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.

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 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.

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.

INTRODUCTION: Neuroinflammation and immune dysregulation are increasingly recognized as early drivers of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), often emerging decades before the onset of clinical symptoms. Despite this, there remains a critical need for non-invasive biomarkers that can capture these early processes, particularly in African Americans, a population at elevated risk for AD/ADRD yet underrepresented in neuroimaging research. In this study, we investigated the relationship between systemic plasma inflammatory markers and brain microstructural integrity in cognitively unimpaired older African Americans. METHODS: Forty-one participants (mean age = 68.68 years) underwent MRI scanning and multi-plex plasma-based inflammatory marker quantification. Microstructural changes were quantified using Diffusion Weighted Imaging (DWI) metrics, including mean diffusivity (MD), radial diffusivity (RD), mean kurtosis (MK), and radial kurtosis (RK). Voxel-wise general linear models, and cluster-based models were used to examine associations between plasma-derived inflammatory markers and brain microstructure. RESULTS: Higher TARC levels were associated with widespread increases in MD and RD across both gray and white matter, implicating reduced microstructural integrity and potential myelin disruption. In contrast, kurtosis-based metrics demonstrated more spatially selective and generally weaker associations, with MK and RK showing limited decreases primarily within white matter tracts. Cluster-level analyses confirmed the robustness of diffusivity findings and highlighted consistent effect sizes across multiple regions. DISCUSSION: These findings suggest that elevated TARC is linked to early microstructural alterations detectable with diffusion MRI, with diffusivity metrics demonstrating greater sensitivity to inflammation-related changes than kurtosis measures in this cohort. This work underscores the importance of incorporating inflammatory biomarkers in neuroimaging studies of aging and highlights diffusion MRI as a promising tool for detecting early neurobiological signatures of AD/ADRD risk in African American populations. Keywords: Systemic Inflammation, TARC, Eotaxin-3, Diffusion MRI, African Americans, ADRD, Aging

Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-{beta} PET, and plasma assay tests for amyloid-{beta} 42, amyloid-{beta} 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-{beta} quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-{beta} at baseline, but the associations were significantly attenuated after further adjusting for amyloid-{beta} and tau, respectively. Plasma amyloid-{beta} 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-{beta}, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-{beta} and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects. Keywords: Alzheimer's disease, Cerebral blood flow, White matter hyperintensities, Tau pathology, Amyloid-{beta}.

Abstract INTRODUCTION APOE genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized. METHODS We performed a cross-sectional analysis of harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging. RESULTS APOE {varepsilon}4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among {varepsilon}4 homozygotes. Associations between APOE and global tau burden were more modest and appeared to be driven mainly by {varepsilon}4 homozygotes, while regional analyses showed localized APOE {varepsilon}4-related associations in medial temporal regions. Independently, higher tau burden was associated with lower memory and language performance. CONCLUSIONS In CU older adults, APOE {varepsilon}4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden.

Young onset Parkinson's disease may be caused by biallelic mutations in PRKN or other autosomal recessive Parkinson's disease genes, but the majority of patients do not carry known monogenic variants. Previous studies have found an increased cumulative burden of common genetic risk variants for Parkinson's disease in young onset patients, but the specific genetic architecture of non-monogenic young onset Parkinson's disease is not well characterized. We conducted a genome-wide association study of 1,528 Parkinson's disease patients with symptom onset between 18 and 40 years and 20,408 controls of European ancestry using data from The Global Parkinson's Genetic Program, the International Parkinson's Disease Genomics Consortium, and the NeuroGenetics Research Consortium. We performed meta-analyses of additive and recessive regression models and investigated associations between age at onset groups and different polygenic risk scores. An additive model meta-analysis identified six independent loci passing a genome-wide significance threshold, including three loci identified in previous genome-wide association studies (near SNCA, GBA1, and HIP1R) and two loci not previously associated with Parkinson's disease (rs74950462, P = 1.24e-8 and rs72848817, P = 4.89e-8). Furthermore, we identified a significant signal at the PRKN locus, prompting a follow-up analysis employing a recessive model. The recessive genome-wide association meta-analysis identified nine loci passing a genome-wide significance threshold, including SNCA, PRKN, and seven novel variants. Patients with onset between 18 and 40 years had significantly higher polygenic risk scores than later onset patients when the score was modelled specifically on genome-wide association statistics from independent young onset Parkinson's disease participants versus healthy controls. This increased polygenic burden was driven in part by loci harbouring mitochondrial pathway genes. Our results indicate that previously unidentified common and low-frequency variants contribute specifically to the young onset subgroup of Parkinson's disease. Association signals detected uniquely with a recessive model suggest that genetic susceptibility to young onset Parkinson's disease may be partially driven by homozygous variation, in line with previous reports of increased runs of homozygosity in this particular group of patients and may be consistent with a loss of function mechanism. The findings support the notion of young onset Parkinson's disease as a partly distinct subphenotype and highlight the mitochondrial pathway. These results may have implications for future precision medicine but should be interpreted with caution pending independent replication.

