Texas Card Sorting Test: a Brief Test of Executive Functioning with Age-Adjusted Norms and External Validation.

Abstract Introduction Even in ‘healthy’ ageing, the immune system undergoes significant changes, with these immune system aberrations being collectively known as immunosenescence. These changes are complex, occurring both in the innate and the adaptive immune system, though recent focus has been on changes in the adaptive immune system due to increasing availability of highly targeted immunomodulatory drugs coming into clinical use. Managing immunosenescence is important for older adults as these immune changes contribute to their increased susceptibility to infections, poor response to vaccines, weakened cancer immunosurveillance and increased risk of autoimmune disease. This narrative review considers the underlying mechanisms of T-cell co-signalling changes, as a potential modifiable target in immunosenescence. Method Structured searches of Medline OVID, SCOPUS, Web of Science and PubMed were performed with MeSH terms relating to ageing, T-cell co-signalling and therapeutic interventions. Duplicates were removed, abstracts screened, and papers organised thematically. Results The literature highlights a general decrease in excitatory signalling, with a concurrent increase inhibitory signalling, in T-cells in healthy ageing. This leads to lower proliferative capacity of T-cells in response to a novel antigen and thus a less competent immune response. Potential interventions to overcome these changes exist, spanning from lifestyle interventions such as horticultural therapy, to use of monoclonal antibody therapies to directly modulate immune responses. Conclusions T-cells have worsening function with age, in part due to weakened excitatory cos-signalling and strengthened co-inhibitory signalling. There is potential for these changes to be modified with novel medical therapies to overcome age-relate immune changes.

Alzheimer's disease (AD) patients experience cognitive decline due to the deposition of beta-amyloid, which particularly affects their ability to retrieve words in language tasks. A mind map is an activity that involves freely associating and retrieving words related to a given category, providing an integrated assessment of cognitive and linguistic abilities. This study aimed to identify the various characteristics observed during the performance of a digital mind map task in patients with AD pathology, with beta-amyloid deposition confirmed by positron emission tomography imaging. The study involved 48 adults aged 50 and over (30 patients with AD pathology and 18 healthy controls, HC). Participants completed a mind map task where they generated and retrieved words related to specific keywords (travel, family and food). Performance was analysed and compared across three main aspects: (1) keyword responses (number of blanks filled, number of words written), (2) performance time (preparation time for retrieval, writing time, total task time), and (3) word diversity (number of unique words, number of repeated words). First, in terms of keyword responses, there was no significant difference between groups in the number of blanks filled; however, the AD pathology group wrote fewer words than HC. Error analysis revealed that the AD patients were more likely to provide elaborations and non-words compared to HC. Second, regarding performance time, the AD pathology group took longer to prepare for word retrieval and to write the words. Third, in terms of word diversity, the AD pathology group generated fewer unique words and tended to repeat words more often than HC. The study confirms that patients with AD pathology experience difficulties in using their mental lexicon to activate and select appropriate words for retrieval due to damage in the temporal-parietal regions caused by beta-amyloid deposition. This study highlights the potential of digital mind maps as a novel word retrieval task for early differentiation of cognitive impairment in AD. What is already known on the subject Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by beta-amyloid(Aβ) plaques and tau tangles, leading to neuronal loss in memory-related regions. Aβ disrupts neural connectivity, especially in the temporal and parietal lobes, impairing memory and language. Traditional language tasks, such as naming and verbal fluency, are used to detect early cognitive changes but often fail to reliably distinguish mild cognitive impairment from early AD due to pathological diversity. Mind mapping, which requires associative word retrieval and integrates executive, semantic, and lexical processes, may provide a more comprehensive assessment, but its diagnostic value in AD pathology group not yet well studied. What this paper adds to the existing knowledge This study is the first to apply a digital mind mapping task to patients with AD pathology who have objectively confirmed Aβ deposition, directly linking pathological biomarkers to cognitive-linguistic performance. The findings demonstrate that patients with AD pathology, compared to healthy controls, exhibit significant deficits in mind mapping: they write fewer words, produce more circumlocutory and non-word responses, require longer preparation and writing times, and generate less diverse vocabulary. By employing a digital platform, the study provides objective, quantitative measurements of word retrieval, response time, and word diversity, offering a novel approach to assessing the multifaceted cognitive-linguistic deficits associated with AD pathology. What are the potential or actual clinical implications of this work? The digital mind mapping task offers a sensitive and ecologically valid tool for detecting early cognitive-linguistic impairment in AD, especially in patients with confirmed Aβ pathology. The multifactorial assessment of word retrieval, timing, and diversity may enhance early differentiation of AD from normal aging and other cognitive disorders, supporting earlier intervention and more precise monitoring of disease progression. Integrating digital mind mapping into clinical practice could improve the identification of subtle language deficits not captured by traditional tasks, contributing to more comprehensive cognitive screening and tailored therapeutic strategies for individuals at risk of or with AD.

