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Abstract BACKGROUND First held in 2020, the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) is a program to train the next generation of Alzheimer's disease (AD) and related dementias (AD/ADRD) clinical trialists. METHODS IMPACT‐AD includes didactic, workshop, and small group components. RESULTS IMPACT‐AD has trained 18 alumni–scholars (accepted from 424 applicants), of whom 67% were female. Forty‐eight (26%) were the first in their family to attend college. Scholars included individuals from all racial and ethnic groups. Each year, participants demonstrated increased learning about AD/ADRD clinical trials through a pre/post‐test model of knowledge assessments. Among those completing annual follow‐up surveys, >84% remain in AD/ADRD trials careers, and 80% have experienced career advances or milestones. In the latter group, > 90% indicated that participating in IMPACT‐AD contributed to this career growth. DISCUSSION IMPACT‐AD is a novel educational program that is achieving its goals. Highlights Over 5 years, the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) has trained 188 scholars. The course has been accessible to a broad range of trainees who were diverse in professional and demographic backgrounds. Objective assessments indicate that participants gain knowledge through participation. Eighty‐four percent of trainees have remained in Alzheimer's disease and related dementias (ADRD) trials careers. Eighty percent of alumni have experienced career advances; nearly all indicated that participating in the course contributed to their success.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

AbstractINTRODUCTIONCerebral microhemorrhages (CMHs) are detectable by magnetic resonance imaging (MRI). CMHs in deep brain regions are linked to hypertensive vasculopathy, while those in lobar regions with amyloid beta (Aβ) deposition in blood vessels. This study aims to determine the association between anti‐thrombotic treatment and CMH prevalence among cognitively asymptomatic adults, and to assess the role of Aβ markers, apolipoprotein E (APOE) ε4 carrier status, and cardiovascular risk factors in CMH development.METHODSUsing baseline data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, we examined CMH presence via 3T MRI, along with medication use, APOE ε4 carrier status, medical history, and blood pressure.RESULTSOur analysis showed a significantly higher prevalence of CMHs in the A4 cohort (17.3%) compared to the LEARN cohort (2.6%).DISCUSSIONFactors such as male sex, age, Aβ markers, and APOE ε4 status were significantly associated with higher CMH prevalence in the A4 cohort. However, anti‐thrombotic treatment did not show association with overall CMHs.Highlights Male sex, age > 75, amyloid beta (Aβ) burden, and apolipoprotein E (APOE) ε4 homozygosity are significantly associated with higher prevalence of CMHs (cerebral microhemorrhages) in a cohort of cognitively asymptomatic individuals. Male sex, age > 75, Aβ burden, and APOE ε4 homozygosity are significantly associated with higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals. Anti‐platelet or anti‐coagulant usage were not associated with an increased prevalence of CMHs in either brain location or overall, in a cohort of cognitively asymptomatic individuals. History of a lipid disorder is associated with a higher prevalence of lobar CMHs in a cohort of cognitively asymptomatic individuals.

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248

Abstract INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

AbstractBackgroundThe Institute on Methods and Protocols for Advancement of Clinical Trials in Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) (IMPACT‐AD) is a novel multi‐disciplinary training program funded by the National Institute on Aging (NIA) and the Alzheimer’s Association for individuals seeking expertise in designing and conducting AD/ADRD trials. IMPACT‐AD offers a Professionals Track for investigators in a variety of trial roles and a Fellowship Track for future AD/ADRD clinical trial principal investigators.MethodTo evaluate long‐term training outcomes, alumni‐scholars from the 2020‐2022 courses (n = 109) were surveyed via REDCap in January 2024. Measured constructs encompassed alumni‐scholar retention in AD/ADRD trials, promotions received, project funding, and the status of the protocol developed during the course, including whether it had been funded, conducted, and published (Fellowship Track). Alumni‐scholars rated the extent to which the course facilitated their achievements (not at all, somewhat, very much).ResultOf the 63 (58%) of alumni‐scholars who responded (48% Professional Track, 69% Fellowship Track), 44 (70%) were female. 21 (33%) identified as African American/Black, Asian, Multiracial or of another race; 7 (11%) self‐identified as Hispanic/Latino ethnicity. 5 (8%) identified as LGBTQ+. 12 (19%) indicated being first in their families to attend college.Since program completion, 87% of survey participants maintained a career in ADRD clinical trials. A majority (63%) experienced a promotion or career advancement, with all indicating that IMPACT‐AD “somewhat” or “very much” contributed. Less than half of scholars (43%) had received project funding since IMPACT‐AD, but 74% of those had credited IMPACT‐AD at least somewhat for this achievement. Among the 34 Fellowship Track respondents, 15 (44%) indicated that the trial proposed at IMPACT‐AD had received funding, 14 (41%) reported its completion, and 5 (15%) had published its results. Nearly all respondents (%) reported assuming additional roles and responsibilities within their current title. In total, 92% of surveyed participants reported at least one positive change across all measured categories.ConclusionIMPACT‐AD is effectively fulfilling its goals of training, nurturing, and diversifying a next generation of AD/ADRD trialists.

