OBJECTIVE:Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. METHOD:Former American football players (n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ1-42, p-tau181, t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. RESULTS:Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. CONCLUSIONS:SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

INTRODUCTION:Data are needed to inform best practices for disclosing apolipoprotein E (APOE) results given increasing indications for testing. METHODS:CONNECT4, a multi-center, randomized trial (NCT02978729) compared disclosure of APOE genotype by videoconference or telephone among cognitively unimpaired adults 60-75 years of age. Outcomes were collected at baseline, 2-7 days, 6 weeks, and 6 months. RESULTS:A total of 301 participants were randomized to telephone and 297 to videoconference disclosure. There were no significant differences between arms for primary or secondary patient-reported outcomes. Moderator analyses found that videoconference reduced depressive symptoms more for older participants (70-75 year), whereas teleconference reduced depressive symptoms more for younger participants (60-64 years) and videoconference increased knowledge for non-White participants as compared to White participants. DISCUSSION:These data suggest that both telephone and videoconference are reasonable options for disclosure of APOE genotype in cognitively unimpaired individuals. Videoconference disclosure may have some benefits for certain demographic groups.

INTRODUCTION:Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS:We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau-PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS:Cortical regions with lower typical GM MWF showed higher tau-PET uptake (β = -0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau-PET covariance (β = -0.238, p < 0.001). Higher typical FC was associated with higher tau-PET covariance (β = 0.447, p < 0.001). DISCUSSION:In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

INTRODUCTION:Repetitive head impacts (RHIs) have been linked to later life neurodegeneration, yet the in vivo structural correlates of cumulative biomechanical loading remain unclear. We examined whether regional ventricular morphology in former American football players reflects exposure burden and traumatic encephalopathy syndrome (TES) classification. METHODS:Participants included 170 male former football players and 54 age-matched asymptomatic male controls from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Subject-specific manual segmentation quantified lateral ventricle, inferior horn, third ventricle, and fourth ventricle volumes. Group and exposure associations were tested using generalized least squares models. RESULTS:Former players showed larger left inferior lateral ventricle volume than controls, with the largest effects among professional players. Greater cumulative linear and rotational acceleration exposure was associated with enlargement across lateral ventricular and inferior horn regions. DISCUSSION:Regional ventricular enlargement may represent an in vivo marker of cumulative biomechanical loading after RHI exposure.

Importance:Apolipoprotein E ( APOE ) ε4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE ε4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE ε4 status in US adults without diabetes. Objective:To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE ε4 carriers and non-carriers. Design Setting and Participants:Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults >50 years with hypertension and increased cardiovascular risk, but without diabetes, prior stroke, or dementia. Primary cognitive follow-up ended July 2018. Participants were further followed with telephone-based outcome assessment from 2019 through 2023. Interventions:Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg). Main Outcomes and Measures:The primary outcome was all-cause probable dementia. Secondary outcomes were mild cognitive impairment (MCI); MCI or dementia; MCI, dementia, or death; and all-cause mortality. APOE ε4 status was the primary effect modifier. Results:Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% ε4 carriers); 7,733 (82.6%) had both genotype and outcome data (mean age, 68 years; 36% female; 28% Non-Hispanic Black). Over a median follow-up of 5.1 years, dementia rates (intensive vs standard) were 9.7 vs 13.2 per 1,000 person-years among ε4 carriers (hazard ratio [HR], 0.73; 95% CI, 0.51-1.04) and 6.1 vs 6.7 among non-carriers (HR, 0.91; 95% CI, 0.67-1.23; P-interaction = .35). Four-year risk differences were -1.7% (95% CI, -3.4% to 0%; number needed to treat, 59) among carriers and 0.2% (95% CI, -0.6% to 1%) among non-carriers (P-interaction = .045). Patterns were similar for the composite of MCI or dementia; effects on MCI were similar between APOE ε4 subgroups. Conclusions and Relevance:Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE ε4 carriers than non-carriers; relative effects were similar. These findings may inform APOE ε4-stratified blood pressure management for dementia prevention. KEY POINTS:Question: What is the effect of intensive vs standard systolic blood pressure (SBP) control on incident dementia by APOE ε4 status? Findings: In SPRINT, intensive vs standard SBP control yielded a significantly larger 4-year absolute risk reduction in dementia among APOE ε4 carriers (-1.7%) than non-carriers (0.2%; P-interaction = .045); the relative-scale interactions were directionally consistent but not significant. Meaning: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute benefit among APOE ε4 carriers than non-carriers; relative benefits were similar. APOE ε4 status may inform risk-stratified blood pressure management for dementia prevention.

