Journal of Alzheimer’s Disease

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.

INTRODUCTION: Alzheimers disease (AD) is a multifactorial disorder, yet current research largely focuses on downstream biomarkers with limited attention to environmental contributors. Experimental studies suggest that per and polyfluoroalkyl substances (PFAS) may contribute to neuroimmune and neurodegenerative pathways relevant to AD. OBJECTIVE: To examine associations between PFAS exposure and neuroimmune and AD related plasma biomarkers in cognitively unimpaired rural adults. METHODS: In a cross sectional pilot study (n=48), serum concentrations of 33 PFAS were measured, including four legacy compounds (PFOS, PFHxS, PFOA, PFNA). Plasma neuroimmune related (ITGB2, SMOC1, TREM2, GFAP) and AD related biomarkers (Ab42/40, ptau217) were detected using proteomic analysis. RESULTS: PFOS showed moderate associations with ITGB2, SMOC1, and Ab42/40 in unadjusted analyses, which attenuated after adjustment for age. PFOA and PFNA demonstrated consistent inverse associations with TREM2 before and after adjustment. DISCUSSION: Findings suggest possible compound specific PFAS associations with immune and amyloid related biomarkers, supporting further investigation in longitudinal and PFAS mixture based studies.

Background: Growing evidence suggests that urinary {beta}-amyloid precursor protein (A{beta}PP) fragments can serve as an early screening biomarker for mild cognitive impairment and dementia. However, in reality, older adults, regardless of the presence of cognitive decline, often suffer from multiple age-related conditions and are on multiple medications. How these comorbidities and treatments affect the performance of early diagnostic biomarkers remains unclear. Methods : This study further validated the sensitivity, specificity, and clinical value of the Qankorey (R) urinary {beta}-amyloid protein detection kit in early dementia screening through a randomized community screening (n=51187) conducted in Changsha, and a multicenter case-control study conducted at Yuquan Hospital (Tsinghua University), Tiantan Hospital (Capital Medical University), Beijing Friendship Hospital, Zibo 148 Hospital (Shandong), and the Third People's Hospital of Yunnan Province. The multicenter case-control study included 898 participants, comprising 266 healthy, age-matched controls without any comorbidities, 167 patients with mild cognitive impairment/Alzheimer's disease (MCI/AD), and 465 non-AD patients with various comorbidities and age-related diseases. Results: The kit showed a significant age-dependent positive rate in both men and women in Changsha, increasing from 6.29% to 15.40%. The number of weakly positive/positive/negative individuals in the healthy group, non-AD group, and MCI/AD group were 8/12/246 (positive rate 7.52%), 41/16/409 (12.23%), and 77/44/46 (72.46%), respectively, with a Kappa value of 0.669, indicating that the method performed well in the clinical diagnosis of MCI/AD, consistent with previously published results. Among the 8 weakly positive healthy subjects, 6 were found to have brain abnormalities by MRI/CT examination. Comorbidity analysis showed that memory decline was the most significant risk factor (P=9.6 x 10^-23, Fisher's exact test), followed by dizziness (P=1.3 x 10^-14;) , hyperlipidemia (P=3.2 x 10^-12) , history of stroke (P=0.0011), and hypertension (P=0.0058). Treatment analysis showed that cardiovascular drugs and antithrombotic drugs significantly reduced the risk of dementia (P values were 0.0061 and 0.0081, respectively), followed by hypoglycemic drugs (P=0.0358). For AD patients, those receiving only memantine showed a slightly lower positive test rate (P=0.0532). Conclusion: Our findings confirm the diagnostic value of urinary {beta}-amyloid protein detection in MCI and AD-related dementia. Furthermore, this kit can be used in practical clinical applications to assess the risk of cognitive decline and treatment efficacy across various diseases.

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.

Importance: Alzheimer disease (AD) pathogenesis begins decades before clinical symptoms, yet environmental determinants of early disease risk, particularly during fetal development, remain largely uncharacterized. Prenatal exposure to dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of DDT, is a biologically plausible early-life contributor to AD risk given long half-life in human tissue and higher levels observed in AD patients. However, prospective human evidence linking prenatal DDE to midlife AD-relevant outcomes is absent. Objective: To determine whether prenatal DDE exposure is associated with plasma AD biomarkers and cognitive performance in early midlife offspring, and whether APOE {epsilon}4 genotype modifies these associations. Design: Observational cohort analysis nested within the Child Health and Development Studies (CHDS), a population-based birth cohort. Setting: CHDS enrolled pregnant women between 1959-1967 in the San Francisco Bay Area. Participants: Among 367 eligible adult offspring who participated in a follow-up study (2010-2013) at mean age 49.3 years, 179 with available prenatal DDE measurements were included. Main Outcomes and Measures: Prenatal DDE levels from maternal serum. Primary outcomes were plasma A{beta}42/40 ratio and Digit Symbol Substitution Test (DSST) performance. Secondary outcomes included plasma pTau217, GFAP, NfL and APOE genotype. Results: Among 179 participants (56% female; 26% APOE {epsilon}4 carriers), mean prenatal DDE was 47.4 (25.4) ng/mL. Higher prenatal DDE was associated with lower DSST scores ({beta}=-0.021, 95% CI, -0.041 to -0.001, P=0.039) and lower plasma A{beta}42/40 ratio ({beta}=-0.079, 95% CI, -0.133 to -0.024, P=0.005) per ng/mL DDE, adjusting for sex, race, education, and APOE {epsilon}4 status. Associations were strongest among APOE {epsilon}4 non-carriers for DSST ({beta}=-0.033, 95% CI, -0.050 to -0.016, P=0.001) and A{beta}42/40 ratio ({beta}=-0.101, 95% CI, -0.161 to -0.040, P=0.001). No significant associations were observed for pTau217, GFAP, or NfL. Conclusions and Relevance: In this prospective birth cohort study, prenatal exposure to a persistent environmental toxicant was associated with lower plasma A{beta}42/40 ratio and worse cognitive performance in early midlife, consistent with DDE accelerating the preclinical trajectory of AD-related biological changes decades before symptom onset. These findings support a life-course framework for AD risk and identify prenatal DDE as a potentially modifiable determinant of early AD-related pathology amenable to prevention.