Age-Related Optic Nerve Optical Coherence Tomography and Optical Coherence Tomography Angiography Changes in Subjects Without Glaucoma: A 5-Year Prospective Study.

AimsHypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs).Methods and resultsWe used tamoxifen (TAM)-inducible, CM-specific von Hippel–Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice.ConclusionSustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.

ABSTRACTAging studies using animal and cellular models have uncovered key proteins and pathways central to organismal aging. However, these models differ genetically and physiologically from human aging, posing challenges in translating discoveries to human contexts. In this study, we present a human normal cell aging model based on the development of cytotrophoblasts (CTBs) to syncytiotrophoblasts (STBs) in the placenta. The in vitro‐derived STBs from human trophoblast stem cells (hTSCs) recapitulate the maturation and major cellular aging features of in vivo CTB‐STB, including multinucleation, hormone secretion, cell cycle arrest, genome instability, epigenetic changes, activation of endogenous transposable elements, and senescence‐associated secretory phenotypes (SASPs). Notably, the progressive senescence in the trophoblast system closely matches the predicted aging trajectory of other human tissue stem cells. Known anti‐aging molecules, such as mTOR inhibitors and senolytics, attenuate senescence signals in STBs. The established CGA‐EGFP reporter hTSC line enables scalable and quantitative screening and identified candidates with it can be further extended to other context‐specific aging processes like that of skin fibroblasts. The hTSC‐STB system represents a novel physiologically accelerated cellular aging model, bridges the gap between fundamental aging research and interventions, and prioritizes anti‐aging candidates for clinical development.

This study investigated whether Whole blood viscosity (WBV) varies with age in clinically healthy Beagle dogs and Korean Shorthair cats and examined the hematologic and biochemical variables associated with WBV. WBV was measured across multiple shear rates using a scanning capillary viscometry; complete blood count (CBC) and serum chemistry profiles were also evaluated. Both species demonstrated characteristic shear-thinning behavior. WBV showed a strong association with red blood cell count (RBC), hematocrit (HCT), and hemoglobin (Hb) in both species, with additional association with serum proteins and cholesterol in dogs. No significant relationship between WBV and age was identified at any shear rate, and principal component analysis (PCA) revealed no age-related clustering in the viscosity profiles. These findings indicated that WBV does not exhibit meaningful age-dependent trends in healthy companion animals. This suggests that, in a clinical setting, deviations in normal WBV are more likely to influence underlying physiological or pathological factors than normal aging.

