Journal of Alzheimer’s Disease

BackgroundEmerging evidence suggests that microbiota play a role in Alzheimers disease (AD) pathology and cognitive performance. Interventions targeting the oral-brain axis may offer neuroprotective benefits, particularly during the early stages of cognitive impairment. This randomized controlled trial (RCT) investigated whether a multistrain probiotic supplement could modulate AD-related plasma biomarkers and cognitive function in older adults with early cognitive impairment. MethodsParticipants from the Gwangju Alzheimers Disease and Related Dementia (GARD) Cohort in Korea were enrolled in a double-blind, randomized, placebo-controlled trial. Older adults with early cognitive impairment were randomized to receive either a multistrain probiotic supplement (KL-P301) or a placebo for 24 weeks. Plasma pTau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were quantified at baseline and follow-up. Cognitive and clinical assessments included the Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), CERAD neuropsychological battery, Stroop test, and Rey-Osterrieth Complex Figure (ROCF). Treatment effects were analyzed using paired t-tests, linear mixed models, and ANCOVA adjusted for baseline and demographic covariates. ResultsOf the 87 participants analyzed (probiotic, n=40; placebo, n=47), the probiotic group exhibited a significant reduction in plasma pTau181 levels compared with the placebo group (p < 0.001). While GFAP and NfL levels remained stable in the probiotic group, the placebo group showed significant longitudinal increases (p = 0.014 and p = 0.041, respectively). Clinically, the probiotic group demonstrated improved CDR (p = 0.010), primarily driven by the memory domain. Domain-specific cognitive analyses revealed that the probiotic group significantly improved in visuospatial construction (Constructional Praxis, p = 0.036; ROCF copy, p = 0.027) and maintained stable constructional recall, whereas the placebo group showed a significant decline (p = 0.025). No significant between-group differences were observed in MMSE, verbal memory, or executive/attentional functions. ConclusionThe multistrain probiotic supplement reduced tau-related pathology and neuroinflammation-associated biomarkers and selectively preserved visuospatial construction and visual memory in older adults with early cognitive impairment. These findings suggest that modulating the oral-immune-brain axis with multistrain probiotics represents a viable, non-pharmacological strategy to slow AD-related pathological progression and cognitive decline in early-stage patients.

This study evaluated hearing loss (HL) as a potential early indicator of dementia. We analyzed 16,270 participants from the All of Us database (1980 to 2022), including 1,224 (7.5%) with dementia, matched to controls by U.S. census demographics. Severe survey-reported HL showed the strongest association with dementia (odds ratio [OR] 6.76), followed by sensorineural HL (SNHL) (OR 3.90), smoking (OR 1.71), parental HL (OR 1.48), and hypertension (OR 1.48), all p < 0.001. Effect sizes were largest for severe survey-reported HL (1.91) and SNHL (1.36). These findings indicate that severe survey-reported HL and SNHL are strongly associated with dementia.

