Oxidative stress is implicated in the etiology of mild cognitive impairment. We hypothesized that oral supplementation with N-acetylcysteine, a precursor to the antioxidant glutathione, would improve cognitive outcomes among individuals with mild cognitive impairment. n this 24-week randomized, double-blind, placebo-controlled trial, participants enrolled in an exercise-based cardiac rehabilitation program with possible vascular mild cognitive impairment were randomized to receive either oral N-acetylcysteine (2400 mg/day) or placebo. Cognition was assessed using a neuropsychological battery, with a standardized executive function composite score as the primary outcome. Secondary outcomes included verbal memory, working memory, non-verbal memory, attention and global cognition. Data were analyzed using linear mixed-effects models, adjusting for relevant covariates. A total of 59 participants [mean (SD) age = 67.6 (7.7), male (

Background:Coronavirus disease 2019 (COVID-19) has been associated with central nervous system dysfunction implicating cerebrovascular and neurovascular units, as reflected in lower regional cerebral blood flow among non-hospitalized individuals that experienced post COVID-19 condition (PCC). This study investigates whether PCC is associated with altered regional cerebral blood volume assessed using Dynamic Susceptibility Contrast (DSC) Magnetic Resonance Imaging (MRI). The comparison control group are individuals without PCC who previously experienced cold or flu-like symptoms, or COVID-19. Methods:Fifty-seven participants were recruited: 36 with PCC (mean age: 42.7, standard deviation: 10.4, 26 females) and 21 controls (mean age: 41.6, standard deviation: 14.7, 13 females). T2*-weighted DSC MRI was performed at 3 Tesla to image the first passage of the bolus. A total of 22 regions of interest (ROIs) were considered. Group differences in DSC-derived cerebral blood volume (rCBV) and cerebral blood flow (rCBF) were evaluated using Bayesian regression, providing median group differences, highest density interval (HDI), and the probability of direction (PD) estimates. Results:The two groups (PCC and controls) were matched for age, sex, days from symptom onset, and number of previous vaccines, but had different degrees of self-report illness severity. The rCBV analysis showed median group differences (range: -0.05 to -0.13), with PD > 0.90, indicating a high probability of decreased rCBV in the PCC group, involving the superior frontal gyrus, thalamus, paracentral lobule, cingulate gyrus, postcentral gyrus, middle frontal gyrus, inferior frontal gyrus, and superior temporal gyrus ROIs. By comparison, group differences in rCBF were muted and did not reach PD > 0.90. Discussion:We found group-level differences that were reflected by lower regional rCBV in PCC relative to controls. The imaging findings are suggestive of cerebrovascular alterations several months after the initial illness.