INTRODUCTION:Plasma phosphorylated tau (p-tau), particularly p-tau217, is a highly specific biomarker of Alzheimer's disease (AD) pathology. However, plasma p-tau217 can be elevated in rare non-AD conditions. Brain-derived (BD) p-tau217 may reduce these off-target effects, but its performance against neuropathology has not been evaluated. METHODS:We compared p-tau217, BD p-tau217, their amyloid beta 42 (Aβ42) ratios, BD p-tau217/p-tau217, and BD p-tau217/BD tau in end-of-life plasma from 288 neuropathologically characterized participants using a fully automated immunoassay. Biomarkers were assessed against National Institute on Aging-Alzheimer's Association (NIA-AA) classification, Thal phase, Braak stage, cognitive decline, and tau-PET (positron emission tomography). RESULTS:All markers tracked neuropathological severity, with BD p-tau217 having larger fold-changes than p-tau217 but BD p-tau217/Aβ42 enhancing this further. BD p-tau217/BD tau achieved the highest area under the curve (AUC) for distinguishing Intermediate/High from Not/Low AD neuropathological change (ADNC) (0.89 vs 0.82 for p-tau217). Although BD p-tau217/p-tau217 showed smaller fold-changes, it had the strongest association with continuous tangle burden in AD (R2 = 0.68) and best predicted Clinical Dementia Rating Sum of Boxes (CDR-SB decline) (R2 = 0.26). DISCUSSION:BD p-tau217 and BD-based ratios enhance dynamic range and prognostic performance while maintaining diagnostic accuracy, supporting further clinical evaluation.

Importance:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

The term “dementia” carries a stigmatic burden that can undermine its clinical utility. Here we argue it should be retired because its continued use constitutes a public health harm by threatening personal identity, deterring care-seeking, discouraging research participation, and contributing to avoidable suffering. Zuendel et al. discuss the stigmatic burden of the term “dementia” and how this can undermine its clinical utility. They argue it should be retired because its continued use constitutes a public health harm by threatening personal identity, deterring care-seeking, discouraging research participation, and contributing to avoidable suffering.

Background:Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods:Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE-ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results:Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion:TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Background:Plasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimer's disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants. Methods:Plasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid ≥24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC. Results:BD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055). Conclusion:BD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.

Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

INTRODUCTION Accurate clinical diagnosis of neurodegenerative diseases remains challenging, particularly when individuals have mixed pathologies. We implemented the generalizable protein-based neurodegenerative disease artificial intelligence (GPND-AI) classifier using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel to classify Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and healthy controls, while disentangling mixed pathologies.METHODS Proteomic and clinical information from the Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight-ADRC) and Movement Disorder Clinic were used to train and test the GPND-AI classifier. External validation was performed in a Banner Sun Health Research Institute cohort and additional Knight-ADRC samples with neuropathologically confirmed diagnoses.RESULTS GPND-AI identified 15 proteins that achieve an area under the curve (AUC) of 0.955 and 92.3% accuracy across five diagnostic categories. In validation cohort, predicted co-pathologies significantly correlated with clinical characteristics.DISCUSSION GPND-AI identified a 15-protein panel that accurately classifies individuals across the four major neurodegenerative diseases. Validation against neuropathology-confirmed diagnoses supports the utility of proteomics-based approaches for mapping disease-specific and co-existing neurodegenerative processes.