ABSTRACT Lithium plating on graphite anodes is a critical degradation pathway in lithium‐ion batteries (LIBs), yet quantitative decoupling of its contribution from normal anode aging remains challenging. Here, we designed controlled Li plating tests using negative‐to‐positive ( N/P ) ratio < 1 LiFePO 4 /graphite cells and then compared them with practical fast‐charging cells ( N/P > 1), quantifying the decomposition of each electrolyte component (solvent, salt, additives) using nuclear magnetic resonance (NMR), mass spectrometry titration (MST), and gas chromatography‐mass spectrometry (GC‐MS). Controlled Li plating occurs after full graphite lithiation, and it leads to rapid vinylene carbonate (VC) depletion, time‐dependent non‐Faradaic consumption of hexafluorophosphate (PF 6 − )/ethyl methyl carbonate (EMC)/ethylene carbonate (EC), and more organic solid‐electrolyte interphase (SEI) formation at higher rates. In routine fast‐charging aging, Li plating occurs before graphite saturation, and we find pronounced EMC consumption under high‐rate conditions compared with low ‐ rate. Our comparative analysis indicates that VC consumption during fast charging originates not only from plating but also significantly from baseline graphite aging. Li plating likely induces SEI rupture, leading to direct contact with electrolyte, thus more organic SEI formation. This quantitative study enables decoupling of Li plating‐induced side reactions from general aging without plating, informing battery design and predictive aging models.

ObjectiveThis study aimed to identify factors related to the successful induction of labor (IOL) among pregnancies complicated with fetal growth restriction (FGR).MethodsWe performed a retrospective cohort study between January and December 2024 at Orléans University Hospital, Orléans, France. The study enrolled all singleton pregnancies complicated by FGR and underwent IOL. Logistic regression was used to reveal the associated factors relating to the success of IOL, following two criteria, including Bishop score after IOL greater than 7 points (criterion 1) and vaginal birth (criterion 2).ResultsBishop score had a negative correlation with IOL duration. This study did not find statistically significant clinical factors related to the success of the Bishop score change of more than 7 points. However, absence of Doppler abnormalities and IOL at term, more than 37 weeks, were related to the success rate of vaginal delivery (OR [95% CI]: 22.5 [3.240–156.269] and OR [95% CI]: 22.5 [3.240–156.269], respectively;p < 0.05).ConclusionBishop score before IOL helps in reducing the duration of IOL. In FGR pregnancies with a normal Doppler ultrasound scan and gestational age at IOL greater than 37 weeks, these are good prognostic factors for vaginal delivery; however, further research is needed to explore more associated factors.

Whether chronological age affects the ability of vascular aging indicators to predict cardiovascular events risk remains unknown. This study sought to examine whether the predictability of vascular aging indicators is better in middle-aged participants than older participants. This prospective cohort study included 8163 participants from a community-based atherosclerosis cohort in Beijing, China. Vascular age (VA) was defined as the predicted age in a multivariable regression model including cardiovascular risk factors and pulse wave velocity. Residuals by regressing VA on chronological age were defined as ∆-age, reflecting vascular aging. We used Cox proportional hazard regression model to examine the association between ∆-age and the risk of cardiovascular events in different chronological age groups. Of all participants, 5691 (69.7%) were between 40 and 60 years old, and 2472 (30.3%) were over 60 years old. During a median 9.9-year follow-up period, 818 (10%) endpoints were observed. After adjusting for confounders, ∆-age was positively associated with the risk of cardiovascular events in middle-aged participants (HR: 1.13, 95% CI: 1.07-1.21; p < 0.001), whereas no significant association was observed in older participants (HR: 1.03, 95% CI: 0.99-1.06; p = 0.148). Interaction analysis in total participants showed that chronological age significantly modified the relationship between ∆-age and the risk of cardiovascular events (p = 0.017). Our findings indicate that the predictive ability of residuals between VA and chronological age for the risk of cardiovascular events is better in middle-aged people than that in older people. The VA assessment may be more valuable to the middle-aged population. The modifying effect of chronological age showed that vascular aging categories in middle-aged participants have stronger predictive ability for the risk of cardiovascular events than that in older participants. MACE, a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality; normal VA, normal vascular aging; EVA, early vascular aging; SUPERNOVA, supernormal vascular aging.