Background: While identifying high-risk carotid disease remains a significant clinical challenge, the specific role of carotid intraplaque hemorrhage (IPH) is poorly understood. Although IPH has been linked to white matter lesion (WML) burden, current assessments overlook the directional impact of plaque instability on the brain. This study sought to determine whether IPH is an independent driver of asymmetric WML pathology and evaluate if this phenotype can identify a high-risk demographic for TIA and stroke. Methods: This multi-center retrospective study analyzed 264 participants (mean age 71.8 years) from the Canadian Atherosclerosis Imaging Network (2010-2015). Participants underwent 3T MRI to assess carotid IPH and WMLs. We quantified WMLs using a deep-learning pipeline to extract three biomarkers: volume (WML-ICV), intensity (WML-Intensity), and intensity ratio (WML-IR). The Asymmetry Index Measure (AIM) defined the inter-hemispheric log-ratio, while the association between IPH and AIM was examined using multivariable linear regression adjusted for age, sex, stenosis, and scanner manufacturer. A secondary composite outcome of TIA/stroke was analyzed via logistic regression to evaluate the interaction between IPH, age, and sex. Results: While whole-brain WML burden did not significantly differ by IPH status (p > 0.60), IPH status was a robust independent predictor of hemispheric asymmetry (WML-ICV: p = 0.01; WML-Intensity, p = 0.01). Post-hoc analysis confirmed WML burden was significantly higher in IPH+ older males (=> 70 years) compared to younger cohorts (p < 0.04). This older male subgroup also demonstrated 4.57-fold higher adjusted odds of TIA/stroke (p = 0.02) compared to other demographic subgroups (all p > 0.87). Conclusions: Carotid IPH is independently associated with a rightward asymmetric WML phenotype not captured by global metrics. This imaging marker identifies a high-risk demographic of older males with a nearly five-fold increase in clinical events, suggesting that hemispheric-level analysis provides critical prognostic value for stroke risk stratification. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND:In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), the cholinergic system has been implicated in cognitive and gait decline. The nucleus basalis of Meynert (NBM), within the substantia innominata (SI), is the main cholinergic nucleus projecting to the cortex. In this study, the relationship between atrophy of the SI on cognitive phenotypes and quantitative gait performance was evaluated in relation to gray matter (GM) volume. METHODS:Ninety-nine participants - 20 control, 42 PD with normal cognition (PD-NC), 19 PD with mild cognitive impairment (PD-MCI) and 18 PD dementia or DLB patients (PDD/DLB) - were examined. Measures included Montreal Cognitive Assessment (MoCA) score, motor symptom severity, quantitative gait analysis measures and dual-task cost (DTC) to gait speed. Manual measurement of SI volume was performed on T1 MRI scans; automated methods were used for GM volumes. The relationships between gait changes, volumetric imaging and clinical measures were assessed. RESULTS:Smaller SI volumes were seen in PD-MCI and PDD/DLB subjects adjusting for age. SI and GM atrophy were both associated with greater step length variability, and GM was associated with increased DTC to gait speed. These were not significant after adjusting for the false discovery rate. Lower MoCA score was associated with impairments in gait speed, DTC to gait speed and gait variability. CONCLUSION:The SI was associated with cognitive impairment in participants with Lewy body diseases. However, more widespread cortical atrophy may be better related to selected cognitive aspects of gait (DTC to gait speed with animal fluency).

White matter hyperintensities (WMHs) in persons with vascular mild cognitive impairment (vMCI), particularly frontal WMHs, have been associated with decreased executive function (EF). While N-acetylcysteine (NAC) and exercise therapy may improve EF in patients with vMCI, identifying predictors of response could help personalize treatment. We hypothesized that lower baseline frontal WMH volume in vMCI patients treated with NAC and exercise will correlate with increasing improvement in EF over 6 months of treatment. Participants received 24 weeks of NAC or placebo in combination with exercise therapy ( n  = 60) as part of the Efficacy and Safety of N-acetylcysteine in patients with mild vascular cognitive impairment (MOVE-IT) clinical trial. Composite z scores for EF were calculated using Trail Making Part Test B, F-A-S Test, and Animal Naming Test administered at baseline, week 12, and week 24. Frontal WMH volumes were captured from baseline MRI scans. Linear mixed models were used that accounted for sex differences, age, years of education, and baseline executive function. Both treatment groups had a significant improvement in EF at midpoint (β = 0.194, SE = 0.059, p  =  0.002) and endpoint (β = 0.342, SE = 0.058, p  < 0.001). Lower baseline frontal WMH and treatment group was not associated with greater improvement in EF at midpoint (β = -0.260, SE = 0.144, p  =  0.075) or at endpoint (β = -0.162, SE = 0.144, p  =  0.266). Lower baseline frontal WMH volume was significantly associated with greater improvement in performance on the Trail Making Test Part B at midpoint (β = -0.597, SE = 0.197, p  =  0.003) but not at endpoint (β = -0.328, SE = 0.197, p  =  0.099) among participants randomized to the NAC and exercise group, but not the placebo and exercise group. This study found a predictive value of frontal WMH burden for novel interventions aiming to improve cognitive outcomes in patients with vMCI. WMH burden could help guide the development of targeted, effective therapies that address the complexities of cognitive impairment in aging populations.

