Journal of Alzheimer’s Disease

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.

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.

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.

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.

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

Background: Cardiovascular health factors are associated with cognitive decline and risk of dementia, including Alzheimer disease (AD); however, this has been mostly studied in late life. We investigated whether vascular and lifestyle factors are associated with AD plasma and imaging biomarkers in midlife. Methods: We investigated 1,406 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with information on vascular and lifestyle factors framed from the American Heart Association (AHA) life's essential 8 (LE8) guidelines for cardiovascular health at early midlife (mean age 45.0 SD 3.6) and AD biomarkers in late midlife (mean age 60 SD 3.5). LE8 was calculated and categorized into poor (0-49), intermediate (50-79), and ideal (80-100) cardiovascular health, based on 8 components including smoking, diet, body mass index (BMI), sleep, fasting glucose, blood pressure, cholesterol, and physical activity. We assessed the AD plasma biomarkers phosphorylated tau 217 (ptau-217) and amyloid beta 42/40 ratio (A{beta}42/40) and the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), an algorithm that characterizes AD-like brain atrophy on brain MRI. We used linear regression to examine the association between LE8 and log-transformed and standardized AD biomarker measures adjusting for age, sex, race, education, and kidney function. Results: Compared to ideal LE8, intermediate (67.9% of participants) and poor (12.6%) LE8 was associated with lower A {beta}42/40 (adjusted mean difference: -2.37, 95% CI: -2.38 to -2.36 and -2.38, 95% CI: -2.40 to -2.36, respectively). There was no association between the LE8 group and ptau-217 level. Moreover, compared to ideal LE8 participants, those with poor LE8 had higher SPARE-AD atrophy pattern (adjusted mean difference: -0.71, 95% CI: -0.81 to -0.62). Conclusion: These findings indicate that poor cardiovascular health in midlife, as defined by the AHA LE8, is linked to less favorable early AD biomarker profiles, particularly reflecting greater amyloid burden and structural brain changes.

ObjectiveNicotinic acetylcholinergic receptors (nAChRs), comprising of and {beta} subunits are present in the brain and whole body. The less abundant 2-subunit is a fast-acting receptor subtype and plays an important role in cognition and learning. To understand cellular functional consequences, this study evaluated glucose metabolism using [18F]FDG PET/CT in 2 knockout (2KO) and 2 hypersensitive (2HS) mice. MethodsControl (CN; 4M, 4F), 2 knockout (2KO; 4M, 4F) and 2 hypersensitive (2HS; 4M,4F), 12-16 month old mice were used. Mice were fasted and injected with [18F]FDG (3-5 MBq) while awake. After 40 minutes they underwent whole body PET/CT. On a separate day, nicotine challenge [18F]FDG studies were done. Reconstructed images were analyzed to obtain standard uptake values (SUV) of [18F]FDG in brain and interscapular brown adipose tissue (IBAT). Statistical analysis was performed. ResultsThe 2HS male mice exhibited the largest brain increase in [18F]FDG compared to 2KO male mice. The rank order of brain [18F]FDG uptake in the 3 groups: 2HS[male]> CN[male]> 2KO[male]> CN[female]= 2KO[female][&ge;] 2HS[female]. Nicotine treatment reduced brain [18F]FDG uptake in all mice. Females had lower [18F]FDG uptake compared to males and were less sensitive to 2 nAChR. In the case of IBAT, 2KO mice had significantly higher baseline [18F]FDG uptake compared to the other two groups: 2KO[male]> 2KO[female]> 2HS[female]> 2HS[male]> CN[female]> CN[male]. Nicotine decreased IBAT in 2KO mice rather than increase as observed in CN and 2HS mice. Conclusions2 nAChRs plays a significant role in brain activation as exhibited by the increase in [18F]FDG in 2HS mice. In the absence of regulatory control by the 2 nAChR, the 2KO mice IBAT exhibited higher [18F]FDG IBAT compared to controls and 2HS mice. Female mice were less affected by nicotine compared to the male mice. Overall, 2 nAChRs played a significant role in glucose metabolism in the brain and IBAT.