Abstract With increasingly stringent emission regulations and fuel consumption standards, lean‐burn technology has become an important development direction for gasoline engines. The emission characteristics of lean‐burn gasoline engines differ significantly from those of conventional stoichiometric engines, and when close‐coupled three‐way catalysts (TWCs) are still applied, it is essential to understand their hydrothermal aging behavior. In this study, six Pd‐only TWC samples with two Pd loadings (high and low) and three aging states (fresh, normally aged and lean‐burn aged) were prepared. Their catalytic performance was evaluated on a flow reactor under steady‐state lean‐burn conditions, measuring NO, HC and CO conversion and NH 3 yield. Structural characterizations were carried out using XRD, BET, SEM and XPS. The results show that lean‐burn aging causes more severe structural degradation and stronger depletion/oxidation of surface Pd species than normal aging, leading to pronounced deterioration of low‐temperature (&lt;300°C) NO and CO conversion. High Pd loading provides higher initial activity and superior high‐temperature (&gt;400°C) conversion, but suffers poorer low‐temperature stability, whereas low Pd loading exhibits better structural stability and improved low‐temperature HC conversion. Although both aging protocols reduce NH 3 yield, lean‐burn aged catalysts show a smaller decrease and even relatively higher NH 3 yield at 300–350°C due to stronger CO oxidation deactivation and the resulting increase in residual CO. These findings provide guidance for optimizing Pd‐based TWCs for lean‐burn gasoline engines, especially when used upstream of PSCR.

Early and premature menopause are positively associated with coronary heart disease and stroke, but there is less evidence regarding its relationship with the onset of diabetes. The primary objective of this study is to assess the association between the timing and type of menopause and the possible development of type 1 or 2 diabetes. Participants from the UK Biobank were enrolled between 2006 and 2010, with follow-up to the end of 2023. The outcome variable was diagnosis of type 1 or 2 diabetes during follow-up, and the main explanatory variable was age at menopause (normal above 45y, early 40-45y, and premature below 40y). Behavioral factors, comorbidities, and blood tests were also collected. Survival models with Weibull distribution were fitted to the time of diabetes onset. Of the 146,764 women analyzed over a mean follow-up of 14.5 years, 6,598 women developed diabetes (cumulative incidence 4.5%). Rates were higher in women with earlier menopause (4.2% at age above 45y, 5.2% at ages 40-45y, and 7.4% before age 40); however, the multivariate analysis showed no independent association (40-45y: hazard ratio: 1.00; <40y, hazard ratio: 0.97), taking the normal age of menopause as the reference. Surgical menopause was likewise not associated with a greater risk of diabetes compared with natural menopause. In a large cohort of women with long-term follow-up, no independent or clinically significant relationship between age or type of menopause and the onset of diabetes was observed.

BackgroundMitochondrial dysfunction and protein aggregation are central features of brain aging and Alzheimer’s disease (AD). To define how AD seed proteins modulate these processes, we applied quantitative proteomics to sarkosyl-insoluble aggregates from C. elegans models of normal aging and from worms expressing human Aβ or Tau transgenes.ResultsNormal aging produced a late-onset accrual of mitochondrial proteins within aggregates, implicating impaired energy metabolism and proteostasis collapse. Aβ expression caused a striking expansion and included glycolytic enzymes, tricarboxylic acid cycle components, ribosomal proteins, and trafficking factors, consistent with broad proteostatic and bioenergetic stress, largely overlapping with aging-associated species, yet advanced in onset. Tau expression yielded a smaller set enriched for cytoskeletal, vesicular, and nuclear pore components. Post-translational modifications (4-HNE adducts, phosphorylation, acetylation, methionine oxidation) revealed distinct trajectories: Aβ imposed early oxidative and phosphorylation burden, whereas Tau and aging showed midlife PTM peaks consistent with delayed proteostasis collapse. Cross-species comparison revealed 68 insoluble proteins shared between worm models and human AD brain aggregates. From these, 17 conserved metabolic, chaperone, and trafficking proteins were prioritized by network metrics and validated functionally: RNAi knockdowns aggravated paralysis or impaired chemotaxis, confirming their functional importance.ConclusionThese findings place mitochondrial proteome collapse at the center of aging and AD-seeded pathology, distinguish Aβ- and Tau-driven proteotoxic routes, and nominate a conserved panel of aggregation-prone proteins as mechanistic drivers and candidate biomarkers for early detection and intervention in AD.