Introduction Un dysfonctionnement du système glymphatique peut être lié à des maladies neurocognitives et peut être évalué par le Diffusion Tensor Imaging–Analysis Along the Perivascular Space (DTI-ALPS). Son rôle demeure mal compris. Objectifs Les objectifs étaient : évaluer l’association du DTI-ALPS initial avec l’évolution de la substance grise (SG) et des anomalies de la substance blanche (ASB), étudier la médiation par la Glial Fibrillary Acidic Protein (GFAP) et l’effet sur le déclin de la vitesse de traitement. Méthodes Dans la cohorte ONDRI (Ontario Neurodegenerative Disease Research Initiative), incluant Maladie d’Alzheimer (MA), dégénérescences lobaires frontotemporales (DLFT) et maladies cérébrovasculaires (CV), nous avons étudié via des des analyses de régressions linéaires et médiations : l’association du DTI-ALPS initial avec l’évolution à un an du volume de SG, des ASB et du déclin de la vitesse de traitement (Trail Making Test A et Symbol Digit Modalities Test), et le rôle de la GFAP plasmatique. Résultats Chez 304 participants (âge moyen 69,7±7,7 ans, 60,8 % hommes) : MA 39,2 %, DLFT 14,7 %, CV 45,4 %, un DTI-ALPS initial plus faible était associé à la diminution de SG (β=0,111, p=0,048) et à l’augmentation des ASB (β=–0,148, p=0,013). La GFAP plasmatique intial médiait l’effet du DTI-ALPS initial sur la perte de SG (effet indirect 845,94±863,52 ; 95 % CI [73,89, 3370,62]). Le DTI-ALPS initial avait un effet sur le déclin de la vitesse de traitement, médié par le volume initial de la SG (effet indirect 0,1385±0,0757 ; 95 % CI [0,042, 0,3016]). Discussion Le dysfonctionnement glymphatique évalué par DTI-ALPS était lié à la perte de SG, à la progression des ASB et au déclin cognitif, avec une rôle de la GFAP, marqueur d’activation astrogliale. Ces résultats soutiennent un modèle pathologique intégrant altération glymphatique, neuroinflammation et modifications structurelles, expliquant le déclin cognitif dans une cohorte mixte représentative des patients des cliniques « mémoire ». Conclusion Le dysfonctionnement glymphatique et la neuroinflammation paraissent des mécanismes clés dans les maladies cognitives et représentent des pistes thérapeutiques potentielles.

INTRODUCTION:South Asian and Chinese individuals are the largest and fastest-growing ethnoracial groups in Canada, yet they remain underrepresented in dementia research. To address this gap, we established the CAnadian Multi-Ethnic Research on Aging (CAMERA) study. METHODS:CAMERA is a longitudinal observational study conducted in Toronto, Canada, enrolling 300 adults aged 55-85 who self-identify as South Asian, Chinese, or non-Hispanic White (NHW). Participants complete in-person visits at baseline, Year 3, and Year 5, which include clinical and cognitive assessments, brain magnetic resonance imaging (MRI), and blood-based biomarkers. Annual remote questionnaires track health and lifestyle factors. RESULTS:Among the first 200 participants, vascular and metabolic profiles differed across groups. In addition, South Asian and Chinese participants reported greater cognitive concerns than NHW participants and had lower Montreal Cognitive Assessment (MoCA) scores. The latter was driven primarily by language-heavy and culturally dependent items. Eye-tracking measures did not differ across groups. DISCUSSION:CAMERA provides a deep phenotyping framework to investigate dementia risk and resilience factors in Asian Canadians.

Oxylipin species are generated from omega-3 and omega-6 fatty acids during inflammation, including fatty acid epoxides by cytochrome P450s (CYP450) and their diol metabolites by soluble epoxide hydrolase (sEH). The CYP450-sEH pathway has been implicated in Alzheimer’s disease (AD) but it remains unclear how plasma oxylipins relate to AD biomarkers and neurodegeneration. Fasting plasma CYP450-sEH total (free + esterified) oxylipins were assayed by ultra-high pressure liquid chromatography-tandem mass spectrometry in participants (NCT04104373) clinically diagnosed with AD or mild cognitive impairment (MCI). Plasma AD biomarkers were assayed by SiMoA. At baseline, 1 and 2 years, regional grey matter and white matter hyperintensity (WMH) volumes were quantified using 3.0 T MRI, and cognitive assessments were performed. At baseline (n = 125), participants with AD vs. MCI had higher CYP450-sEH pathway metabolites, apolipoprotein E (APOE) ε4 carriers vs. non-carriers had higher diol levels, and females vs. males had higher omega-6 vs. omega-3 oxylipins. An oxylipin profile of higher diols and lower epoxides was associated with higher pTau181, temporal lobe and hippocampal atrophy, and declines in cognitive performance in multiple domains over 2 years. Higher CYP450-sEH pathway metabolites were associated with the progression of WMH. Larger oxylipin relationships with atrophy and cognitive decline were seen at the MCI stage, in APOE ε4 carriers, and in females. Elevated sEH metabolites were related to biomarkers of AD pathogenesis, and they predicted atrophy, white matter changes, and cognitive decline over 2 years.

