Carrillo, María C.

Abstract INTRODUCTION Brief digital cognitive measures may be a valuable and scalable alternative to traditional tests for improving early detection and disease monitoring in patients with early‐onset Alzheimer's disease (EOAD). METHODS We examined the convergent, diagnostic, and neuroanatomical validity of Tablet‐based Cognitive Assessment Tool (TabCAT) tests in the multisite Longitudinal Early‐Onset Alzheimer's Disease Study. Four hundred seventy‐five participants from 16 sites (83 cognitively unimpaired participants, 146 individuals diagnosed with mild cognitive impairment [MCI], and 246 with mild dementia) underwent TabCAT testing, including two executive/attentional tasks (Match and Flanker) and two visuospatial tasks (Line Length and Line Orientation). RESULTS TabCAT tests showed good convergent validity with traditional pen‐and‐paper tests. Match was the most accurate TabCAT test in differentiating among clinical groups (controls vs. MCI vs. dementia) and predicting amyloid positron emission tomography (PET) positivity in clinically impaired participants. TabCAT tests were associated with regional tau PET patterns. DISCUSSION TabCAT digital measures have promise for frontline identification of patients with EOAD. Highlights Four hundred seventy‐five participants from 16 US sites underwent tablet‐based cognitive assessment. Digital tests assessed executive function and visuospatial abilities. Digital tests correlated with traditional pen‐and‐paper cognitive tests. Match (test of executive function) differentiated clinical groups. Digital tests were associated with amyloid positron emission tomography (PET) status and regional tau PET patterns.

Abstract As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau‐targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau‐targeting therapeutics, and interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials.

Abstract The landscape of Alzheimer's disease (AD) and related dementias (ADRD) diagnosis is evolving rapidly, driven by advances in disease understanding, biomarker tools, and disease‐modifying therapies. Modern diagnostic approaches emphasize biological precision, early detection, and dynamic frameworks that adapt to treatment‐induced changes in disease biology. These frameworks enable opportunities for personalized interventions—encompassing pharmacological and non‐pharmacological strategies—and for enhanced clinical trial design. However, implementing these advancements globally is influenced by diverse cultural, infrastructural, and regulatory factors. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis, held in Japan, provided a unique platform to explore these global dynamics, particularly from an Asian perspective. This article highlights key discussions from the conference, exploring the role of biomarker‐based diagnostic frameworks in shaping the future of AD/ADRD research, diagnosis, and treatment. We highlight regional challenges and successes and emphasize ethical considerations and practical strategies needed to ensure equitable access to diagnostic and therapeutic innovations. Highlights Advances in biomarkers are reshaping Alzheimer's disease diagnosis and treatment. Modern diagnostic frameworks highlight biological precision, early detection, and dynamic frameworks. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis explored challenges and opportunities in global biomarker implementation. The conference explored geographic‐specific impacts, focusing on Asia.

Abstract OBJECTIVE AND SCOPE A panel of clinicians, subject‐matter experts, and guideline methodologists convened by the Alzheimer's Association conducted a systematic review and formulated evidence‐based recommendations for using blood‐based biomarkers (BBMs) in the diagnostic workup of suspected Alzheimer's disease (AD) within specialized care settings. The scope focuses on individuals with objective cognitive impairment, including those with mild cognitive impairment (MCI) or dementia, who are undergoing evaluation by providers trained and experienced in memory disorders, where AD is the suspected underlying etiology. METHODS The panel conducted a systematic review to assess the diagnostic accuracy of BBMs in detecting AD pathology. The BBMs of interest included plasma phosphorylated‐tau (p‐tau) and amyloid‐beta (Aβ) tests measuring the following analytes: p‐tau217, ratio of p‐tau217 to non‐p‐tau217 ×100 (%p‐tau17), p‐tau181, p‐tau231, and ratio of Aβ42 to Aβ40. The reference standard tests included cerebrospinal fluid (CSF) AD biomarkers, amyloid positron emission tomography (PET), or neuropathology. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence and the GRADE evidence‐to‐decision (EtD) Framework to develop its recommendations. RECOMMENDATIONS The key recommendations in this Clinical Practice Guideline (CPG) are: (1) BBM tests with ≥90% sensitivity and ≥75% specificity can be used as a triaging test and (2) BBM tests with ≥90% sensitivity and specificity can serve as a substitute for amyloid PET imaging or CSF AD biomarker testing in patients with cognitive impairment presenting to specialized care for memory disorders. The panel cautions users of this guideline that there is significant variability in diagnostic test accuracy and many commercially available BBM tests do not meet these thresholds, especially using a single cutoff. Additionally, these tests do not serve as a substitute for comprehensive clinical evaluation by a healthcare professional and should be used only as part of a full diagnostic workup of patients with cognitive impairment presenting to specialized care settings, and with careful consideration of pretest probability of AD pathology. CONCLUSIONS AND PRACTICAL IMPLICATIONS This CPG provides performance‐based, brand‐agnostic recommendations for the use of BBMs in the diagnostic workup of suspected AD within specialized care settings. By linking recommendations to a systematic review and associated living updates, and using a robust and transparent methodology, the guideline ensures scientific rigor, adaptability, and sustained relevance as evidence evolves. Clinicians are encouraged to stay informed about emerging paradigms—such as biomarker combinations or ratios and multi‐threshold testing—that may further refine the diagnostic accuracy of BBMs as the field evolves.

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.

Abstract The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti‐amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future. Highlights The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid‐beta Targeted Treatments on Biomarkers and Clinical Endpoints.” The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load. Based on data from multiple phase 2 and 3 clinical trials of anti‐amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near‐normal levels is associated with positive changes in tau biomarkers and clinical endpoints. Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

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.