function throughout the aging process and better resist age-related synaptic dysfunction.

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.

Healthy older adults exhibit both selective impairments in episodic memory - memory for events situated within a specific time and place - and deficits in executive function, reflected by difficulty switching between different tasks and inhibiting task-irrelevant information. Prior work has shown that older adults show diminished mnemonic brain state engagement - recruitment of whole brain activity patterns that selectively support memory encoding and memory retrieval. Our hypothesis is that older adults are biased toward the retrieval state and, due to executive function deficits, cannot easily switch out of this state when task-irrelevant. Our goal was to determine the extent to which stimulus processing time impacts older adult mnemonic state engagement, with the expectation that longer processing times would enable older adults to switch out of a task-irrelevant retrieval state. We recorded scalp electroencephalography (EEG) while younger and older adult participants explicitly encoded and retrieved object stimuli under variable stimulus durations. Using a combination of multivariate decoding approaches, we find that under time constraints, older adults both under-recruit a young-adult like retrieval state when task-relevant, but over-recruit a participant-specific retrieval state when task-irrelevant. Older adults may thus recruit idiosyncratic activity patterns to compensate for difficulties engaging young-adult like mnemonic brain states. Taken together, these findings suggest that although older adults retain the ability to engage encoding and retrieval brain states, they require more processing time to both initiate and maintain goal-relevant mnemonic states.

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.

Mislocalization and aggregation of transactive response DNA-binding protein 43 kDa (TDP-43) represent a neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and are increasingly recognized in Alzheimers disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, the in vivo value of CSF TDP-43 as a biomarker and its relation to established markers remains unclear. We quantified CSF concentrations of TDP-43 using ELISA in 25 controls, 32 ALS, 9 probable LATE, and 24 AD patients. CSF TDP-43 levels differed significantly between groups, with the highest concentrations in LATE, exceeding both ALS and AD. ALS and AD showed intermediate, comparable increases versus controls. In parallel, conventional AD biomarkers (t-tau, p-tau, and amyloid-b) showed the expected AD-typical profile but remained largely unaltered in probable LATE, indicating a dissociation between TDP-43 an AD-type pathology. These findings identify CSF TDP-43 as a promising candidate biomarker for LATE, characterized by disproportionate elevation in the absence of AD-type biomarker changes, and neurodegeneration in aging populations.

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.

Alzheimer's disease is a progressive neurodegenerative disorder that poses a growing global public health challenge. Early and accurate diagnosis is critical for effective treatment, clinical trial participation, and disease management. This systematic review and meta-analysis evaluates the diagnostic performance of machine learning (ML) and deep learning (DL) algorithms for detecting Alzheimer's disease (AD) and mild cognitive impairment (MCI) using neuroimaging and clinical data. Relevant studies were identified from PubMed, IEEE Xplore, and arXiv (2015 to 2025). Random-effects models were applied to estimate pooled performance metrics (AUC, sensitivity, specificity, and F1-score), and subgroup analyses compared results by model type, imaging modality, and validation strategy. Thirty studies met inclusion criteria. The pooled AUC was 0.962, indicating high overall discriminative accuracy. However, studies relying solely on internal validation or with smaller datasets often reported inflated metrics, suggesting potential overfitting and optimism bias. ML and DL methods demonstrate strong potential for early AD detection, but standardized evaluation protocols and external validation are necessary for clinical translation.

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.

Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time x Condition interactions, indicating differential texture trajectories between Osc+ and Osc-. In the hippocampus, this pattern was further qualified by a Time x Condition x Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.