Abstract Importance Patients are increasingly learning Alzheimer’s disease (AD) genetic and biomarker results through electronic health portals. Evaluation of alternative scalable delivery models for return of AD risk information is needed to best support patient understanding and psychological well-being. Objective To determine whether a patient-centered digital platform is comparable to clinician-mediated telehealth sessions for returning APOE and plasma pTau-217 results on outcomes of knowledge and psychological well-being. Design The Evaluation of Self-Mediated Alternatives for Risk Testing Education and Return of Results (eSMARTER) study was a noninferiority trial of a patient-centered digital platform compared to clinician-mediated disclosure of APOE genotype and optional pTau-217 disclosure. Setting Decentralized, fully remote trial enrolled participants in the contiguous United States (U.S.) between October 2024 and February 2025, with follow-up completed in November 2025. Participants Eligible participants were aged 60-80 and had previously undergone APOE genotyping (without disclosure) via the GeneMatch program, passed psychological screening, had internet access, and were English-speaking. Interventions Participants were randomized, 2:1, to the eSMARTER digital platform or clinician-mediated disclosure of APOE genotype. Following the 6-month post- APOE assessment, participants were offered optional pTau-217 disclosure via the same randomized modality. Main Outcomes and Measures Primary outcomes at 1-7 days following APOE disclosure included changes in anxiety, disease-specific distress, and AD-related knowledge within a priori non-inferiority margins. Results 674 persons (mean [SD] age 68 [4.7] years; 451 [67%] female; mean [SD] telephone MoCA=19 [2]) were eligible and provided demographic information. 651 participants were randomized to clinician-mediated (n=216) or digital disclosure (n=435) and completed APOE disclosure (66 [10%] APOE4 homozygotes, 377 [58%] heterozygotes, 208 [32%] non-carriers). 604 participants completed the study; 500 completed optional pTau-217 disclosure. Baseline characteristics were balanced across groups. At 1-7 days following APOE disclosure, scores on AD-related knowledge, PROMIS Anxiety, and disease-specific distress measures met non-inferiority. Conclusions and Relevance Disclosure of APOE genotype by the eSMARTER digital platform is non-inferior to clinician-mediated telehealth disclosure. No significant between group differences were found following disclosure of pTau-217 results. Together, these results suggest that this digital platform may provide an evidence-based scalable approach for returning AD genetic and biomarker results. Trial Registration ClinicalTrials.gov Identifier NCT06459583

IntroductionTAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer’s Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.MethodsIn this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer’s Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.ResultsOur results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.DiscussionThis study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.

BACKGROUND:The Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial evaluated the biological, cognitive, and clinical effects of crenezumab, an anti-oligomeric and monomeric amyloid-beta (Aβ) monoclonal antibody, in 30-60-year-old PSEN1 E280A mutation carriers without cognitive impairment from the world's largest ADAD kindred, finding no significant treatment effects on Alzheimer's disease progression. This article describes baseline biomarker, cognitive, and clinical measurements and placebo-related longitudinal changes in the randomised prevention trial's mutation carrier and non-carrier groups. METHODS:Crenezumab and placebo-treated mutation carriers and placebo-treated non-carriers were assessed using amyloid and fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, plasma, and optional tau PET and cerebrospinal fluid (CSF) biomarker, cognitive, and clinical measurements over 5-8 years. FINDINGS:94% of the 252 kindred members (85 crenezumab-treated mutation carriers, 84 placebo-treated carriers, and 83 placebo-treated non-carriers) completed the trial. 55% of the carriers had baseline PET evidence of substantial Aβ plaques. 32.9% and 6.8% of amyloid PET-positive and PET-negative carriers, respectively, 36.5%, 13.2%, and 0% of pTau217-positive, pTau217-intermediate, and pTau217-negative carriers, respectively, and no non-carriers became cognitively impaired over the next 5 years. Carriers were distinguished from non-carriers by several baseline and longitudinal Aβ, tau, neurodegenerative, and inflammatory biomarker measures, but not by CSF oligomeric Aβ measurements. INTERPRETATION:Despite the absence of significant treatment effects, these findings and the trial itself continue to inform the course of preclinical ADAD, advance Alzheimer's disease prevention research, and provide a shared resource of data and samples for the field (ClinicalTrials.gov ID: NCT01998841; trial completed). FUNDING:National Institute on Aging, Banner Alzheimer's Institute, Genentech, Inc., and F. Hoffmann-La Roche Ltd.

