Tampi, Malavika P.

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Abstract Background Cognitive impairment often goes undetected by clinicians due to time constraints, limited expertise, and lack of standardized tools. Structured cognitive assessments improve detection accuracy compared to unstructured clinical judgment. In 2013, the Alzheimer’s Association published recommendations to help primary care clinicians incorporate cognitive assessments into the Medicare Annual Wellness Visit. Since then, advances in cognitive assessment tools, availability of disease‐modifying therapies, and shifting expectations around early diagnosis have highlighted the need for updated guidance. In response, the Alzheimer’s Association is developing an evidence‐based clinical practice guideline for cognitive testing in primary care, using the GRADE approach, informed by a systematic review of the best available evidence. Method A multidisciplinary panel formulated a clinical question to inform the development of this guideline. A systematic review was conducted (search range: 1999‐2024) to evaluate the diagnostic accuracy of ten cognitive tests (5‐Cog, AD8, GPCOG, IQCODE, Mini‐Cog, MIS, MoCA, QDRS, RUDAS, and SLUMS) for the early detection of cognitive impairment (including MCI and dementia), in adults aged 55+ in ambulatory settings. The panel also narratively summarized data on emerging digital tools. Result Forty‐one studies meeting eligibility criteria were included in the systematic review. Results were analyzed separately by test (including short‐IQCODE and short‐MoCA) and for primary care and for ambulatory clinic settings (e.g., neurology, memory disorder clinics), as well as for English and Spanish language, resulting in 21 separate analyses. Only three analyses, all related to MoCA, allowed for meta‐analysis. The panel will use the evidence to inform conditional recommendations for or against each specific test. Conclusion By evaluating the diagnostic performance of selected tests, this guideline aims to support healthcare professionals in primary care settings in effective triaging of individuals who may benefit from further cognitive evaluation. To enhance real‐world applicability, considerations such as administration time, ease of scoring, and diagnostic accuracy ‐ along with appropriate cut‐offs by race/ethnicity, education, and language ‐ should be prioritized. This guideline will be regularly updated over time to reflect emerging evidence and the needs of diverse populations.

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.

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.

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.