INTRODUCTION: The Framingham Risk Score (FRS) indexes cardiovascular risk (CVR), but age weighting may confound associations with brain and cognitive outcomes. METHODS: In 923 amyloid-positive ADNI participants, we compared FRS against a Multiple Indicators Multiple Causes (MIMIC)-derived age-adjusted measure (CVRmimic) using sex-stratified linear mixed efefcts (LME) and latent growth curve mediation (LGCM) models of hippocampal-to-ventricle ratio (HVR) - cognitive coupling. RESULTS: FRS predicted hippocampal atrophy in all six LGCM models; CVRmimic in none of the six. HVR - cognitive coupling held in four of six FRS and four of six CVRmimic models. Indirect effects reached significance in four of six FRS and none of the six CVRmimic models. LME 3-way interactions (years x risk x HVR) survived FDR correction in all six FRS versus none of the six CVRmimic models. DISCUSSION: FRS "effects" on hippocampal-cognitive decline largely reflect age-related variance. Age adjusted measures complement FRS by isolating cardiovascular effects from aging.

Introduction: Brain-predicted age, estimated from structural MRI data, is a machine-learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population. Methods: T1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic). Results: Higher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes. Conclusions: Elevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.

Regions within ventral occipito-temporal cortex exhibit category-selective BOLD responses during episodic encoding and retrieval of visual information. How these regions interact with other brain areas during successful encoding and retrieval, and whether these interactions relate to memory performance, remains unclear. The present study examined category-selective functional connectivity using psychophysiological interaction (PPI) analyses in younger and older adults during the encoding and retrieval of word-image associations. Seed regions comprised three scene-selective regions - the parahippocampal place area, medial place area, and occipital place area - and one object-selective region, the lateral occipital complex (LOC). During encoding, scene-selective regions exhibited greater connectivity with posterior occipital and occipitotemporal regions during scene relative to object encoding, whereas the LOC exhibited less extensive connectivity with similar posterior regions during object encoding. During retrieval, both scene- and object-selective regions demonstrated increased connectivity with left lateral prefrontal and parietal cortices during the retrieval of their preferred category. Age differences in scene-selective connectivity were evident at both phases. Moreover, associations between source memory performance and scene-selective connectivity were significant only in younger adults. These findings suggest that scene- and object-selective regions exhibit convergent patterns of functional connectivity during encoding and retrieval which, for scenes, vary with age.

To resolve discrepancies in the literature regarding the association between Alzheimers disease (AD) and Biondi body (BB) amyloid in choroid plexus epithelial cells (CPECs), we investigated postmortem hippocampal paraffin blocks with and without a neuropathological diagnosis of AD (n=26-27 each). Similar to previous studies, age was associated with an increased fraction of hippocampal-associated CPECs bearing thioflavin S-positive BBs (p=0.004). In addition, we found that paraffin block storage time was associated with decreased BB detectability (p=0.038) while sex had no effect (p=0.577). Controlling for age, sex, and storage time, AD was associated with a near-significant increase in the BB-containing CPEC fraction (p=0.066) and a significantly greater load of BB-like amyloid in hippocampal-associated ependymal cells (p=0.032). The AD-BB association contrasts with our findings on choroid plexus from the atrium of the lateral ventricle, which lacked this association. We discuss potential explanations for the apparent discrepancy such as regional amyloid cross-seeding.

The precise coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement (NREM) sleep supports memory consolidation and may serve as a sensitive marker of cognitive aging. However, longitudinal changes in their oscillatory dynamics in midlife and older age remain poorly understood. Using polysomnography with high-density EEG at two timepoints over [~]2.5 years, we examined changes in local NREM slow wave (SW), sleep spindle (occurring in the 11-16 Hz sigma range), and SO-sigma coupling strength in cognitively unimpaired middle-aged to older adults at risk for Alzheimers disease. Fronto-central SO-sigma power coupling strength significantly declined over time, independent of changes in multiple measures of SW and sleep spindle expression. Local declines in multiple sleep spindle measures were also observed. Greater baseline levels of cerebrospinal fluid (CSF) neurogranin, a postsynaptic protein abundantly expressed in the dendritic spines of the hippocampus and cerebral cortex and implicated in calcium-dependent synaptic plasticity, predicted the magnitude of longitudinal decline in SO-fast sigma coupling strength, which in turn predicted episodic memory performance changes. These findings suggest that longitudinal changes in local sleep oscillatory dynamics are related to decreased synaptic integrity and may serve as an early indicator of memory decline in older adults at risk for Alzheimers disease.