AbstractBackgroundScalable, efficient methods are needed to enroll diverse populations of older adults into AD observational studies and clinical trials. We evaluated preliminary feasibility of a novel, digital, culturally informed approach to recruit and screen participants for the Alzheimer’s Disease Neuroimaging Initiative (ADNI4).MethodsDigital advertising tailored towards Black/African American and Latinx older adults residing near six clinical ADNI sites directed potential participants to a recruitment website (Figure 1). They completed digital surveys of demographics, ADNI exclusion criteria, memory concerns and changes, self‐report cognitive impairment, and the Everyday Cognition Scale (ECog)‐12 item. Participants also completed Novoic Storyteller, a self‐administered speech‐based cognitive test. Digital assessment results were used to prioritize those from minoritized ethnocultural groups, with low educational attainment, and possible Mild Cognitive Impairment (MCI) for remote blood draw at local Quest phlebotomy centers to obtain AD plasma biomarkers. Completion rates and digital assessment performance were compared between minoritized and non‐minoritized groups.ResultsOf 989 participants recruited from digital advertising efforts who provided contact information, 230 (23%) signed consent, and 183 (19%) completed at least one remote assessment (Table 1). 45% were from minoritized ethnocultural groups, 4% had ≤12 years of education, and 53% had evidence of possible MCI from digital assessments. 34 (19%) were referred to the plasma biomarker study, of which 21% completed blood draw. Compared to non‐minoritized participants, minoritized participants were less likely to report a diagnosed cognitive impairment or a family history of AD, less likely to have ECog scores indicative of MCI, and less likely to have a study partner. Minoritized participants had lower ECog and Novoic Storyteller completion rates.ConclusionRecruitment and assessment of a diverse cohort of older adults, including those with possible cognitive impairment, is feasible using culturally informed digital advertising. Improving study engagement and achieving educational diversity are key challenges. This approach is now being scaled up to facilitate recruitment into in‐clinic ADNI4, with the goal of enrolling 500 new participants: >50% from minoritized groups, 40% with MCI, and 80% amyloid positive across diagnostic groups. This approach can be adapted to facilitate recruitment and longitudinal assessment in other AD studies and trials.

AbstractBackgroundAnti‐amyloid immunotherapies modestly slow disease progression in early symptomatic AD; addition of other therapeutic modalities may be necessary to achieve larger treatment effects. Therapies that directly target tau can potentially produce substantial clinical benefit because the accumulation of insoluble tau protein is strongly correlated with the progression of AD. Which tau therapies are likely to be efficacious, whether or not to combine them with anti‐amyloid therapies, and which individuals are most likely to benefit are important unresolved questions that would require multiple parallel design trials to answer. Platform (umbrella) trials test multiple therapies in the same trial, allowing for substantial savings in time, cost and participant burden.MethodATP is a new NIH‐funded Phase 2 clinical trial platform that will be conducted as part of the AD Clinical Trials Consortium (ACTC) in partnership with industry and philanthropic groups. The goal is to investigate the effects of tau therapies on the biological hallmarks of AD including insoluble and soluble tau species, amyloid and other biomarkers of neurodegeneration. ATP will initially evaluate two tau therapies alone or in combination with an anti‐amyloid therapy. 900 participants with late preclinical or early prodromal AD (CDR 0 or 0.5) will be randomized to six arms for two years of blinded treatment, followed by an optional open label extension (Figure 1). At least 20 percent of participants will be from underrepresented groups. The primary endpoint is 18F MK6240 tau PET, with key secondary endpoints including plasma P‐tau and MTBR243‐tau, amyloid PET and clinical assessments (CDR‐SB, PACC5). Inclusion criteria are based on plasma P‐tau217, clinical status and regional 18F MK6240 uptake.ResultTwo tau therapies and an anti‐amyloid therapy have been chosen for inclusion in ATP and startup is underway. The final design, choice of therapies and design as well as plans for inclusion of additional tau therapies after the trial begins and other details will be presented.ConclusionThe ATP is a six arm factorial design platform trial that is planned to begin in late 2024 or early 2025 that will support efficient development of tau and combination therapies for early, sporadic AD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐ score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐ score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.