INTRODUCTION:Obstructive sleep apnea (OSA) is a prevalent sleep disorder associated with cognitive impairment and cerebral small vessel disease (CSVD), including enlarged perivascular spaces (PVS). PVS are hypothesized to play a role in brain metabolite clearance. While some studies suggest an association between OSA and PVS enlargement, findings are inconsistent, and the specific physiological aspects of OSA driving these changes remain unclear. This study aimed to identify latent variables underlying sleep apnea physiology and relate them to PVS burden in a large community-based cohort. METHODS:We conducted a cross-sectional study of 614 participants from the Ontario Health Study who underwent home sleep apnea testing and brain MRI within 3 years. We computed 9 individual measures of sleep apnea physiology and performed factor analysis to identify latent variables. Linear regression models, adjusted for age, sex, and vascular risk factors, were used to assess associations between these latent variables and basal ganglia (BG) and non-basal ganglia (non-BG) PVS counts and volumes. RESULTS:Factor analysis yielded three latent variables accounting for 71.5% of the variance: an "apnea burden factor" (respiratory/desaturation event frequency), a "hypoxia factor" (chronic hypoxia), and a "duration factor" (event duration). In age- and sex-adjusted models, higher levels of the apnea burden factor were associated with higher BG-PVS counts (Estimate = +0.000040, SE = 0.000015, p = 0.007), while higher levels of the hypoxia factor were associated with higher non-BG PVS counts (Estimate = +0.068, SE = 0.0, p = 0.02). DISCUSSION:Our findings indicate that distinct physiological aspects of OSA are differentially associated with PVS burden. Greater respiratory event frequency is significantly associated with higher BG-PVS counts This highlights the importance of characterizing specific OSA endotypes to identify individuals at highest risk for PVS enlargement and to target relevant physiological pathways for intervention. Additional studies are needed to confirm causality and explore the impact of OSA treatment on PVS progression.

Prior studies have focused on tau spread from the entorhinal cortex along first-order (short-range) connections within anatomical brain space (seed-to-target). Here, we explore tau spread along long-range connections within a novel coordinate space called connectome gradients, which is reflective of the brain's hierarchical organization. Exploring tau spread within this new framework offers insights into long-range connectivity alterations and network susceptibility in Alzheimer's disease (AD). We included 213 participants from TRIAD (103 A- CN, 103 A+ CN, and 75 A+ CI) with diffusion-weighted MRI, resting-state functional MRI, and 18F-MK6240 tau-PET. First, we employed graph theory-based stepwise connectivity analyses to unveil long-range connectivity patterns from the entorhinal cortex to the rest of the brain. Differences in connectivity patterns were compared between A+ vs A- groups, adjusted for age, sex, and APOE-ε4. Second, we investigated the stepwise connectivity patterns in relation to tau within a novel coordinate system spanned by the principal functional and structural connectome gradients. In the preclinical stage (A+ CN) compared to controls (A- CN), we observed connectivity increase through functional gradient space (Figure 1A red). In the clinical stage (A+ CI), connectivity reduced from the entorhinal cortex to the transmodal end of the functional gradient (DMN/limbic; Figure 1A blue) and to the posterior end of the structural gradient (temporo-occipital; Figure 1B blue). Long-range connections from the entorhinal cortex showed increased connectivity toward the unimodal and anterior ends of the functional and structural gradient, respectively (Figure 1A, B red), potentially initiating new paths for tau spread. Indeed, tau–connectivity correlations shifted spatially within gradient space with disease progression (Figure 2), moving from the highest-order (DMN/limbic) cognitive system of the functional gradient in A+ CN to the second-highest order (frontoparietal) system in A+ CI. We employed a novel integration of stepwise connectivity and connectome gradients to enable a better understanding of how connectivity is related to tau spread along the major axes of brain organization. We observed widespread network reorganization in AD and notably that the tau–connectivity correlations shifted between major networks of the functional connectome gradient with disease progression.

