Carrillo, Marı́a C.

Abstract Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep‐rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14–15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.

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.

INTRODUCTION Recent work has identified unique cognitive profiles for early‐onset Alzheimer's disease (EOAD) relative to late‐onset Alzheimer's disease (LOAD), however, examination has been limited in determining whether the association between age and cognitive severity at presentation also differs across conditions. METHODS A series of linear spline regression models was conducted across baseline cognitive data from 325 EOAD and 314 LOAD participants, after accounting for education, sex, and apolipoprotein ε4 status. RESULTS Significant differences existed in the relationship between baseline age and cognitive performance between EOAD and LOAD samples for Processing Speed/Attention, Executive Functioning, and Episodic Immediate Memory. Younger participants from both EOAD and LOAD groups performed disproportionately worse on non‐amnestic cognitive domains, with this occurring to a greater extent in EOAD than LOAD. DISCUSSION In the age of disease‐modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants each displayed cognitive impairments relative to same‐aged peers across most domains. Both groups displayed positive relationships between impairment among non‐amnestic cognitive domains and baseline age. This relationship displayed a significantly greater effect in EOAD than LOAD, with domains of Processing Speed/Attention and Executive Functioning skills being the most pronounced. Of those participants developing AD, age displayed a disproportionate impact on their symptom onset.

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.

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 design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti‐amyloid, disease‐modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease‐modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well‐defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers. Well‐defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design. Staging criteria and biomarkers must be coordinated to yield high‐quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.