BackgroundRNA editing is a post-transcriptional modification that alters the sequence of an RNA transcript. Two types of RNA editing were found in mammals, involving the enzymatic deamination of either adenosine to inosine (A-to-I) or cytidine to uridine (C-to-U) nucleotides in RNA. A-to-I, which is the most common form of RNA editing, is mediated by the ADAR (adenosine deaminases acting on RNA) family of enzymes, ADAR1, ADAR2, and ADAR3. The editing event alters the hydrogen bond pairing of nucleobases, and the editing site will be recorded as guanosine rather than the original adenosine. Indeed, RNA editing deregulation has been linked to several nervous and neurodegenerative diseases. In this project work is done on Alzheimers disease (AD) and the samples are from anterior cingulate cortex of human brain tissue. AD is the main dementia in the world and a neurodegenerative condition prevalent in the elderly. MethodologyA total of 20 raw RNA-sequencing data samples containing 10 controls and 10 Alzheimers disease (AD) cases were collected from NCBI using SRA Toolkit. Quality assessment was performed using FastQC and processed using Trimmomatic. Alignment was done using STAR RNA-seq aligner. RNA editing detection was performed using REDItools, detected sites were subsequently annotated against the REDIportal database. The resulting control-specific and disease-specific novel editing sites were merged into a single dataset containing exclusively novel, group-specific A-to-I editing events. This merged dataset was subsequently used for downstream feature extraction and machine learning analysis. Probability-based filtering was done to extract high-confidence disease associated sites and their gene list was used for computational level biological validation, pathway and functional enrichment analysis as well as overlap with known AD loci. ResultsRandom Forest showed the highest accuracy score (0.804) and ROC-AUC score (0.854). Most important features that differentiated control and diseased novel sites in random forest were coverage ([~]0.35), editing level ([~]0.33) and GC content ([~]0.15). The AEI mean values is higher in both male and female diseased cases ([~]0.48-0.50) but less in male and female control cases ([~]0.14-0.21). The mean values of ADAR1_CPM higher in control cases (123.65-143.30) and is less in diseased cases (88.35-97.93), ADAR2_CPM is almost equal in all cases ([~]3.7-4.7) and ADAR3_CPM is very less in all the cases ([~]0-0.02). Most candidate editing site were present in exon ([~]62-67 %) CDS regions ([~]17-21%) and relatively smaller fraction of gene ([~]15-16 %). Editing alterations preferentially affect molecular systems governing synaptic structure, neurotransmission, and central nervous system integrity. In the main set -of the 2576 high-confidence genes identified, 33 overlapped with AD GWAS loci. In the core set -of the 1367 high-confidence genes identified, 11 overlapped with AD GWAS loci. ConclusionFeature like coverage, editing level and GC content contributed most. Alu sites are negligible as compared to non-alu sites but the AEI mean values are higher in diseased cases than in control cases. The mean values of ADAR1_CPM are higher than ADAR2_CPM and ADAR3_CPM.Sex does not play a major factor. High-confidence disease-associated RNA editing sites are strongly biased toward transcript-centric regions, particularly exons, with a notable subset affecting coding sequences. Importantly, enrichment of neurodegeneration-associated pathways and cognition-related human phenotypes further supports the disease relevance of these gene networks. RNA editing events in Alzheimers cortex may represent a regulatory mechanism largely independent of inherited genetic susceptibility loci.

IntroductionDisruption of brain glucose and lipid metabolism contributes to Alzheimers disease (AD) and often emerges before clinical symptoms. Women are at elevated AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Womens risk of AD is further elevated by the APOE4 allele, the strongest genetic risk factor for late-onset AD. MethodsTo investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages of peri-to postmenopausal transition. ResultsAPOE3/3 mice exhibited dynamic regulation of brain metabolic systems that supported postmenopausal bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice displayed accelerated and altered metabolic shifts, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and alterations in brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits. DiscussionOutcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.

BackgroundAlzheimers disease (AD) is a neurodegenerative disorder marked by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves factors such as amyloid plaques, tau tangles, neuroinflammation, and synaptic dysfunction, but the precise mechanisms remain unclear, hindering effective treatment. Genetic, environmental, and lifestyle factors contribute to AD risk, yet their interactions are poorly understood. Recent advances in transcriptomics and metabolomics have shed light on the molecular underpinnings of AD, with gene expression alterations and metabolic disruptions implicated in disease progression. These multi-omics disruptions highlight the need for integrative analytical approaches to better characterize AD-relevant biology and advance biomarker discovery. ObjectivesTo integrate genetically imputed whole blood transcriptomics and plasma metabolomics to predict cognitive performance (PACC3) and to identify risk genes and metabolites contributing to prediction, thereby characterizing molecular signatures associated with cognitive performance in AD. MethodsThis study applies a machine learning algorithm to integrate genetically imputed whole blood transcriptomics and measured plasma metabolomics data to predict cognitive performance, as measured by PACC3 score, using data from the Wisconsin Registry for Alzheimers Prevention (WRAP) cohort (N = 1,046). After training a machine learning model on WRAP, the predictive performance was evaluated using an independent dataset from the Wisconsin Alzheimers Disease Research Center (ADRC) cohort (N = 85). Feature importance was assessed to identify genes and metabolites that may play a role as potential risk factors in AD. ResultsThe machine learning model achieved a normalized root mean squared error (NRMSE) of 0.743 {+/-} 0.037 and an R{superscript 2} of 0.311 {+/-} 0.016 across 5-fold holdout test folds in WRAP (p = 5.93 x 10-30), and an NRMSE of 0.915 and an R{superscript 2} of 0.061 when applied to the Wisconsin ADRC cohort. Feature importance revealed transcriptomic biomarkers such as RIPK1, IL6ST, and BIN1 whose higher imputed expression levels were associated with poorer cognitive performance whereas other potential biomarkers including UGP2, NDUFB5, and TMOD2 were associated with better cognitive performance, reflecting mitochondrial energy metabolism and molecular processes associated with cognitive resilience. Several predictive metabolites including benzoate, 3-phenylpropionate, and imidazolelactate also mapped to AD vulnerability signatures, while acyl-carnitine species such as hexanoylcarnitine (C6) and propionate-related metabolites aligned with metabolic resilience. ConclusionIntegrated analysis of transcriptomics and metabolomics demonstrated potential utility for identifying candidate biomarkers associated with cognition in AD. Genes and metabolites reflecting inflammatory signaling, mitochondrial dysregulation, and lipid metabolism emerged consistently among the most influential contributors. These findings align with well-established AD vulnerability pathways and highlight convergent biology across two omics layers. Collectively, this supports the value of multi-omics integration for improving molecular characterization of AD and advancing biomarker prioritization for future mechanistic and translational studies.

