Edelmayer, Rebecca M.

Abstract Background In recent years, blood‐based biomarkers (BBMs) have transformed the diagnostic landscape of Alzheimer’s disease (AD), with some now approaching readiness for clinical implementation. This progress aligns with the growing importance of accurate early diagnostics and availability of anti‐Aβ therapies for the treatment of early symptomatic AD, reinforcing the need for more rapid and early diagnostic capabilities. To address this need, the Alzheimer’s Association convened a multidisciplinary panel of clinical experts, subject‐matter specialists, and guideline methodologists to conduct a systematic review and develop evidence‐based recommendations for the use of BBMs in the diagnostic evaluation of AD. The scope of this guideline is focused on individuals with cognitive impairment ‐ either MCI or dementia ‐ who are undergoing diagnostic assessment in secondary or tertiary care settings. Method The panel conducted a systematic review to assess BBMs' diagnostic test accuracy in detecting amyloid pathology for triaging (≥90% sensitivity, ≥75% specificity) and confirmatory (≥90% sensitivity and specificity) diagnostic workup. The BBMs of interest included plasma p ‐tau and Aβ tests measuring the following analytes: p ‐tau217, % p ‐tau217, p ‐tau181, p ‐tau231, and Aβ42/Aβ40 ratio. The reference standard tests included CSF, amyloid PET, or neuropathology examination. The panel applied the GRADE approach to assess the certainty of the evidence and the GRADE Evidence‐to‐Decision Framework to develop its recommendations. Result Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were evaluated. Using predefined decision thresholds, the panel determined whether each test has 1) sufficient diagnostic test accuracy to be used as a triaging test where a positive test is to be confirmed by PET or CSF, 2) sufficient diagnostic test accuracy as a confirmatory test to replace PET or CSF, or 3) insufficient diagnostic test accuracy to recommend current use in clinical practice. Recommendations will be provided in case any BBMs met a priori DTA thresholds. Conclusion BBMs can improve early AD diagnosis and expand access to disease‐modifying therapies. Evidence‐based guidelines are key to standardizing their use and will be updated as new evidence and applications emerge.

Abstract BACKGROUND This systematic review and meta‐analysis aimed to assess the diagnostic test accuracy of blood‐based biomarkers (BBMs) for detecting Alzheimer's disease (AD) pathology in cognitively impaired individuals in specialized care settings. The overarching goal is to inform the development of a clinical practice guideline, led by the Alzheimer's Association, for use in clinical practice. METHODS A systematic search of MEDLINE, Embase, and Cochrane Library was conducted from January 2019 to November 2024. Studies evaluating the diagnostic test accuracy of plasma phosphorylated tau (p‐tau) and amyloid beta (Aβ) tests (p‐tau217, %p‐tau217, p‐tau181, p‐tau231, and Aβ42/Aβ40) compared to reference standard tests (cerebrospinal fluid [CSF] AD biomarkers, amyloid positron emission tomography [PET], or neuropathology) in individuals with cognitive impairment (mild cognitive impairment or dementia) in specialized care settings were included. Pooled diagnostic test accuracy measures were calculated, including sensitivity, specificity, and likelihood ratios. Across a range of pre‐test probabilities, we evaluated how much a positive or a negative test result would lead to a change in the probability of having amyloid positivity (post‐test probability). All analyses were conducted for each test within each biomarker. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to evaluate the risk of bias, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were examined. When evaluated using a single cut‐point, the diagnostic test accuracy varied considerably across tests: the pooled sensitivity ranged from 49.3% (95% confidence interval [CI]: 41.2–57.4) to 91.4% (95% CI: 86.6–94.6), and the pooled specificity ranged from 61.5% (95% CI: 45.6–75.3) to 96.7% (95% CI: 87.8–99.2). Differences in post‐test probability based on a range of pre‐test probabilities varied greatly across tests. Furthermore, the certainty of evidence across tests ranged from moderate to very low. Most included studies were judged to be at high risk of bias, particularly in domains related to patient selection, index test conduct, and reference standard. CONCLUSION This systematic review provides a comprehensive synthesis of the current evidence on the diagnostic accuracy of BBMs for detecting AD pathology in cognitively impaired individuals in specialized care settings. The findings serve as a foundation for an accompanying clinical practice guideline that provides evidence‐based recommendations for BBM use in the clinical diagnostic pathway. Given continuous developments in this rapidly evolving field, ongoing evaluation will be critical to ensure the synthesized evidence and clinical guidelines remain up to date and maintain clinical relevance. Highlights This is the first comprehensive systematic review and meta‐analysis to evaluate the diagnostic accuracy of blood‐based biomarker (BBM) tests specifically in individuals with objective cognitive impairment seen in specialized care settings. Across 49 studies, BBM test performance varied widely. Pooled sensitivity ranged from 49.3% to 91.4% and specificity from 61.5% to 96.7%, depending on the analyte and assay platform. This review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess the certainty of evidence. This review served as the evidence base for the Alzheimer's Association's new clinical practice guidelines on BBMs, providing structured, evidence‐based guidance for implementing BBMs in the diagnostic workup of suspected Alzheimer's disease. The review underscores that BBM test performance is assay‐ and platform specific and advises clinicians and laboratory directors to interpret results in the context of the specific test used and integrate the results with a comprehensive clinical assessment.