Early detection of disease progression using clinically-relevant biomarkers in animal models is important for mechanistic studies and for developing therapeutics in neurodegenerative diseases including Alzheimers disease (AD). The preclinical stage of AD, when amyloid-{beta} (A{beta}) starts to accumulate before cognitive decline, provides a critical window for disease modification. In humans, decreases in cerebrospinal fluid (CSF) A{beta}42 and the A{beta}42/A{beta}40 ratio in preclinical AD are considered to reflect the preferential sequestration of aggregation-prone A{beta}42 into {beta}-sheet-rich deposition in the brain, with corresponding changes being detectable in plasma. However, the extent to which these biomarker-pathology relationships are recapitulated in AD model mice remains incompletely defined. Here we show that CSF and plasma A{beta}42 and the A{beta}42/A{beta}40 ratio decline with age in parallel with the progression of {beta}-sheet-rich A{beta} deposition in preclinical 5XFAD mice, one of the most widely used AD mouse models, as assessed through monthly profiling of these biomarkers. Notably, the CSF A{beta}42/A{beta}40 ratio showed a negative correlation with {beta}-sheet-rich A{beta} deposition in the brain, whereas CSF A{beta}40 did not show a comparable association. In addition, the plasma A{beta}42/A{beta}40 ratio showed a positive correlation with the CSF A{beta}42/A{beta}40 ratio, suggesting that the plasma A{beta}42/A{beta}40 ratio may also reflect brain A{beta} deposition in this model. The strength of these correlations differed by sex, suggesting that sex-dependent differences in the A{beta} kinetics in this model may influence how closely fluid biomarkers reflect pathological progression. These findings support the potential utility of fluid A{beta} as a pathology-linked, translatable biomarker in preclinical 5XFAD mice. Highlights- Fluid A{beta} biomarkers are associated with early A{beta} deposition in preclinical 5XFAD mice. - The CSF A{beta}42/A{beta}40 ratio negatively correlates with {beta}-sheet-rich brain A{beta} deposition. - The plasma A{beta}42/A{beta}40 ratio positively correlates with the CSF A{beta}42/A{beta}40 ratio. - Monthly profiling defines fluid A{beta} biomarker dynamics in preclinical 5XFAD mice. - Sex differences may affect biomarker-pathology relationships in these mice.

Background: Intracranial atherosclerosis is a major cause of ischemic stroke. Asymptomatic intracranial atherosclerotic stenosis (ICAS) represents a subclinical and potentially modifiable stage preceding ischemic stroke, yet the nutritional factors associated with asymptomatic ICAS remain poorly defined. This study aimed to identify dietary factors associated with asymptomatic ICAS in community-dwelling older adults. Methods: This cross-sectional, population-based study included 962 Japanese adults aged {greater than or equal to}65 years from the Yahaba Active Aging and Healthy Brain study, conducted in Yahaba town, Japan, between July 2016 and July 2017. Asymptomatic ICAS was defined as {greater than or equal to}50% intracranial arterial stenosis evaluated by magnetic resonance angiography (MRA) without a history of stroke or transient ischemic attack. All participants underwent dietary assessment using a food frequency questionnaire. We examined the association between nutritional factors and ICAS using multivariable logistic regression models with adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, body mass index, smoking, and alcohol use. Results: After exclusions, 850 participants were analyzed. The mean age was 73.4 {plus minus} 6.5 years, and 52% were female. ICAS was identified in 135 participants (15.9%). Participants in the highest quartile of dietary fiber intake had lower odds of ICAS than those in the lowest quartile (OR, 0.45; 95% CI, 0.26-0.80). Potassium intake showed a similar inverse association (OR, 0.49; 95% CI, 0.27-0.89). When both nutrients were included in the multivariable model as continuous variables, neither remained significant, with moderate collinearity (variance inflation factor, 4.16). Conclusions: Higher dietary fiber intake was inversely associated with asymptomatic ICAS among community-dwelling older Japanese adults. Potassium intake also showed an inverse association, although this relationship was less consistent after accounting for collinearity with dietary fiber.

BackgroundAlzheimers disease (AD) can be diagnosed using cerebrospinal fluid (CSF) biomarkers reflecting amyloid and tau pathology. However, it provides no information about functional network status. We aimed to determine whether CSF biomarkers (A{beta}42, p-Tau, t-Tau, and A{beta}42/p-Tau ratio) are associated with altered stimulus differentiation in vergence and pupil responses during an oddball task, and to evaluate oculomotor metrics as predictors of CSF core AD biomarkers in patients at mild cognitive impairment (MCI) stage. MethodsThirty-eight participants with abnormal CSF core AD biomarkers at MCI stage completed a visual oddball task while oculomotor responses were recorded. Linear mixed-effects models examined condition x biomarker interactions, controlling for sex, age, and MMSE. Temporal and magnitude features were tested as predictors using linear regression. ResultsHigher p-Tau levels were negatively associated with target-distractor differentiation in cognitive vergence ({beta} = -0.035, p < 0.001) and pupil responses ({beta} = - 0.060, p < 0.001). Higher A{beta}42 and A{beta}42/p-Tau showed positive associations with vergence differentiation but opposite effects on pupil responses. Oculomotor features predicted p-Tau levels (R2 = 0.20-0.21). ConclusionOculomotor differentiation metrics capture functional signatures of tau-related network dysfunction, positioning them as accessible biomarkers complementing CSF measures for detecting network disruption at MCI stage.