IntroductionAlzheimers disease (AD) disproportionately affects women, with accumulating evidence suggestion a contributary role of hormones in this disparity. Given the known influence of hormones on brain health and cognition, characterizing specific profiles in dementia is crucial. In addition, sex-stratified hormonal alterations in AD and other dementias remain poorly understood. MethodsWe quantified nine steroid hormones: 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, cortisol, dihydrotestosterone, estrone, progesterone, testosterone and estradiol. The hormones were quantified in cerebrospinal fluid (CSF) and plasma from 204 participants across five cognitive categories: no cognitive impairment (n=32), mild cognitive impairment (MCI) non-AD (n=38), MCI due to AD (n=21), AD dementia (n=81), and vascular dementia (VaD) (n=32). Participants were recruited at the Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark. Hormone levels were measured using liquid chromatography-tandem mass spectrometry. Sex-stratified generalized linear models were adjusted for age. Overall, 50.5% of participants were women with a mean age of 69 (SD = 9.8) compared to men with a mean age of 70 (SD = 9.1). ResultsIn women with AD, CSF cortisol and 11-deoxycortisol were significantly elevated compared to women with no cognitive impairment (Fold Change (FC) (95% CI) = 1.13 (1.01-1.27), p-value = 0.04 and (FC (95% CI) = 1.01, (1.00-1.01), p-value = 0.03, respectively). Plasma progesterone was decreased (FC (95% CI) = 0.90 (0.81, 0.99), p-value = 0.04). Women with VaD exhibited reduced CSF estradiol (FC (95% CI) = 0.86 (0.74, 0.98), p-value = 0.03). In men with AD, plasma aldosterone was elevated (FC (95% CI) = 1.19 (1.06, 1.33), p-value = 2.81e-03). Correlation analyses revealed that CSF cortisol in women was significantly correlated with CSF AD pathology markers in amyloid-beta 42 (r = -0.29, p-value = 3.02e-03) and phosphorylated tau (r = 0.2, p-value = 0.04). The increase of cortisol was validated in an external cohort where t-test showed significant difference in cortisol between people with AD and cognitively healthy controls (CN), this difference was larger in women (mean AD = 0.26 vs mean CN = 0.21, p-value = 1.79e-06) than men (mean AD = 0.23 vs mean CN 0.21, p-value = 0.04) ConclusionOur findings demonstrate sex-dependent dysregulation of steroid hormone in dementia. Specifically, cortisol and aldosterone are highlighted, which are potential modifiable targets.