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are reciprocal risk factors, and both elevate dementia risk. Dysregulation of programmed cell death is implicated in T2DM, MDD, and neurodegeneration, but proteomic markers of apoptosis have yet to be studied as dementia predictors in people with T2DM and/or MDD. This study examines apoptosis markers in comorbid T2DM and MDD, and their associations with cognitive, dementia, and neuroimaging outcomes. The retrospective sample (n = 15,765) consisted of UK Biobank participants (MDD only n = 1230; T2DM only n = 3644; comorbid T2DM + MDD n = 721). Individuals with T2DM + MDD comorbidity had poorer cognitive performance, and a higher 15-year dementia incidence (HR = 4.44, 95% CI = [3.23,6.11]). Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone. Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk. Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes. These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

Vascular mild cognitive impairment (vaMCI) is a prodromal stage of dementia defined by cognitive deficits due to cerebrovascular disease. Increased white matter hyperintensity (WMH) volume has been associated with reduced executive function (EF). We explored whether lower baseline frontal and global WMH volume predicted an improvement in EF in vaMCI participants treated with N-acetylcysteine (NAC) and exercise as compared to placebo and exercise. Fifty-eight individuals with vaMCI received exercise therapy and were randomized to NAC or placebo. EF was assessed using the Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and a test of phonemic fluency, at baseline, 3 months, and 6 months. WMH volumes were measured from baseline magnetic resonance imaging scans. Linear mixed models were used. All participants improved on TMT-B (β = -0.185, SE = 0.046, p < 0.001) and phonemic fluency (β = 4.440, SE = 0.911, p < 0.001) over 6 months. A significant three-way interaction between baseline frontal WMH volume, treatment group, and timepoint predicted TMT-B performance at 3 months (β = 0.160, SE = 0.076, p = 0.039), but not at 6 months. No significant interactions were found for DSCT or phonemic fluency. Global WMH did not predict treatment response. Participants demonstrated improvement in EF regardless of treatment group and WMH volume. Lower frontal WMH volume predicted a greater improvement in TMT-B performance at 3 months in those treated with NAC versus placebo. These findings underscore the importance of considering participant heterogeneity in trials for vaMCI.

Background : Excessive alcohol use is associated with memory impairment due to its effects on encoding and retrieval of information. However, the underlying mechanisms in those with neurodegenerative disorders is not well understood. Objective: We evaluated the effects of alcohol on verbal memory processes in those with mild cognitive impairment (MCI).Methods Data came from two cohorts, the Comprehensive Assessment of Neurodegeneration and Dementia and the Ontario Neurodegenerative Disease Research Initiative. Participants were diagnosed with MCI due to Alzheimer's disease or cerebrovascular disease, and categorized into "zero", "low-medium", or "high" alcohol use groups. We compared occurrence of any intrusion, total intrusions, change in intrusions post-interference, and intrusion subtypes on the Rey Auditory Verbal Learning Test across groups. Results We analyzed 521 participants with high (n = 79), low-medium (n = 304), and zero (n = 138) alcohol use. Mean (SD) age was 71.6 (7.4) years and did not differ between groups. The high alcohol use group had higher occurrence of any intrusions (96.2%) compared to the low-medium (87.2%), and zero (92.8%) alcohol use groups (p = 0.027). Alcohol use was associated with increased post-interference intrusions, with the high group adjusted mean (M), standard error (SE) = 1.7 (0.3), low-medium group M(SE) = 1.0 (0.2), and zero group M(SE) = 0.9 (0.2), (p = 0.027). Other intrusion subtypes did not differ between groups. Conclusions: Individuals with MCI and excessive alcohol use are more susceptible to interference from recently learned task-irrelevant information. Findings may inform future research regarding mechanisms of alcohol related memory impairment.

