Machado, Luiza Santos

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 Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.