Objectives:Vascular aging (VA) is a prognostically relevant aspect of biological aging. We investigated its prevalence and determinants in Austria.Methods:The LEAD (Lung, Heart, Social, Body) study is an ongoing, longitudinal, population-based observational study, which started in 2011 in Vienna and six villages from Lower Austria. Within the study, carotid-femoral pulse wave velocity (cfPWV) was measured using applanation tonometry. Based on a reference population (no history of overt cardiovascular disease, no diabetes, no pharmacological treatment for hypertension or dyslipidemia), sex-, and age-specific Z-scores for cfPWV were calculated. Healthy (HVA), normal (NVA), and early (EVA) vascular aging were defined as cfPWV Z-score <10th, 10th–90th, and >90th percentile, respectively.Results:In the overall population (n = 7926, 54.2% women, age 18–82 years), the prevalence of HVA/NVA/EVA was 9.1/78.6/12.2%, respectively, with EVA prevalence increasing in older age. The risk of EVA, as compared to HVA, was independently and directly associated with female sex (odds ratio, OR 2.8), systolic (OR 1.04) and diastolic (OR 1.02) blood pressure, heart rate (OR 1.06), body height (OR 1.03), and diabetes mellitus (OR 3.0), and inversely related to appendicular lean mass index (OR 0.82), postbronchodilation FEV1 (OR 0.81), and healthy nutrition (OR 0.69). The results were similar for the comparison of EVA and NVA, adding an independently increased risk for EVA with regular alcohol intake (OR 1.37) and low income (OR 1.21).Conclusions:We observed a high percentage of EVA in Austria, determined by classical and nonclassical risk factors. The latter may offer novel targets for prevention.

Non-cognitive, neuropsychiatric symptoms (NPS) are nearly universal in Alzheimer's disease (AD), but investigation of their underlying biology is complicated by comparative medicine approaches that incompletely capture spontaneous disease, primarily using transgenic rodent models. The aged companion dog, which spontaneously develops an AD-like disease called canine cognitive dysfunction (CCD), may help fill this translational gap. Using data from the Dog Aging Project with > 10,000 aged dogs (> 8years old), we identify numerous behaviors in dogs "at-risk" for and with CCD that mirror NPS in humans. Compared to dogs without CCD, our analysis shows that dogs with CCD are less physically active, exhibit fewer previously trained behaviors, demonstrate fewer motivated behaviors, have more daytime sleep, demonstrate more separation anxiety, have altered anxious responses to novelty, have changes in aggressive behaviors, and exhibit lower appetite. Using k-means clustering, we did not find evidence for behavioral sub-phenotypes. Overall, our analysis of a large number of aged dogs suggests clinically significant NPS are associated with CCD and that the companion dog may serve as an important comparative medicine approach to understand these debilitating symptoms across species.