Objective : To evaluate whether the combination of fluoxetine and therapeutic exercise enhances lower extremity motor recovery after stroke. Design : Randomized, double-blind, placebo controlled clinical trial. Setting : Eight sites from the CanStroke Recovery Trials Platform (www.canadianstroke.ca). Participants : Individuals 25 years of age or older, 2 to 12 months post-stroke, with lower extremity hemiparesis. Intervention : Participants were randomized (1:1) to either 20 mg daily of fluoxetine or placebo. All participants received 12-weeks of intense task-specific exercise. Main Outcome Measure : The primary outcome measure was lower extremity motor function as measured using the Fugl-Meyer Assessment of Lower Extremity (FMA-LE) immediately following the 12-week exercise program. Secondary outcomes included the 6-Minute Walk Test (6MWT) and the Patient Health Questionnaire-9 (PHQ-9). Results : 55 participants were recruited and completed the primary outcome measure (30.9% female, average age: 61.0 [SD 11.0], average days post-stroke: 204.1 [SD 96.0]), with 25 participants receiving fluoxetine and exercise, and 30 in the placebo and exercise group. The baseline adjusted mean difference in post-exercise FMA-LE score between the fluoxetine and placebo groups was 0.47 (95% CI: [-1.36,2.3]; p=0.61). Participants in both groups demonstrated a clinically meaningful increase in 6MWT scores that was maintained for at least 6 months beyond the end of the intervention. Conclusions : Fluoxetine plus exercise did not demonstrate any additional improvement in lower extremity motor recovery compared to placebo and exercise in participants 2-12 months post-stroke. This study did not meet its planned sample size due to recruitment issues primarily attributed to the COVID-19 pandemic. Given that participants made clinically meaningful improvements in walking, this study highlights the importance of exercise beyond the traditional subacute post-stroke period. Future studies should utilize a “no exercise” control group to account for natural recovery to accurately interpret the results from the exercise protocol.

Importance:APOE-ε4 is an established risk factor for Alzheimer's disease (AD) and confers greater risk in women than in men. Earlier age at menopause also increases AD risk in women. Yet whether menopause timing influences APOE-ε4-related AD risk remains unclear. Objective:To examine whether age at menopause modifies the association of APOE-ε4 with AD risk. Design setting and participants:Data were analyzed from postmenopausal women free from known dementia at study entry in two longitudinal datasets: (1) the harmonized data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS), and (2) the Wisconsin Registry for Alzheimer's Prevention (WRAP). Data were collected between 1994-2025. Main outcomes and measures:In both datasets, neuropsychological tests assessed longitudinal memory performance, and MRI quantified cortical thickness and brain volume in AD vulnerable regions. In WRAP, which included in vivo AD biomarkers, AD pathology was assessed using longitudinal plasma p-tau217 and cross-sectional beta-amyloid (Aβ) PET. Menopause history was self-reported, and APOE status was classified as ε4 carrier vs. non-carrier. Linear mixed-effects or linear regression models were used, as appropriate, to test interactions between APOE-ε4 carrier status and age at menopause on memory decline, brain atrophy, p-tau217 accumulation, and Aβ-PET burden, adjusting for relevant covariates. Results:The study included 2,625 women in ROS/MAP/MARS (mean [SD] age=77.4 [7.77], mean [SD] age at menopause=47.9 [7.10]) and 512 women in WRAP (mean [SD] age=60.2 [5.57], mean [SD] age at menopause=50.1 [6.29]). In both datasets, earlier age at menopause strengthened associations of APOE-ε4 with memory decline (ROS/MAP/MARS: β=0.068, p=.02; WRAP: β=0.092, p=.03) and MRI measures of brain atrophy (ROS/MAP/MARS: β=0.071, p=.05; WRAP: β=0.256, p=.03). In WRAP, earlier menopause also amplified associations of APOE-ε4 with p-tau217 accumulation (β=-0.029, p=.05) and global Aβ-PET burden (β=-0.146, p=.01). Conclusions and relevance:Earlier menopause strengthened the associations between APOE-ε4 and key AD outcomes. These findings suggest that menopause timing may influence APOE-ε4-related susceptibility to AD, highlighting midlife endocrine processes as potential targets for prevention in women.