BackgroundThe AT(N) biological framework classifies Alzheimers disease (AD) pathology using CSF biomarkers, with the A+T+ profile defining biological AD and the A-T+ profile representing a biologically distinct entity consistent with suspected non-Alzheimers pathophysiology, such as primary age-related tauopathy. Functional assessment capable of differentiating these profiles non-invasively remains limited. This study investigates whether cognitive vergence and pupillary temporal dynamics during a visual oddball task can distinguish A-T+ from A+T+ biological profiles in individuals with mild cognitive impairment (MCI). MethodsThirty-eight participants with MCI (12 A-T+, 26 A+T+) classified by CSF biomarkers completed a visual oddball task (80% distractors, 20% targets) under continuous eye-tracking. Linear mixed-effects models examined profile x condition interactions on full time series and six trial-level temporal features. Participant-level differentiation was assessed using binomial logistic regression, adjusting for age, sex, and MMSE. ResultsBoth profiles showed comparable overall oculomotor response magnitudes but diverged markedly in temporal organization. Significant profile x condition interactions emerged for cognitive vergence global slope, time to peak, and pupillary time to peak. Logistic regression confirmed that timing features discriminated biological profiles at the participant level, with differentiation reversing direction between distractor and target conditions. A-T+ participants also maintained superior target detection accuracy (89.3% vs. 82.4%, p = 0.001). ConclusionCognitive Vergence and pupillary temporal dynamics during an oddball task provide condition-dependent functional oculomotor signatures that systematically differentiate AT(N) biological profiles in MCI, suggesting that oculomotor assessment may offer an accessible, non-invasive complement to CSF-based profile characterization.

Background: Social determinants of health (SDOH) are increasingly recognized as contributors to Alzheimer disease (AD) risk, yet the impact of multidimensional social disadvantage early AD-related pathophysiology remains poorly understood. Methods: We studied 1,466 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with SDOH assessed in early midlife (mean age 40, SD 3.6 years) and plasma AD biomarkers measured 20 years later. A comprehensive SDOH index was constructed from 12 indicators spanning five domains (economic stability, education, neighborhood and physical environment, community and social context, and health care access). We examined associations between SDOH quartile and log-transformed, standardized plasma phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and amyloid-lower case Greek beta42/40 (Alower case Greek beta42/40) using linear regression adjusted for age, sex, race, and estimated glomerular filtration rate. Linear trends across SDOH quartile were also evaluated. Results: Participants in the most disadvantaged SDOH quartile had higher p-tau217, higher NfL and lower Alower case Greek beta42/40 level compared with those in the least disadvantaged quartile (p-tau 217: lower case Greek beta = 0.12, 95% CI 0.03-0.21, p = 0.008; NfL: lower case Greek beta = 0.20, 95% CI 0.05-0.35, p = 0.009; lower case Greek beta42/40: lower case Greek beta = -0.15, 95% CI -0.30-0.00, p=0.05). There was also a significant trend across quartile (p-tau 217: p for trend = 0.012; NfL: p for trend= 0.001). Analyses of individual SDOH domains indicated that lower economic stability, poorer health care access, and lower education were associated with higher NfL, and poorer health care access was associated with higher p-tau217. Conclusions: Greater SDOH disadvantage in early midlife was associated with higher levels of plasma AD biomarkers reflecting AD pathology and neurodegeneration decades later. These findings suggest that social disadvantage during midlife may contribute to early AD-related biological changes and highlight potentially modifiable social factors relevant for dementia prevention.