Background and ObjectivesCarotid plaque reflects systemic atherosclerosis and may serve as an early marker of cognitive decline, but its longitudinal association with cognitive trajectories remains unclear. We investigated whether carotid plaque status (small-to-medium size) was associated with cognitive performance over time in a population-based cohort. MethodsThis prospective cohort study followed-up neuropsychological assessment battery quadrennially in two cycles (2015-2018 and 2019-2022) from the baseline (2011-2014). Of 2,819 participants, 2,176 participants who were free of dementia and cerebrovascular disease at baseline with cognitive function testing at least two time points over the follow-up time were analyzed. Carotid plaque assessed by B-mode ultrasound sonography five segments were scanned in both left and right sides. The plaques were graded based on vessel thickness and the diameter of the lumen (none, small-to-medium, and large). We categorized our participants into without (none) and with the plaques (small-to-medium, and large combined) at baseline. The main outcomes were multivariable adjusted mean differences of cognitive test performances by baseline plaque status over time. The neuropsychological assessment battery included story recall, visual reproductions, verbal fluency, trail making, digit symbol - coding, and Stroop tests. ResultsOf the total, 291 (13.4%) participants had carotid plaque at baseline. There were no differences at baseline and 4-year. At 8-year follow-up, participants with carotid plaque performed significantly worse than participants without carotid plaque in visual reproduction delayed recall [mean difference -0.525 (95% CI: -0.915 to -0.135), p=.008], Stroop word reading [mean difference -2.732 (95% CI: -5.164 to -0.300), p=.028] and color reading [mean difference -3.573 (95% CI: -5.199 to -1.948), p<.001]. Additionally, participants with carotid plaque performed lower than those without carotid plaque on logical memory delayed recall [mean difference -1.577 (95% CI: -2.843 to -0.311), p=.015] at 8-year follow-up period. DiscussionIn this large cohort study, carotid plaque status at baseline was independently associated with in cognitive function decline, especially in non-verbal memory and executive functioning over 8-year follow-up period in the general population. Therefore, it may be important for earlier intervention on carotid plaque to preserve neurological health in middle-aged to older population.

INTRODUCTION: Bilingualism is a proposed cognitive reserve factor that delays symptom onset in Alzheimer's disease (AD), though current evidence lacks biomarker confirmation. This retrospective study examined bilingualism's association with symptom onset across AD clinical stages, including biomarker-confirmed cases. METHODS: Participants from the Sant Pau Memory Unit spanning amnestic mild cognitive impairment (MCI), amnestic dementia, and biomarker-confirmed AD were analyzed, with balanced representation of active and passive Spanish-Catalan bilinguals. Linear regression models evaluated associations between bilingualism and reported age at symptom onset, controlling for education, sex, and disease severity. RESULTS: Active bilingualism was associated with delayed symptom onset in amnestic MCI (2.21 years), amnestic dementia (1.42 years), and biomarker-confirmed AD (1.45 years; ps < .05). Higher education was associated with earlier onset, likely representing healthcare seeking behavior. DISCUSSION: Bilingualism protects against earlier symptom manifestation in MCI and AD, supporting bilingualism as a contributor to cognitive reserve.

BackgroundStroke remains a leading cause of mortality worldwide. Ischemic stroke, caused by arterial occlusion, induces sensorimotor deficits and memory impairments. Excessive activity of the brain angiotensin II type 1 receptor (AT1R) is associated with hypertension and cerebral ischemia. Candesartan (CN), an AT1R blocker, improves cerebrovascular blood flow. Pomegranate (Punica granatum) is rich in polyphenolic antioxidants that reduce oxidative stress and inflammation, suggesting potential neuroprotective effects in cerebral ischemia. AimThis study compared the neuroprotective effects of CN administered alone or in combination with pomegranate (POM) in a rat model of cerebral ischemia induced by chronic unilateral carotid artery ligation. MethodsCerebral ischemia was induced by ligation of the right common carotid artery (RCCA) in adult rats. Animals were randomly assigned to four groups: sham control, untreated ischemic, ischemic treated with CN, and ischemic treated with CN + POM. Sensorimotor and cognitive functions were assessed 1-15 days post-surgery using beam balance (BB), beam walking (BW), modified sticky-tape (MST), novel object recognition (NOR), and the Morris water maze (MWM) tests. ResultsRCCA ligation induced marked sensorimotor deficits and memory impairments. Both CN monotherapy and CN + POM treatment equally restored sensorimotor function to sham-control levels, as demonstrated by BB, BW, and MST tests. In contrast, CN + POM treatment showed greater efficacy than CN alone in improving short-term recognition and spatial memory, as demonstrated by NOR and MWM performance. ConclusionCN effectively reverses ischemia-induced sensorimotor deficits, whereas the addition of POM confers specific and enhanced protection against cognitive impairment, indicating distinct mechanisms underlying sensorimotor and memory recovery after cerebral ischemia.