PurposeThe purpose of this study was to evaluate change in visual functions over 3 years in normal macular health, and early and intermediate age-related macular degeneration (AMD) including tests of rod-, cone-, and mixed rod-cone-mediated visions; and to evaluate whether visual function change over 3 years meets the minimal clinically important difference (MCID), defined as meaningful to patients in everyday life.MethodsEight visual functions were evaluated at baseline and 3-year follow-up (acuity, low luminance acuity, photopic and mesopic contrast sensitivity, mesopic and scotopic light sensitivity, and rod-mediated dark adaptation [RMDA] at 5 degrees and 12 degrees). The Age-Related Eye Disease Study (AREDS) 9-step classification system defined AMD severity.ResultsIn normal aging and intermediate AMD, 6 of 8 visual functions had statistically significant worsening over 3 years; mesopic contrast sensitivity and mesopic light sensitivity, respectively, showed no change. In early AMD, five of eight visual functions showed worsening over time, with photopic and mesopic contrast sensitivity and scotopic sensitivity unchanged. The largest percentage of eyes in each group meeting MCID was RMDA at 5 degrees or 12 degrees (38%–55%). The lowest percentage of eyes meeting MCID was visual acuity and photopic contrast sensitivity (0%–10%).ConclusionsWhereas most visual functions evaluated have statistically significant worsening over 3 years in normal aging to intermediate eyes, the percentage of eyes reaching MCID was low for most visual functions except RMDA, which met MCID for almost half the eyes.Translational RelevanceThe natural history of change in visual function over time in normal aging to intermediate AMD should be characterized in terms of MCID, not only statistical significance.

Retrospective cohort study comparing sagittal spinopelvic alignment in patients with lumbar spinal stenosis (LSS) to age- and sex-matched normative data and evaluating postoperative changes following decompression surgery. To determine whether LSS represents a distinct sagittal alignment phenotype beyond normal aging and to assess alignment changes up to two years after decompression surgery. Sagittal alignment in healthy populations and adult spinal deformity is has been widely studied. However, the sagittal alignment specific to LSS remains poorly researched. Patients undergoing decompression without fusion for LSS between 2014 and 2022 at a single institution were included. Exclusion criteria were prior surgery, infection, tumor, scoliosis, or lack of radiographic data. Sagittal parameters were measured preoperatively and at two-year follow-up. We calculated normative value using a large population-based Japanese cohort. Comparison between LSS and controls were performed using one-sample t-tests. 448 patients were included for analysis. Compared to controls, LSS patients had significantly higher SVA and PT, and lower LL, SS, and TK. Postoperative alignment improved but did not normalize. Residual malalignment persisted across all age groups, indicating a distinct alignment phenotype in LSS. LSS is associated with a unique sagittal alignment profile that exaggerates age-related changes. Decompression surgery partially improves sagittal alignment. These findings suggest intrinsic structural differences in LSS and highlight the need for individualized treatment and long-term follow-up. 3.

BackgroundAlzheimer's disease is characterized by progressive atrophy of hippocampus and parahippocampal structures including entorhinal cortex and parahippocampal gyrus. Predicting longitudinal volume changes remains challenging as they can occur due to normal ageing and disease progression.MethodFrom the ADNI dataset (n = 480), we used two years of baseline data including demographics, cognitive assessment scores (CDR‐SB, MMSE), and FreeSurfer‐extracted MRI measurements to predict third and fourth‐year Hippocampus volume, parahippocampal volume and thickness. We employed a GRU‐based Bayesian Encoder‐Decoder architecture (GRU‐BEND) with a 70:10:20 train‐validation‐test split. We evaluated our model over five‐fold cross‐validation and used the Integrated Gradient method for feature importance analysis. Figure 1 shows the degradation of the region's volumes over the year for different diagnosis cohorts.ResultThe model demonstrated strong predictive performance for all the target variables. We employed the metrics Mean Absolute Error (MAE) and Mean Absolute Percentage Error (MAPE) to evaluate our model. As expected, the predictions for the third year were more accurate than the fourth year. MAPE for the third year ranged between 4.3% to 4.9%, while 5.1% to 6.6% for the fourth year. MAE ranged between 0.03 to 0.06. The Left and right hippocampus volume prediction was most accurate over both years (Y3: MAE: 0.039±0.002, MAPE: 4.4±0.1%; Y4: MAE: 0.045±0.003, MAPE: 5.1%). The important features contributing to the predictions for hippocampus (left) and parahippocampal volume (left) are shown below in Figure 2 and 3. The role of CDR‐SB and MMSE in the prediction was minimal. Surprisingly, amygdala and ventricle volume were among the least contributing factors for hippocampus predictions.ConclusionIn this study, we demonstrate that a GRU‐BEND model which is able to effectively predict longitudinal changes in volumes of hippocampal and parahippocampal structures in Alzheimer's disease based on two years of data. This may be helpful in prognosticating patients and quantitative estimation of treatment effects.