Decades of research on biomarker identification and integration in Alzheimer’s disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the target population. We describe how these lessons are being applied in Parkinson’s disease, Huntington’s disease, multiple sclerosis, and psychotic disorders as use cases to inform biomarker-based approaches across central nervous system disorders.

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 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 Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

AbstractBackgroundThe rapid development of blood‐based biomarkers (BBMs) has improved Alzheimer’s disease (AD) diagnostics with some tests now potentially suitable for clinical use. This aligns with the clinical availability of anti‐Aβ immunotherapies for early symptomatic AD, where BBMs can help address the increasing need for more rapid and early diagnosis. Clinical practice guidelines (CPG) can help guide healthcare professionals in incorporating BBMs into their clinical practice. The Alzheimer’s Association is collaborating with methodologists and a panel of 11 clinical and subject‐matter experts to develop a CPG for specialists, informed by a systematic review, on the use of BBMs for AD.MethodThe panel drafted several clinical questions prioritizing two questions on the use of BBMs in cognitively impaired or cognitively unimpaired individuals as the populations of immediate interest. Plasma p‐tau and Aβ biomarkers tests are index tests, and amyloid PET imaging, neuropathology, and CSF are reference standards. Experts in the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach are conducting a systematic review of the diagnostic accuracy of BBMs index tests by searching three databases (Pubmed, Embase, Cochrane Library) and will include assessments of the quality of collected evidence to inform the panel’s decision‐making process. Patients/caregivers and key external organizations will be engaged throughout.ResultThis session will cover preliminary evidence for answering the two clinical questions. At the time of abstract submission, the search strategy resulted in 880 titles/abstracts for the study selection process. Data abstraction, analysis, and evidence development are pending. Recommendations for answering clinical questions will be developed after July 2024, and all recommendations will be finalized and published by early 2025.ConclusionThe integration of BBMs into clinical care offers the potential to improve earlier and more accurate AD diagnosis for a broader patient population and expand access to new AD therapies. The development of evidence‐based CPGs is a critical step forward in optimizing and standardizing the clinical use of BBMs. As the field of AD diagnostics and treatment continues to evolve, this CPG on the use of BBMs for AD will expand and be regularly updated to include new target audiences/settings, patient populations, and associated evidence.

Background: Cortical spreading depression (CSD) is a wave of depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex. CSD is believed to be the underlying mechanism of aura in migraine; however, whether CSD can elicit pain associated with migraine headache is unclear. Methods: Awake, freely moving rats were monitored for both CSD events and behavioral responses resulting from dural-cortical pinprick and/or KCl injection to the occipital cortex. Results: We observed tactile allodynia of the face and hindpaws, as well as enhanced Fos expression within the trigeminal nucleus caudalis (TNC) following CSD induced by KCl injection into the cortex, but not by pinprick. Application of KCl onto the dura elicited cutaneous allodynia and increased Fos staining in the TNC but did not elicit CSD events. Conclusions: These data suggest that sustained activation of trigeminal afferents that may be required to establish cutaneous allodynia may not occur following CSD events in normal animals.