Multiple lines of evidence indicate that alterations in glial cells and the blood-brain barrier (BBB) contribute to anxiety- and depression-like behaviors in murine models of depression and chronic stress. Although behavioral and psychological symptoms of dementia (BPSD) represent a major feature of Alzheimers disease (AD), this relationship has received limited attention in this pathology. Using the 3xTg-AD mouse model of AD at an early pathological stage, this study explored the relationship between BPSD and variations of BBB and glial cell markers in specific brain regions (hippocampus, basolateral amygdala [BLA], and prefrontal cortex). Memory and emotional behaviors were assessed using a battery of behavioral tests. Endothelial tight junction (TJ) proteins, along with astrocyte and microglial markers, were quantified by western blotting or/and immunohistochemistry in the hippocampus, BLA, and prefrontal cortex. While spatial and recognition memory remained intact, 3xTg-AD mice exhibited an anxio-depressive-like phenotype, impaired coping strategies, and reduced cognitive flexibility. Compared with control mice, 3xTg-AD mice displayed an increased expression of TJ proteins in the hippocampus and BLA, increased microglial cell density in the BLA and the dentate gyrus, and fewer and shorter microglial cell branches in the BLA. A principal component analysis revealed a positive correlation between anxio-depressive-like behaviors and altered microglial morphology in the BLA, whereas impaired cognitive flexibility positively correlates with ZO-1 expression and microglial cell density in the hippocampus. These findings demonstrate an early association between the BBB, glial cells and AD-related BPSD symptoms in 3-month-old 3xTg-AD mice.

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimers disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models. MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-{beta} (A{beta})42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. ConclusionShort-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.

ObjectiveBoth the phosphatidylinositol binding clathrin assembly protein gene (PICALM) and the embryonic ectoderm development gene (EED) have been implicated as causal genes driving a genome-wide association for Alzheimer disease (AD) risk. We employed a new virtual approach using genome-wide chromatin interactions (Hi-C) called enhanced Hi-C Capture Analysis (eHiCA) to identify the genes and regulatory regions that are driving this important AD risk association. MethodsHi-C data from the frontal cortex of eight AD patients, as well as inducible pluripotent stem cell-derived microglia and spheroids of AD and control patients were used. We applied 14 eHiCA baits each containing a GWAS SNP to identify the cis regulatory interactions in this GWAS locus at a 5kb resolution. ResultsThe baits derived from the GWAS associated haplotype primarily interacted with the PICALM promoter and the large cis-regulatory elements cluster (CREe) lying upstream of the EED promoter. The EED promoter interacts with PICALM gene body and promoter region but not directly with the associated risk haplotype. Although the AD-associated variants segregate together as a haplotype in the population, each bait exhibited distinct functional chromatin interactions. InterpretationThe PICALM gene is the primary driver of the association in microglia along with the CREe locus. Different SNPs in a segregating haplotype can display different physical Hi-C interactions. This study demonstrates that eHiCA can help resolve the casual genes driving complex GWAS associations, opening new pathways to study Alzheimer disease and other disorders.

BackgroundGeroprotective interventions, including the mTOR inhibitor rapamycin, slow aging in preclinical models. Translation to humans remains challenging because clinical trials require endpoints detectable within feasible timeframes. Multi-modal in vivo imaging could address this limitation by enabling simultaneous assessment of age-related pathology across multiple organ systems, but its feasibility in clinical trials is uncertain. ObjectiveTo evaluate the feasibility of deploying a multi-modal, multi-organ imaging battery in a geroprotective intervention trial of rapamycin and to collect exploratory efficacy data across multiple domains of age-related pathology. MethodsIn a single-center, open-label, single-arm pilot trial, 14 participants with early-stage Alzheimers disease (MCI or mild dementia; Montreal Cognitive Assessment [&ge;]18; amyloid-positive) received oral rapamycin 7 mg once weekly for 26 weeks. Participants underwent baseline and end-of-treatment imaging including retinal optical coherence tomography (OCT); [18F]FDG positron emission tomography/computed tomography (PET/CT) of the head, thorax, and lower spine; dentomaxillofacial MRI; and cardiac MRI with stress perfusion and arterial pulse wave velocity. Feasibility outcomes included completion rates and technical or logistical barriers. Exploratory pre-post changes were assessed using paired t-tests. ResultsOf the 14 enrolled participants, 13 completed follow-up imaging. Among these, completion was 100% for OCT, [18F]FDG PET/CT, and dentomaxillofacial MRI. Cardiac MRI and pulse wave velocity were completed in 69% (9/13), primarily limited by scanner access during a healthcare worker strike. No imaging-related adverse events occurred. Exploratory analyses showed nominally significant pre-post increases in cardiac output (p=0.017), late diastolic (A-wave) kinetic energy (average: p=0.044; peak: p=0.024), left retinal ganglion cell layer thickness (p=0.044), and optic nerve head [18F]FDG uptake (p=0.040). Bone mineral density showed no significant pre-post changes, while muscle cross-sectional area decreased numerically but not significantly (p=0.058). In exposure-response analyses, higher rapamycin blood concentration was significantly correlated with greater skeletal muscle density (r=0.64, p=0.035) and, albeit not significantly, smaller loss of cross-sectional area (r=-0.53, p=0.097). ConclusionsA multi-modal imaging battery spanning several organ systems was successfully integrated into a clinical trial, with high completion rates for most modalities. Logistical constraints were the primary barriers affecting cardiac measures. These findings inform the design of future randomized trials of geroprotective interventions, where such imaging batteries may help detect changes in age-related pathology over relatively short timeframes.

