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The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less

Atherosclerosis (AS), a chronic vascular pathology characterized by endothelial dysfunction, arises from the interplay of lipid dysregulation, oxidative stress, and inflammatory activation. Reactive oxygen species (ROS) overproduction triggers Nod‑like receptor protein 3 (NLRP3) inflammasome signaling, exacerbating inflammatory cascades that drive plaque progression. The nuclear factor erythroid 2‑related factor 2 (Nrf2)‑mediated antioxidant pathway serves as a critical counterbalance to ROS/NLRP3 axis dysregulation, positioning pharmacological Nrf2 activation as a promising therapeutic strategy. The present study investigated the anti‑atherosclerotic potential of ginkgolide C (GC), a terpene lactone from Ginkgo biloba with established anti‑inflammatory and anti‑ischemia/reperfusion injury properties, through coordinated modulation of redox‑inflammatory pathways. Complementary Show less

Associations between television/computer use and dementia in socially inactive older adults remain unclear, and optimal limits are unknown. We followed 89,671 dementia-free, socially inactive adults aged ≥55 from UK Biobank for a mean of 12.2 years. Adjusted Cox models assessed associations with incident all-cause dementia and subtypes. Computer use ≤2.4 h/day was associated with lower all-cause dementia risk (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.82-0.94), whereas higher use increased risk (HR 1.19, 95% CI 1.05-1.34); patterns were similar for Alzheimer's and vascular dementia. Television viewing showed no association below 2.06 h/day but higher risk thereafter (HR 1.17; 95% CI 1.03-1.32), with a roughly linear increase for vascular dementia. Heavy computer use in apolipoprotein E (APOE) -ε4 homozygotes and higher television viewing in adults < 65 were more harmful. In socially inactive older adults, moderate computer use may be protective, whereas higher computer use and television viewing are linked to increased dementia risk. Show less

Alzheimer's disease (AD), particularly its sporadic form (SAD, 95 % AD patients), is strongly associated with the apolipoprotein E4 (ApoE4) genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe Show less

There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use. To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use. This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women's Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis. Plasma p-tau217, quantified using the ALZpath Simoa assay. The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models. Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude for women randomized to estrogen plus progestin (HR, 4.18; 95% CI, 3.41-5.13) vs placebo (HR, 3.07; 95% CI, 2.41-3.91) (P for interaction = .04) but did not significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women. In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes. Show less

Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation Show less

Apolipoprotein E (APOE) regulates lipid metabolism and neuronal repair, yet its alleles show contrasting effects on hemorrhagic stroke (HS) risk. While some variants increase susceptibility, others appear protective, leading to inconsistent findings. This meta-analysis systematically evaluates the APOE-HS association to clarify its role in stroke pathophysiology. A comprehensive literature search was conducted across multiple databases up to January 31, 2025, using the keywords: ("Apolipoprotein E" OR "APOE" OR "APOE genotype") AND ("Single Nucleotide Polymorphisms" OR "SNP") AND ("Hemorrhagic stroke" OR "HS" OR "Intracerebral Hemorrhage" OR "ICH"). The APOE ε3/ε3 genotype served as the reference genotype in all studies, and only those studies with ε3/ε3 genotype were included in the analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and statistical analyses were performed using STATA version 13.0 (StataCorp LLC, College Station, Texas, United States). A total of 24 studies comprising 8,269 HS patients and 26,321 controls were included. Meta-analysis revealed a significant association of APOE ε2/ε2 (OR = 1.93, 95% CI = 1.32-2.81), ε4/ε4 (OR = 1.60, 95% CI = 1.21-2.13), ε2/ε4 (OR = 1.81, 95% CI = 1.34-2.44), ε2 (OR = 1.23, 95% CI = 1.12-1.35), and ε4 (OR = 1.31, 95% CI = 1.14-1.51) with an increased risk of HS. Our findings suggest that APOE ε2/ε2, ε2/ε4, ε2, and ε4/ε4 genotypes and the ε4 allele are associated with an elevated risk of HS. These results highlight the potential role of APOE genotypes in HS susceptibility and warrant further investigation. Show less