Recently, the amyloid-beta (A{beta}) targeting antibody lecanemab has demonstrated modest therapeutic efficacy in slowing cognitive decline in people with Alzheimer's disease (AD). Lecanemab clears amyloid plaques from the brain; however, plaque load does not correlate strongly with cognitive function. The strongest neuropathological correlate of cognitive decline in AD is synapse loss, which is exacerbated in the halo surrounding neuritic amyloid plaques where A{beta} accumulates in remaining synapses. Here, we hypothesised that, through clearing plaques and the associated halo of soluble A{beta} that can directly damage synapses, lecanemab could temper plaque-associated synapse loss. High-resolution imaging of temporal cortex tissue from people who died with AD (N=20) and age-matched controls (N=19) reveals lecanemab staining within individual pre and post-synaptic excitatory terminals in addition to plaque staining. The percentage of pre-synapses containing lecanemab-positive A{beta} was over 200% higher in AD and the percentage of post-synapses was over 150% higher in AD than control tissue, with highest levels of synaptic lecanemab staining observed near plaques. These data demonstrate that lecanemab antibody recognises A{beta} within synapses, warranting future work to determine whether lecanemab treatment slows cognitive decline, at least in part, through both clearing plaques and facilitating clearance or neutralisation of synaptic A{beta}.

Increased iron in the substantia nigra has been thought to be a mechanism potentially related to the etiology and/or progression of Parkinson's disease (PD). We hypothesized that genetic variants of HFE, a major iron regulatory gene, would influence substantia nigra iron accumulation in PD. The HFE genotype was obtained from 195 subjects (102 PD and 83 Controls) who participated in the PD biomarker program (PDBP) in central Pennsylvania, United States. For this study, carriers of two SNPs (HFE H63D and/or C282Y) were considered as variants and the others as wildtype. Susceptibility MRI metrics (QSM, R2*) were assessed at baseline, 18, and 36 months. The primary region of interest was the substantia nigra, the key pathology focus of PD. Group differences in substantia nigra QSM and R2* between HFE variants carriers and wildtype were compared between PD patients and controls at baseline and in progression over time using linear mixed-effects model. We also used interaction analyses to explore if HFE genotype impacts clinical measures of PD progression. Of the 102 PD patients, 72 were wildtype, and 30 HFE variant. Of the 83 controls, 56 were wildtype and 27 were HFE variants. There was a total of 451 data points available for analysis. Compared to wildtype patients, patients with HFE variants showed higher baseline substantia nigra QSM (p=0.006), but not higher R2* (p=0.487). Controls had no HFE-dependent differences. Longitudinally, substantia nigra QSM and R2* increased significantly over both 18- and 36-months regardless of HFE status (p's<0.05). Compared to wildtype, PD subjects with HFE variants showed an overall faster increase in R2* (p=0.004) and QSM (p=0.003) over the total 36-month epoch, and this reached the statistical significance for R2* during the first 18-months (p=0.026) and for QSM in 36-months (p=0.005). HFE status showed a significant interaction with motor scales [MDS-UPDRS II (p=0.006), III (p=0.0002)], suggesting a faster symptomatic progression in PD patients with HFE variants compared to wildtype. Although HFE genotype has been shown not to associate with the occurrence of PD, these data demonstrate for the first time that in PD patients substantia nigra iron accumulation and disease progression are affected by HFE genotype. The underlying mechanisms may be important in the progression of PD and the development of personalized treatment.