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.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

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.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

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.

Digital health technologies (DHT) offer a promising solution to the timely identification of early Alzheimer's disease (eAD) to enable early treatment. This study evaluated the feasibility, acceptability, adherence, reliability, and preliminary clinical and content validity of the novel AD Digital Assessment Suite (AD-DAS). 123 individuals (32 healthy controls (HC), 31 amyloid-PET negative (SCDn), 30 amyloid-PET positive (SCDp) with subjective cognitive decline, and 30 early AD (eAD)) participated. AD-DAS was remotely deployed for 28 days. Remote testing was feasible (97.6% completers), acceptable (>85% ''good''), and associated with high adherence (96%). Metrics showed moderate to excellent test-retest reliability (ICC 0.53-0.91), associations with clinical comparators (adjusted R2 0.01-0.24), differentiated eAD from other known groups (absolute log odds differences 0.6-3.28), and correlated with brain atrophy in expected regions. Episodic and working memory AD-DAS metrics differentiated SCDp from SCDn participants. These preliminary findings suggest that AD-DAS may be a promising tool for detecting cognitive impairments in early AD stages.

BackgroundThe current biomarker framework for the diagnosis and staging of Alzheimers disease (AD) relies mainly on neuropathological features; thus, its performance for diagnosis is limited prior to the initiation of neurodegeneration. Here, we leveraged transcriptomic data to develop a new framework for omic-informed blood-based diagnostic biomarkers for AD from early-stage. MethodsMicroglial gene expression from single-nucleus (sn)RNA-seq data was analyzed via 6 statistical methods to identify candidate panels of genes predictive of AD. A total of 78 gene panels, 30-2000 genes in size, were selected and evaluated for their ability to distinguish AD patients from controls. Three top-ranked panels of 300, 50 and 30 genes were transferred to blood (monocyte) transcriptomic data obtained from living subjects via a graph-based mapping approach based on optimal transport statistics. ResultsThe 300-panel method resulted in an AUC of 0.7 and moderate accuracy (75%) in classifying AD; however, the accuracy in predicting cognitively normal patients was lower (53%). While the 300 genes provided high accuracy, inspection of the distribution of p values for the gene set revealed that the panel could be greatly reduced in size to capture the most significant differences between AD patients and cognitively normal individuals. The accuracy and specificity of the 50 and 30 panels demonstrated similar AUC values but improved the balance between the prediction of AD patients and normal controls. Specifically, the 50-gene panel resulted in an AUC of 0.7, with 65% AD accuracy and 71% normal accuracy. ConclusionsIntegrating multiomics datasets into the AD biomarker discovery pipeline offers a powerful modality to increase precision and comprehensiveness in AD research and clinical applications.

INTRODUCTION: Postmenopausal estrogen decline may contribute to Alzheimer's disease (AD) risk, but longitudinal evidence linking circulating estrogens to cerebrospinal fluid (CSF) biomarkers is lacking. METHODS: We analyzed 866 female participants from the European Prevention of AD Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography tandem mass spectrometry and repeated CSF measurements of amyloid-beta (A{beta})42, phosphorylated (p) Tau181, and total (t) Tau. RESULTS: Neither estradiol nor estrone was associated with longitudinal A{beta}42. Higher estradiol was associated with lower baseline tau and slower tau increases over time. Baseline estradiol-tau associations were stronger in apolipoprotein E (APOE) {epsilon}4 carriers, though APOE{epsilon}4 did not modify longitudinal associations. Amyloid positivity did not moderate hormone-tau associations but was associated with steeper tau increases over time. Estrone showed no significant associations. DISCUSSION: These findings suggest a more consistent relationship between estradiol and tau-related rather than amyloid-related pathology.

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

BackgroundThe hallmark lesions of the Alzheimers disease (AD) brain are amyloid plaques consisting of the {beta}-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and A{beta} production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear. MethodsWe overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq. ResultsWhile neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by A{beta} antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation. ConclusionsDystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation.

Introduction. There is consistent evidence of a disadvantage in bilinguals' speech production compared to monolinguals in healthy individuals, but studies investigating this phenomenon in clinical populations such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) are scarce. Given that both clinical groups are characterized by wordfinding difficulties, understanding how bilingualism influences speech production in these populations is essential. Methods. Early and highly proficient Catalan-Spanish bilinguals (active bilinguals) were compared to Spanish-dominant speakers with low proficiency in Catalan (passive bilinguals) using a picture-naming task. The study included 58 older adults, 66 patients with AD, and 124 individuals with MCI. Reaction times, accuracy, and error types were collected in the naming task in each individual's dominant language. Results. First, active bilinguals demonstrated faster naming latencies than passive bilinguals, particularly for low-frequency words. Second, active bilinguals with MCI exhibited more naming errors than passive bilinguals with MCI, including a higher incidence of crosslanguage intrusions and anomia. Third, passive bilinguals with MCI and AD showed more semantic errors than active bilinguals. Discussion. These findings underscore the impact of second language use on naming performance in MCI and AD. Moreover, they provide insight into the potential mechanisms underlying lexical retrieval differences in bilinguals, including lexico-semantic processing and language control.

ObjectiveImpaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population. Materials and MethodsNeurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimers Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). ResultsSignificant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population. ConclusionOur findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.

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