This study aims to systematically investigate the multi-target mechanisms of cobalamin in the treatment of ischemic stroke using network pharmacology and molecular docking approaches. We screened databases to identify the targets of cobalamin and performed intersected with with ischemic stroke-related targets to construct a “drug-target-disease” interaction network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to identify key biological processes and signaling pathways. Additionally, molecular docking simulations were performed to assess the binding affinity between cobalamin and hub proteins. Molecular dynamics (MD) simulations were used to assess the stability of the protein–ligand complexes over a 500 ns simulation period. Additionally, ADME (Absorption, Distribution, Metabolism, Excretion) and blood–brain barrier (BBB) permeability predictions were made using ADMETlab 3.0 and admetSAR 3.0. A total of 95 therapeutic targets of cobalamin for ischemic stroke were identified. Network analysis and molecular docking highlighted eight core targets—ALB, TIMP1, PLG, FN1, AGT, SERPINE1, APOE, and SPP1—with high binding affinities to cobalamin. GO analysis suggested that cobalamin regulates inflammatory responses, post-translational modifications, complement binding, and lipoprotein particle binding. KEGG analysis identified complement and coagulation cascades, the PI3K/AKT pathway, and inflammation-related signaling as central to its therapeutic effects. Molecular docking showed strong binding to ALB and TIMP1, which was further confirmed by MD simulations, with minimal conformational changes. The PLG-cobalamin complex exhibited more fluctuations. ADME analysis revealed low passive permeability, particularly across the blood–brain barrier, but moderate distribution and high plasma protein binding. This study provides evidence that cobalamin may offer neuroprotective effects in ischemic stroke by interacting with key target proteins involved in coagulation, inflammation, and lipid metabolism. The findings highlight the potential of cobalamin as a therapeutic agent, although its limited ability to cross the blood–brain barrier may restrict its oral use. Further experimental validation and development of suitable delivery methods are needed to fully realize cobalamin’s potential in stroke therapy. The online version contains supplementary material available at 10.1038/s41598-026-41564-6. Show less

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer's disease (AD) mouse models, partly by upregulating apolipoprotein E ( Show less

Aortic dissection is a life-threatening cardiovascular disease whose complex cellular pathophysiology is studied using various mouse models. To systematically evaluate their fidelity, we performed cross-species single-cell RNA sequencing, integrating data from human aortic dissection with five mouse models (BAPN, Ang-II, Ang-II apoE Show less

We investigate whether common circle of Willis (CoW) variants relate to cerebral blood flow (CBF) characteristics among aging adults. Vanderbilt Memory and Aging Project participants free of clinical stroke ( Show less

Untargeted mass spectrometry remains underutilised for blood-based biomarker discovery in dementia research from large cohorts, where affinity-based approaches dominate. To address this, we examined mass-spectrometry-derived proteomic correlates of cognitive function, genetic predisposition to cognitive health, Show less

Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology. Show less

Periodontitis is implicated in a range of systemic conditions, including cardiovascular disease, diabetes, and respiratory disorders. Emerging evidence suggests a link between periodontal infection, inflammation, and the neurodegenerative process of Alzheimer's disease (AD). This paper aimed to systematically review observational studies examining the association of periodontal pathogens and their inflammatory products with AD neurodegeneration. The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO - No. CRD42020150043). Methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search (PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Web of Science, Scopus, Cochrane Library, grey literature) was conducted until September 2025 with no language or date restrictions. Two independent reviewers screened and extracted data. The risk of bias was assessed via the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS‑E) tool. Of 1,421 identified citations, eight studies met the inclusion criteria. Participant numbers ranged from 349 to 2,191, and ages ranged from 40 to 90 years old. Meta‑analysis was not feasible due to methodological heterogeneity. Risk of bias was moderate in five studies and serious in three. Findings indicated that higher serum IgG antibodies to periodontal pathogens and elevated inflammatory mediators, notably tumor necrosis factor-alpha (TNF‑α), correlated with greater cognitive decline and markers of AD neurodegeneration, including MRI outcomes and APOE ε4 status. In conclusion, the current body of evidence suggests a potential association between periodontitis‑related inflammatory mediators, particularly TNF‑α, and elevated antibody responses to periodontal pathogens with AD progression. However, causality remains unestablished. Future prospective cohort and interventional studies are warranted to clarify the role of periodontal infection and inflammation in AD and to guide clinical strategies that may improve outcomes in AD populations. Show less

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has been implicated in vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signaling of M1 macrophages and if its neutralization with alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. ApoE Alirocumab reduced plaque lesion (0.42-fold; PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in patients with ACS, independently of LDL-C levels. PCSK9 may directly promote macrophage-driven inflammatory responses through the TLR4-NFκB-NLRP3 signaling, but its neutralization with alirocumab attenuated this inflammatory axis and limited atherosclerotic progression, supporting an anti-inflammatory benefit secondary to PCSK9 inhibition. Show less