We reported previously that diet-induced obesity exacerbates early-stage Alzheimers disease (AD)-like pathology in TgF344-AD rats. Our findings also suggested that TgF344-AD rats may be prone to weight gain during early AD development, which we assessed here. Energy intake, body composition, and the impact of glucose administration on blood glucose were also assessed. Body temperature, intrascapular brown adipose tissue (iBAT) mass, and iBAT uncoupling protein-1 (UCP1) expression were used as indicators of thermogenic function. Soluble amyloid {beta}40 (A{beta}40) and A{beta}42 were quantified in hypothalamus. Male TgF344-AD rats began to outweigh wildtype (WT) littermates by 5 weeks of age; this increase emerged later in female TgF344-AD rats (~5 months). Female TgF344-AD rats ingested more energy from chow and a high fat, high sugar (HFHS) diet, gained more weight on the HFHS diet, and had lower UCP1 than WT rats, effects not observed in male TgF344-AD rats. Surprisingly, male and female TgF344-AD rats had increased body temperatures. This was restricted to the dark phase in females, which is when they ingest excess calories. Finally, the HFHS diet disrupted glucose regulation in male but not female TgF344-AD rats. These findings suggest that increases in energy intake and decreases in UCP1 may contribute to the additional weight gain in female TgF344-AD rats. The causes for these increases in males remain unclear. Hypothalamic A{beta}42 correlated with glucose dysregulation in male TgF344-AD rats and BAT mass in female TgF344-AD rats, raising the possibility that increases in A{beta}42 in hypothalamus produce sex-specific disruptions in energy homeostasis.

Age and coronary artery disease (CAD) are known risk factors for cognitive decline and dementia, in which cerebral blood flow (CBF) has as a key role. Cardiorespiratory fitness (CRF) has shown consistent links with brain health and dementia, though its association with CBF and whether it differs depending on age or disease status remains limited. The main aim of this study was to examine the association of CRF, assessed through the six-minute walk test (6MWT) and peak oxygen uptake (VO2peak), with CBF in cognitively normal older adults and individuals with CAD. We hypothesized that CRF will be positively associated with global and regional CBF. Seventy-nine cognitively normal older adults from the AGUEDA trial and 84 individuals with CAD from the Heart-Brain trial were included in this cross-sectional analysis. Participants underwent 6MWT, and a 3D arterial spin labelling magnetic resonance imaging scan to assess global and regional CBF. In the Heart-Brain project, participants additionally conducted a cardiopulmonary exercise test from which VO2peak was determined. In the Heart-Brain sample, after adjusting for age, sex, education, mean arterial pressure and APOE4, CRF was positively associated with global CBF (6MWT: {beta}=0.26, P=0.04; VO2peak: {beta}=0.33, P=0.02). At a regional level, CRF was positively associated with CBF in the posterior cingulate cortex (6MWT: {beta}=0.26, P=0.04; VO2peak: {beta}=0.31, P=0.02), the anterior cingulate cortex (6MWT: {beta}=0.29, P=0.02), the precuneus (6MWT: {beta}=0.28, P=0.02; VO2peak: {beta}=0.32, P=0.01) and the hippocampus (VO2peak: {beta}=0.29, P=0.03). No significant associations were observed in the AGUEDA sample (all P>0.05). When adding body mass index (BMI) to the models, the associations were no longer statistically significant in either sample. The association between VO2peak and CBF was significantly mediated (i.e. indirect effect) by BMI (Indirect effect: {beta}=0.250 (95% CI 0.02;0.486), percentage of mediation=72.67%). CRF was positively associated with CBF in individuals with CAD, but not in cognitively normal older adults. Interestingly, the association of CRF with CBF was largely explained and mediated by BMI. Further studies are warranted to clarify the role of CRF and BMI in relation to CBF, the mechanisms involved and the implications for dementia risk prevention in older adults and individuals with CAD.