Abstract Advances in biomarker technology, digital cognitive assessments, and amyloid‐targeting therapies have redefined the opportunities for accurate and early diagnosis and care of Alzheimer's disease (AD). These advances also create new possibilities for intervention before the onset of cognitive impairment. This paradigm shift has increased the focus on Stages 1 and 2 of AD, in which individuals are cognitively unimpaired but exhibit biological evidence of disease. While early identification of AD offers an opportunity to intervene early to delay progression and preserve quality of life, it also presents complex challenges related to communicating diagnostic results to patients and their families, contextualizing the cost effectiveness of early diagnosis and treatment, and implementation of and equitable access to treatments. Recent, successfully enrolled, preclinical AD trials highlight the complex strategies required to identify asymptomatic, biomarker‐positive individuals on a large scale, and demonstrate critical knowledge gaps in inclusion, follow‐up, and long‐term outcome measurement. The Spring 2025 Alzheimer's Association Research Roundtable (AARR) meeting brought together academics, clinicians, industry, and regulatory leaders to exchange perspectives on current challenges, key learnings, and potential strategies for identifying and treating individuals in very early stages of AD, effectively and safely. This paper presents key takeaways from the Spring 2025 AARR meeting. Highlights New criteria for Alzheimer's disease (AD) enable early identification of AD pathology. Blood tests and digital cognitive assessment tools may facilitate early and personalized care. Plasma biomarkers may be scalable in clinical settings but need confirmation or follow‐up assessments in those individuals with equivocal results. Early therapy shows best results in people with lower initial amyloid and tau burden.

Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched controls and prevalent cases, and/or (2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example. Participants in the All of Us Research Program over the age of 49 at enrollment (n = 229,722) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). ADRD diagnoses were determined using available electronic health records and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression and presented as adjusted generalized ratios (AGR). The mean age of the cohort was 64 ± 9 years, and it was 57

BACKGROUND AND OBJECTIVES:The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. METHODS:Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR2) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. RESULTS:Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR2 = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR2 = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR2 = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR2 = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR2 = 0.05 [0.003-0.14], p = 0.007; MD: ΔR2 = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. DISCUSSION:In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

The 2025 Leon Thal Summit convened an international panel of clinicians, neuroscientists, neuropathologists, and neuroimaging specialists to evaluate the current state of biomarker development for chronic traumatic encephalopathy (CTE) and to outline priorities for advancing translational research for this important area. Discussions integrated emerging findings from longitudinal cohorts, new molecular and neuroimaging approaches, expanding post mortem evidence, and evolving insights into exposure biology and genetic modifiers. Consensus themes emphasized the need for biomarkers that detect CTE-specific tau proteoforms, integration of existing imaging and fluid markers into traumatic encephalopathy syndrome research criteria, and refinement of multimodal magnetic resonance imaging and blood-based tools that capture early CTE pathology. The group underscored the importance of coordinated, longitudinal clinicopathological studies and collaborative research frameworks to validate candidate biomarkers and accelerate progress toward accurate diagnosis, disease monitoring, and therapeutic development for individuals at risk for or exhibiting signs of CTE.