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

BackgroundIndividual clinical cognitive assessments (CCA) for Alzheimers disease (AD) provide broad disease stratification but are limited in sensitivity and specificity, requiring integration of multiple CCA for optimal disease staging. Recent work from our lab suggests that neuro-metabolic and vascular dysregulation (MVD) occurs early in AD, prior to clinical symptoms, and may provide higher sensitivity and specificity than CCA alone. In this study, we combined three widely accepted CCA with MVD readouts and developed a multimodal ensemble machine learning approach across the AD spectrum to predict disease stage and grade. MethodsAD subjects (N=372) across the disease spectrum with imaging (PET:18F-FDG, MRI:T1w, T2 FLAIR, ASL) and CCAs (ADAS-Cog, CDR, MoCA) data were analyzed from ADNI. Imaging data were registered to MNI152+, z-scored relative to cognitively normal controls, and processed for MVD. A clinical-set-enrichment analysis (CSEA) was developed to link regional brain changes with CCA scores, map changes to functional categories, project them into a 3D Cartesian space, and model trajectories, thus revealing at-risk and resilient regions. In addition, an ensemble machine-learning approach was utilized for disease stage classification, and a disease grading scheme across the AD spectrum was developed to further stratify within disease stages. FindingsRegional data followed an MVD pattern across AD stages stratified by CSEA scores. Females showed greater stage separation along the CCA axis within each region, indicating faster disease progression. Moreover, progression in at-risk brain regions (e.g., mid- and inf-temporal gyri, amygdala) was associated with longer disease path lengths, whereas progression in resilient brain regions (supramarginal gyrus) was not. Moreover, our classification and grading approach can predict AD stage and grade independent of amyloid-beta and tau with high precision and accuracy. InterpretationA framework was developed to evaluate MVD and CCA variations across the AD spectrum, thereby distinguishing at-risk and resilient brain regions. Distinct disease trajectories were identified, and a new data-driven grading scheme was proposed to highlight the potential for precision medicine and therapeutic evaluation. FundingNIH T32AG071444

BackgroundOlder adulthood is often accompanied by declines in auditory processing and cognitive functioning, increasing the risk of reduced autonomy and quality of life. Multidomain lifestyle interventions have shown potential to counteract these changes, and choir-based activities represent a promising approach by simultaneously engaging auditory, cognitive, physical, and social domains. However, evidence regarding their feasibility and neurophysiological impact in community-dwelling older adults, particularly those without formal musical training, remains scarce. MethodsThis 9-month quasi-experimental feasibility study involved 54 community-dwelling older adults (mean age = 72.9 years) with no formal musical background. Participants self-selected into a choir-based intervention group, an active control group engaging in non-musical leisure activities, or a passive control group; however, some participants in the control groups were selected from the waiting list for the choir. Assessments were conducted at baseline and follow-up and included measures of global cognition, cognitive reserve, psychological well-being (Flourishing Scale), multidimensional frailty (Selfy-MPI), music perception, pure-tone audiometry, and auditory evoked potentials recorded using a standardized clinical oddball paradigm. ResultsThe choir-based intervention was feasible in a community setting. At the neurophysiological level, choir participation was associated with a bilateral, significant shortening of the N2-P3 inter-peak latency, indicating faster auditory-cortical processing. Additionally, through explorative analyses multidimensional frailty, as assessed by the Selfy-MPI, showed a significant reduction in individuals engaging in a higher number of activities, irrespective of group allocation. Similarly, psychological well-being revealed a decrease in flourishing scores in the passive control group relative to the choir group. No changes were observed in audiometric thresholds or music perception measures. ConclusionChoir-based multidomain participation is a feasible intervention for community-dwelling older adults without formal musical training and is associated with selective benefits in cognitive reserve, psychological well-being, auditory-cortical processing speed, and multidimensional frailty. These findings provide a foundation for a larger randomized controlled trial aimed at clarifying the cognitive, psychosocial, and neural mechanisms underlying choir-based interventions in ageing. Trial RegistrationThe upcoming trial has been prospectively registered on ClinicalTrials.gov (ID: NCT06767410; registration date: January 9, 2025).

Methods: DigiCog is a single-center cross-sectional study conducted within the Luxembourgish Predi-COVID cohort (NCT04380987). Participants aged 25-65 years, with and without persistent COVID-19 symptoms, are invited to participate. Cognitive assessments are performed during face-to-face sessions by trained nurses and neuropsychologists using both the VMTech device and standardized neuropsychological tests. Additional data on PCC symptom status, CR, sociodemographic characteristics, fatigue, and psychological factors are also collected. Agreement between digital and standard cognitive assessments will be evaluated using Cohen's kappa coefficient, with sensitivity, specificity, and receiver operating characteristic analyses as secondary measures. Cognitive performance will be compared between participants with and without PCC, and associations with CR proxies will be explored.