BackgroundAlzheimers disease (AD) causes progressive decline in language and cognition. Automated speech analysis has emerged as a promising screening tool, yet clinical data scarcity limits progress. To address this, we generated a large-scale simulated speech dataset to model linguistic and acoustic deterioration across cognitive stages, Control, Mild Cognitive Impairment (MCI), and AD. MethodsUsing Monte Carlo simulations, we emulated the Pitt DementiaBank "Cookie Theft" narratives. Acoustic features (speech rate, pause duration, jitter, shimmer) and linguistic features (type-token ratio, unique-word count, filler usage) were synthetically sampled from real-world DementiaBank distributions. We trained an XGBoost classifier to distinguish diagnostic groups, and applied SHAP (Shapley Additive exPlanations) to assess feature importance. ResultsThe model achieved high discriminative performance (AUC {approx} 0.94; accuracy {approx} 85%). Compared to controls, simulated MCI and AD groups showed progressive declines in fluency and lexical diversity, and increases in disfluencies and voice instability. SHAP analysis revealed that key predictors included reduced type-token ratio, higher pause and filler rates, and elevated jitter/shimmer. Classification was most accurate for Control vs. AD; MCI misclassifications highlighted intermediate profiles. InterpretationOur framework, FMN (Forget Me Not), captures clinically relevant speech changes using simulated data, offering an explainable and scalable approach for cognitive screening. While not a substitute for real datasets, FMN validates a pipeline that mirrors known AD markers and can guide future real-world deployments. External validation remains a key next step for translational impact.

BackgroundThe triglyceride-glucose-frailty index (TYGFI) is an emerging marker of metabolic-geriatric risk; however, its association with stroke and the mediating role of body mass index (BMI) remain underexplored in large, representative populations. MethodsWe conducted a cross-sectional analysis of 9,913 adults aged [&ge;]50 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Stroke was defined based on self-reported diagnosis. TYGFI was calculated as a composite of the triglyceride-glucose (TyG) index and the frailty index (FI). BMI was evaluated as a continuous mediator. We employed multivariable logistic regression, restricted cubic spline (RCS) models, threshold effect analysis, receiver operating characteristic (ROC) curve analysis, subgroup analysis, and causal mediation analysis, adjusting for key sociodemographic and clinical confounders. ResultsElevated TYGFI was strongly associated with increased odds of stroke (fully adjusted odds ratio OR = 3.64, 95% confidence interval CI: 3.06-4.33, p < 0.001). RCS analysis revealed a significant nonlinear positive relationship (p-nonlinearity < 0.001), with an inflection point identified at TYGFI = 1.094. TYGFI was positively associated with BMI (fully adjusted {beta} = 4.09, 95% CI: 3.78-4.41, p < 0.001). Causal mediation analysis indicated that BMI exerted a significant negative indirect effect on the TYGFI-stroke association in the core model (average causal mediation effect ACME =-0.0051, 95% CI:-0.0082 to-0.0025, p < 0.001), mediating -18.28% of the total effect. However, this indirect effect became negligible after adjusting for the body roundness index (BRI) (ACME = 0.0000, 95% CI:-0.0001 to 0.0003, p = 0.670). Subgroup analyses demonstrated consistent risk elevation across all strata (all p for interaction > 0.05). The fully adjusted model yielded an area under the curve (AUC) of 0.80 (95% CI: 0.78-0.82). ConclusionHigher TYGFI is robustly associated with increased stroke risk among US adults aged [&ge;]50 years. While BMI acts as a significant negative mediator, this effect is abrogated upon adjustment for central adiposity (BRI). These findings support a metabolic-geriatric pathway linking metabolic dysregulation, body composition, and cerebrovascular risk, positioning TYGFI as a promising target for stroke risk stratification in middle-aged and older adults.

aStructured abstractO_ST_ABSBACKGROUNDC_ST_ABSOver the past couple of decades, the role of infections, as well as the involvement of the immune system, have been highlighted in the development of dementia. METHODData from the Wisconsin Registry for Alzheimers Prevention cohort were utilized for the analysis. A history of medical conditions was searched across the cohort, and known infections and autoimmune conditions were recorded for each participant. These conditions were then compared with the diagnosis and cognitive performances of each participant. Furthermore, plasma markers were analyzed using two different protein quantification methods. RESULTSOur analysis revealed poorer cognitive performances among participants with listed medical conditions. In plasma samples, Ab42/ICAM1 was identified as a protein ratio with significant variation across condition statuses. DISCUSSIONOur study confirmed that infections and autoimmune conditions contribute to cognitive decline. Ab42/ICAM1 was identified as a relevant marker.