Background: While genetic factors strongly influence brain aging trajectories, variants conferring cognitive resilience remain poorly characterized. The neurokinin-3 receptor (NK3-R), encoded by Tachykinin Receptor 3 (TACR3), modulates cholinergic signaling in memory circuits vulnerable to aging. Previous studies linked the non-WT expression of the TACR3 variant rs2765 with cognitive decline and reduced volume of the hippocampus and basal forebrain, but systematic replication and mechanistic validation were lacking. Methods: We investigated rs2765 in the preregistered AgeGain cohort of cognitively healthy older adults (n=188) with independent validation in the ADNI cohort (n=809) which includes persons with and without Alzheimers Disease (AD) that show healthy cognition, mild cognitive impairment or dementia. Analyses integrated structural neuroimaging, longitudinal cognitive assessments, epigenetic aging (PhenoAge), genome-wide methylation profiling, and mechanistic validation through luciferase assays and cross-species protein expression studies. Results: The infrequent protective rs2765 WT variant, found in 12.8% of Europeans, conferred 49% slower cognitive decline (p = 0.002) for amyloid-positive individuals of the ADNI cohort and 3.7 years younger epigenetic age (p = 0.013, 95% CI: 0.79-6.67 years) in the cognitively healthy AgeGain cohort. WT carriers showed larger hippocampal and basal forebrain volumes across cohorts, with Allen Brain Atlas integration revealing these outcomes to occur exclusively in regions where TACR3 expression positively correlated with gray matter volume. Mechanistically, the non-WT variant ameliorated RBMX-mediated post-transcriptional regulation, reducing NK3-R protein expression by 25-40% in vitro and ex vivo murine brain slice models. Senescence-accelerated mice exhibited reduced endogenous NK3-R expression, phenocopying the predicted functional consequences of the variant. In AgeGain participants, genome-wide methylation profiling identified 2,313 differentially methylated CpGs affecting 228 pathways spanning glutamatergic signaling, acetylcholine receptor pathways, chromatin remodeling, and angiogenesis, suggesting coordinated molecular reprogramming from synaptic function to systemic aging. Conclusions: rs2765 WT confers resilience to age- and AD-related cognitive decline through RBMX-dependent regulation of NK3-R expression, with effects of remarkable size cascading from memory to systemic aging. rs2765 genotyping could stratify individuals for NK3-R modulator therapy (e.g., fezolinetant or senktides) and identify those maintaining function despite pathological burden, complementing APOE-based risk assessment in precision geromedicine.

Incomplete letter recognition tasks are frequently used to detect visual deficits arising from neurodegenerative syndromes, including Posterior Cortical Atrophy (PCA; visual-variant Alzheimers disease). A recent development of this approach is the Graded Incomplete Letters Test (GILT), which measures recognition thresholds for letters degraded by removing pixelated sections (decreasing completeness). Although GILT thresholds are strongly elevated in PCA relative to typical adults, the precise cortical visual impairments underlying these deficits are unclear, as is the potential contribution from age-related optical limitations. We compared candidate cortical factors (crowding and global integration) with optical limitations (blur and low contrast) by simulating these factors in typical adults (n=6) viewing incomplete letter stimuli. Participants identified foveally presented letters (12 alternatives), with completeness varied using QUEST. At baseline, thresholds averaged [~]5% completeness. Optical factors were simulated by separately applying blur and lowered contrast. These factors had minimal effect on thresholds, except where blur/contrast levels approached visibility limits, where thresholds rose modestly but remained far below clinical levels in PCA. Cortical factors were simulated by increasing crowding (disruptions from clutter) through peripheral presentation, with global-integration impairments simulated by varying pixel size to alter the distribution of degradation (limiting spatial integration) or degrading letters dynamically with limited-lifetime pixels (limiting temporal integration). These manipulations substantially elevated thresholds, with combined crowding and global-integration impairments increasing thresholds to levels comparable with PCA. We conclude that impaired incomplete letter recognition is driven primarily by cortical rather than optical factors, and that neurodegenerative deficits may reflect the combined impact of multiple cortical limitations.

Mitochondrial diseases (MDs) are genetically and phenotypically diverse and can be difficult to diagnose. Prevalence estimates derive largely from diagnosed cases and may underestimate population MD risk. Population-based studies are limited in scope and number but indicate MD variants are common. As genomic sequencing advances have made comprehensive population-based evaluation feasible, we sought to evaluate nuclear MD variation in a population cohort to understand variant prevalence and differences in MD risk estimates We identified disease-associated nuclear gene variants in 270 nuclear MD genes across 2,845 healthy older individuals in the Medical Genome Reference Bank. From Pathogenic or Likely Pathogenic Variants (PLPVs) we estimated autosomal recessive (AR) and autosomal dominant (AD) MD risk for individual genes and all nuclear variant-associated MDs. We identified 554 PLPV alleles representing 357 unique variants in 145 genes. Combined AR MD risk was estimated at 25.8 per 100,000 (95% CI 18.7 to 32.9), or 1 in 3,880 individuals. SPG7 (12.65 per 100,000; 95% CI 7.52-20.6) and POLG (4.23 per 100,000; 95% CI 2.10-8.01) contributed the greatest single gene AR MD risks and OPA1 variants posed the greatest AD MD risk. We observed a high rate of MD-associated nuclear gene variation in this healthy older cohort. The estimated lifetime AR MD risk was higher than commonly quoted prevalence estimates for all MDs, and the presence of common AD variants suggests variant penetrance may be lower than previously understood. These data help contextualise population MD risk and may inform clinical counselling and care.