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA2DS2-VASc scores of 0 or 1, excluding female sex) were randomized 1:1 to receive rivaroxaban 15 mg daily or placebo. The primary outcome was a composite of cognitive decline (≥2-point drop in Montreal Cognitive Assessment), stroke or transient ischemic attack with a motor deficit or aphasia. The trial was halted after meeting the predetermined futility criterion following a planned interim analysis, with 1,235 of the intended 1,424 participants (919 men; 316 women) enrolled. Over a median follow-up of 3.7 years, the primary outcome occurred in 256 (20.7%) participants, at an annual rate of 7.0% with rivaroxaban versus 6.4% with placebo, yielding a hazard ratio of 1.10 (95% confidence interval (0.86-1.40); P = 0.46). Conditional power analysis indicated a 1.2% probability of achieving a statistically significant treatment effect if the trial had been continued to its planned total of 410 events. Major bleeding occurred in two patients treated with rivaroxaban (0.09% per year) and five patients treated with placebo (0.21% per year). In conclusion, despite the high incidence of cognitive decline observed among patients with AF and low stroke risk, the BRAIN-AF trial, which tested a low dose of rivaroxaban to prevent stroke, transient ischemic attack and cognitive decline in patients with prior AF, was stopped early due to futility. ClinicalTrials.gov registration: NCT02387229 .

Brain white matter hyperintensities (WMH) are vascular lesions commonly observed in Alzheimer's disease (AD). WMH were previously shown to be associated with greater brain amyloid, but the molecular pathways underlying their complex relation remain unclear. Here, we aim to identify single nucleotide polymorphisms (SNP) that modify the relationship between WMH and AD amyloid biomarkers. We conducted a genome-wide interaction study in participants with AD, mild cognitive impairment, and normal cognition from the Alzheimer's Disease Neuroimaging Initiative (ADNI). WMH were measured from FLAIR MRI using an automated atlas-based segmentation. Amyloid-β 42 (Aβ42) in cerebrospinal fluid (CSF) were measured using immunoassays. Interactions between SNPs and WMH volumes on CSF-Aβ42 were assessed via a linear regression model adjusting for age, sex, diagnosis, MMSE, APOE -ε4 status, head-size, and 4 genetic principal components in PLINK2. The most influential SNP was identified via Sum of Single Effects (SuSiE) regression. Significant SNP-WMH interactions were validated in participants from the UK Biobank (UKB) with available plasma-Aβ42 data quantified by liquid chromatography-mass spectrometry. SNP-WMH interactions in relation to amyloid pathology (diffuse and neuritic plaque burden) was investigated in the Religious Orders Study/Rush Memory and Aging Project (ROSMAP). A 28-variant intergenic locus on chromosome 18 (top SNP: rs72899960 T>A, p  = 5.66x10 -9 , MAF=11.1%, Imputation R 2 >0.99%, n  = 863) interacted with WMH to predict Aβ42 (nearest gene: U7 small nuclear RNA (snRNA) XR_007066478.1 [-111KB]). The effect of this SNP was also significant in the dominant and recessive genetic models (relative to the minor A-allele). This SNP-WMH interaction was replicated in UKB ( n  = 645) in both additive (B=0.91, p  = 0.017) and dominant models (B=0.96, p  = 0.024). In ROSMAP ( n  = 195), significant SNP-WMH interaction was observed on diffuse plaque burden in the additive (B=-0.46, p  = 0.049) and dominant (B=-0.51, p  = 0.046) models. The minor A-allele exhibited a protective effect by being associated with higher circulating Aβ42 (in ADNI and UKB) and lower diffuse plaque burden (in ROSMAP) in individuals with greater WMH. Genomic variants moderated the relationship between WMH and amyloid biomarkers, suggesting a novel regulatory role for snRNA. This genome-wide interaction study highlights the potential contributions of snRNA and related pathways to the relationship between vascular disease and amyloid biomarkers in AD.