Background Autosomal dominant Alzheimer's disease (ADAD) serves as a model for presymptomatic biomarker discovery. Characterising the temporal profile of plasma biomarker levels in presymptomatic individuals may enhance understanding of disease pathogenesis, inform future clinical trials, and guide clinical interpretation. Methods We evaluated 124 proteins using a NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) panel in 270 plasma samples from a longitudinal cohort study of ADAD, comprising 113 individuals (73 mutation carriers and 40 non-carriers). We determined the plasma proteomic changes that distinguished mutation carriers from non-carriers. We then used predicted age at symptom onset to determine the approximate timing of presymptomatic divergence in biomarker levels in carriers relative to non-carriers. Results Nine proteins (A{beta}42, BACE1, GFAP, pTau181, pTau231, pTau217, MAPT, NfL, and AChE) robustly differed between carriers and non-carriers, cross-sectionally. Longitudinal analyses showed A{beta}42 levels were elevated in carriers at least 26 years before expected symptom onset. Carriers diverged from non-carriers in phosphorylated tau markers at 21-24 years before expected symptoms, total-tau at 19 years, GFAP and BACE1 at 14 years, and NfL at 6 years. Differences in AChE were seen in symptomatic individuals, likely reflecting cholinesterase inhibitor use. Conclusion Multiple plasma proteins are elevated in presymptomatic and symptomatic autosomal dominant AD mutation carriers relative to non-carriers. Changes in eight biomarkers occur sequentially from 26 to 6 years prior to symptom onset. Combining biomarkers may help in staging presymptomatic AD and optimise clinical trial inclusion. Further work is needed to assess how these findings generalise to non-monogenic AD.

BackgroundTraumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimers disease (AD) biology remain incompletely defined. APOE {varepsilon}4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE {varepsilon}4 to amplify late-life amyloid and tau burden. Methods429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (<10 vs >10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE {varepsilon}4, including an APOE*TBI-LOC status interaction term, while Fishers exact tests evaluated TBI recency and biomarker positivity. ResultsIn CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE {varepsilon}4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE {varepsilon}4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present. ConclusionsHistory of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE {varepsilon}4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.

The Alzheimers Amyloid Precursor Protein (APP) has determinant roles in neuronal development and function, both in its full-length conformation and as some of its proteolytic peptides, particularly secreted (s)APPa. Given that APP phosphorylation tightly regulates its trafficking, proteolysis, and protein-protein binding, it consequently affects several APP functions. The S655 residue, located in the basolateral sorting motif YTSI at APP C-terminus has been observed to be phosphorylated in mature full-length APP and its C-terminal fragments. Previously observed to modify APPs protein interactions, resulting in altered endolysosomal trafficking, andincreased half-life and sAPPa generation, phosphoS655 APP has potential to modulate APP-mediated neuronal differentiation. To study the phosphoS655 differential interactome relevant for neuronal differentiation, SH-SY5Y cells expressing Wt or S655 phosphomutants APP-GFP were differentiated at two time points. APP-GFP and their respective interacting partners were immunoprecipitated using GFP-trap, and interactors identified by mass spectrometry. Both dephospho and phosphoS655 interactomes were generally enriched in similar processes, primarily RNA processing and translation, as well as signal transduction, metabolism, and cytoskeleton remodeling. The smaller phosphoS655 interactome contributes for functional specialization via binding to e.g. FUBP3, ELAVL4, ATXN2, Tubulin, INA. Several of these specific binding partners are known to promote neurite outgrowth and likely underlie our experimental observation that phosphoS655 APP promotes neuritogenesis, particularly the formation of longer neuritic extensions. These results are not only important for the body of knowledge on this Alzheimers disease core protein, but may also aid in future therapies against this disease.

INTRODUCTION: Bilingualism may confer resilience via enhanced neural integrity. However, evidence for bilingualism's neuroprotective effect is mixed, and studies across Alzheimer's disease (AD) variants are scarce. This study examined gray matter volume (GMV) differences between bilinguals and monolinguals with amnestic AD and logopenic variant primary progressive aphasia (lvPPA). METHODS: In 136 amnestic AD and 88 lvPPA participants with neuropsychological assessments and structural MRI, we analyzed differences between monolinguals and bilinguals within each variant, controlling for demographic covariates. RESULTS: Amnestic AD bilinguals exhibited less GMV in hippocampal, fusiform, and occipital regions compared to monolinguals. LvPPA bilinguals had less temporal and occipital volumes, but they had greater volumes in inferior parietal regions, which are considered a disease epicenter in lvPPA. Cognitive performance in monolinguals and bilinguals was comparable within variants. DISCUSSION: Bilingualism may support cognitive reserve (preserved cognition despite reduced GMV) in both AD variants, with additional brain reserve in lvPPA.