Alzheimers disease (AD) is characterized by the mis-aggregation of amyloid {beta} (A{beta}) and tau, which is proposed to be driven by impaired A{beta} and tau clearance. While sleep-active glymphatic transport contributes to the clearance of A{beta} and tau in humans, studies have yet to demonstrate that it is possible to enhance glymphatic transport in humans and that augmenting glymphatic transport improves the clearance of A{beta} and tau from the human brain. In two cross-over clinical trials in healthy older adults, we demonstrated that a fixed-dose combination therapy of intravenous dexmedetomidine (0.7 g/kg/h) and 10 mg oral midodrine (ACX-02), that suppressed central noradrenergic tone while maintaining systemic arterial pressure, increased EEG slow waves, enhanced cerebrovascular pulsatility, and reduced parenchymal resistance to perivascular fluid flow, that have shown to be key determinants of glymphatic transport. Dynamic shifts in plasma mass balance indices of clearance within the brain demonstrated that pharmacological enhancement of glymphatic transport increased A{beta} and tau clearance by approximately 9%-10% during a single 4h 15min sleep opportunity. Bayesian mediation analysis demonstrated that increasing EEG slow waves and declining parenchymal resistance were key mediators, and cerebrovascular compliance was a moderator, of the effect of ACX-02 on plasma AD biomarker dynamics. These findings demonstrate that pharmacologic enhancement of glymphatic transport increased brain-to-blood clearance of A{beta} and tau in human participants. This suggests that enhancement of A{beta} and tau clearance may serve as a complementary approach to existing disease-modifying therapies, and as a therapeutic approach in AD and AD-related proteinopathies.

Background: Alzheimer's disease (AD) exhibits marked sex differences. While sex hormone levels across the lifespan likely contribute to this, little remains known about their causal impact and their relation to sex-biased genetic risk for AD. We therefore sought to identify potential shared genetic architectures, as well as causal genes and relationships, between sex hormone-related traits and AD risk. Methods: Large-scale AD sex-stratified genome-wide association study (GWAS) results were available from case-control, proxy-based, and population-based cohorts, including the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, UK Biobank, and FinnGen. Sex hormone-related trait GWAS were available for age at menarche, menopause, and voice breaking, as well as testosterone, sex hormone-binding globulin (SHBG), progesterone, follicle stimulating hormone, luteinizing hormone, and estradiol levels. Cross-trait conjunctional analyses were conducted to identify pleiotropic overlap between sex-hormone traits and AD, followed by prioritization of candidate causal sex-biased AD genes through quantitative trait locus genetic colocalization analyses. The potential regulatory impact of sex hormones on these genes was assessed through transcription factor motif analyses. Finally, sex-stratified mendelian randomization analyses were used to infer causal effects of sex hormones on AD risk. Results: Genome-wide pleiotropy analyses demonstrated enrichment of AD with testosterone, SHBG, and age-at-menarche traits in women. We identified 12 high-confidence pleiotropic loci, 9 of which showed stronger AD effect sizes in women (3 in men) and 8 that were novel. Genes at these loci were often causally implicated in brain tissues and enriched for promoter-associated androgen receptor transcription factor binding motifs. Mendelian randomization indicated higher bioavailable testosterone in women (OR:0.88; 95%-CI:0.82-0.96) and higher SHBG levels in men (OR:0.86; 95%-CI:0.77-0.96) were associated with lower AD risk. Conclusions: Our findings reveal sex-specific shared genetic architectures between AD and sex hormone-related traits and nominate related genes that may drive sex-biases in AD risk. Several of the implicated female-biased genes are relevant to phosphatidylinositol and lipid metabolism, including Fatty Acid Desaturase 2 (FADS2). While we observed no causal effect of estradiol-related traits on AD risk, the protective effects of bioavailable testosterone in women and SHBG in men provide targets for sex-informed AD risk stratification and prevention strategies.