BackgroundAging is a major risk factor for Alzheimer's disease (AD), but the molecular processes linking aging to AD remain unclear. Epigenetic modifications, particularly DNA methylation (DNAm), play a crucial role in understanding aging and AD.MethodWe studied brain DNA methylation (DNAm) changes in normal aging versus AD in late life. We performed a comprehensive meta‐analysis of two large cohorts of postmortem prefrontal cortex samples from subjects over 65 years old. Our analysis adjusted estimated cell‐type proportions (i.e., the proportion of neurons), sex, and batch effects, and corrected for inflation and multiple testing.ResultWe identified numerous DNAm differences consistently associated with aging in both cohorts, highlighting key genes such as ELOVL2, ISM1, and KLF14, which are implicated in various aging processes. These DNAm differences are predominantly hypermethylated, enriched in promoter regions, and associated with genes involved in immune processes and metabolic functions. Our results also revealed significant overlaps between aging‐associated DNAm differences and those involved in AD, supporting the hypothesis that aging and AD are interconnected at the molecular level. Intriguingly, nearly all DNAm differences significantly associated with both age (at death) and AD Braak stage showed concordant effect sizes in the same direction.ConclusionOur study provides valuable insights into the aging‐associated epigenetic landscape and its potential implications for AD. As aging and AD are intertwined, targeting age‐related epigenetic modifications may offer new therapeutic strategies for AD.

BackgroundInteraction of Alzheimer's Disease (AD) pathology and vascular comorbidities is difficult to study in humans due to slow course of AD and high prevalence of patients with mixed pathologies. Vascular comorbidities (e.g., with obesity) are highly prevalent and increase the risk of developing dementia. There is thus a pressing need to examine experimental AD models incorporating obesity and to establish sensitive and translational imaging assays therein.MethodTgF344‐AD (TgAD) rats and their non‐transgenic (nTg) littermates were given three months ad lib access to high carbohydrate high fat (HCHF) food items, so as to imitate the highly palatable foods consumed in the obesogenic population, before MR imaging them at 12 months of age (established AD). Pseudo continuous arterial spin labeling (pCASL) MRI was utilized to establish an assay of hippocampal neurovascular compromise and its sensitivity to AD and its interaction with obesity.ResultIn CHOW‐fed cohorts, hippocampal functional hyperemia (CBF change and volume of activation) in response to electrical stimulation of the forepaw was attenuated in TgAD rats (CBF change: 7 ± 14 ml/100g/min and volume of activation: 0.03 ± 0.08) relative to nTg rats (CBF change: 49 ± 21 ml/100g/min, p = 0.029 and volume of activation: 0.34 ± 0.14, p <0.001). In contrast, the functional hyperemia was enhanced with HCHF diet in TgAD rats (CBF change: 60 ± 26 ml/100g/min, p <0.001 and volume of activation: 0.25 ± 0.15, p <0.001).ConclusionThe observed rescue of functional hyperemia with HCHF in established AD, but not in normal aging, is speculated to result from metabolically dysregulated AD brain profiting from calorie‐dense food consumption. This work demonstrates a non‐invasive neuroimaging assay to assess hippocampal neurovascular function in AD and its vascular comorbidities, offering high translational potential. This assay affords ease of delivering somatosensory stimuli and limited effect of aging and neurodegeneration on somatosensation, making somatosensory protocol a particularly easy one to deploy in patients.