Chronic obstructive pulmonary disease (COPD) is a systemic condition with comorbidities beyond the lung (eg, cardiovascular and metabolic disorders), and gastrointestinal (GI) disorders are also common. The shared genetic basis of COPD-GI comorbidity and its mediating factors remain unclear. We hypothesized that COPD and GI diseases share pleiotropic genetic architecture implicating lipid-metabolic pathways, with smoking mediating part of the association. We analyzed publicly available European-ancestry GWAS summary statistics for COPD (Global Biobank Meta-analysis Initiative), 15 GI diseases (FinnGen), and smoking phenotypes (UK Biobank). Genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Multi-trait analysis of GWAS (MTAG) boosted COPD discovery by leveraging genetically correlated GI traits. We integrated locus-to-gene mapping with multi-tissue expression quantitative trait loci (eQTL) and plasma protein quantitative trait loci (pQTL) evidence to prioritize shared loci, genes, and proteins. Bidirectional two-sample Mendelian randomization (MR) tested causal directions, and two-step mediation MR evaluated smoking. COPD showed significant genetic correlation with nine GI diseases. We identified six comorbidity-associated loci (three with CADD > 12.37) and 13 unique candidate pleiotropic genes; APOE was supported by proteomic evidence. Enrichment analyses highlighted lipid-metabolism pathways. MR suggested COPD increases risk of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), acute appendicitis, and gastric ulcer, while diverticular disease showed reverse causality toward COPD. Smoking partially mediated the COPD effect on GERD, acute appendicitis, and gastric ulcer. COPD and multiple GI disorders share a distributed pleiotropic genetic basis within the broader systemic comorbidity spectrum of COPD. Multi-omics evidence supports a genomic pulmonary-intestinal axis in which lipid metabolism and smoking-related mechanisms contribute to COPD and GI comorbidity, providing targets for risk stratification and potential intervention. Show less

Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals at high risk of progression is crucial for public health strategies. The INTERCEPTOR project included 398 MCI individuals. Baseline assessment included harmonized procedures for sociodemographic, clinical, neuropsychological, genetic (apolipoprotein E), cerebrospinal fluid (amyloid beta tau), electroencephalogram (brain connectivity), magnetic resonance imaging (hippocampal volumetry), and fluorodeoxyglucose positron emission tomography. The baseline and follow-up were completed by 351 individuals with MCI with neuropsychological tests every 6 months for 3 years. Dementia developed in 104 individuals (29.6%), including 85 (22.4%) who met core clinical criteria for probable and possible Alzheimer's disease dementia. A Cox model combining clinical and sociodemographic data achieved a concordance index of 72%, which increased to 82% when neuropsychology and biomarkers were added. The INTERCEPTOR nomogram represents a tool for predicting dementia progression risk, supporting public health strategies, including screening for risk assessment and risk/benefit ratio in innovative treatments. Show less

The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. ClinicalTrials.gov Identifier: NCT03802396. Show less

The rare APOE3-Christchurch (APOE3Ch) variant is linked to resistance against PSEN1 p.E280A-driven autosomal dominant Alzheimer's disease (AD). Recent studies in AD mouse models have demonstrated an effect of APOE3Ch in reducing tau pathology and tau propagation, yet its effects on amyloid pathology and related toxicity are not fully understood. While prior studies have reported reduced amyloid pathology with APOE3Ch, we extended this knowledge by investigating how astrocyte-specific expression of APOE3Ch impacts amyloid pathology and related responses in 5xFAD mice, an amyloid mouse model. Using adeno-associated virus (AAV)-mediated gene delivery, we overexpressed APOE3 or APOE3Ch in astrocytes of 5xFAD mice at the neonatal stage, then analyzed their effects during the advanced stage of amyloid pathology. Astrocytic APOE expression significantly reduced amyloid burden, neuritic dystrophy, and gliosis compared to GFP controls. Notably, astrocytic APOE3Ch expression, relative to APOE3, markedly lowered oligomeric Aβ levels and promoted the formation of more compact, fibrillar plaques, suggesting a shift toward a less toxic aggregation profile. Transcriptomic profiling of cortical tissue revealed broad downregulation of immune-related and proteostatic pathways. These findings indicate that astrocytic APOE3Ch sufficiently attenuates Aβ pathology and related toxicity, supporting its potential as a therapeutic modifier for AD. Show less

Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population. To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E (APOE) genotypes. This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024. Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote. Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure. Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (-1.1 [4.2]). In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk. Show less

Alzheimer's disease (AD) is a devastating neurodegenerative disorder driven by complex interactions between neuroinflammation, immune dysregulation, metabolic impairment, and disrupted synaptic plasticity. Emerging evidence highlights maladaptive microglial activation, chronic cytokine signaling (including IL-1β, TNF- Show less