Blood-Based Biomarker Guidelines for Alzheimer Disease Diagnosis

Blood-based biomarker testing may aid in diagnosing Alzheimer disease (AD) in specialized care settings, according to a newly published Alzheimer’s Association Clinical Practice Guideline in Alzheimer’s & Dementia.

Although cerebrospinal fluid (CSF) analysis and amyloid positron emission tomography (PET) are established tools for detecting AD pathology, their invasiveness, cost, and limited accessibility have driven interest in blood-based biomarkers as more practical alternatives.

A multidisciplinary panel reviewed 49 observational studies assessing plasma phosphorylated-tau (p-tau) and amyloid-beta (Aβ) assays, specifically p-tau217, p-tau217, p-tau181, p-tau231, and Aβ42/Aβ40 ratios, against reference standards of CSF biomarkers, amyloid PET, or neuropathology. The included studies encompassed 31 blood-based biomarker tests and a mean sample size of 560 participants (range, 70-2244). The average patient age across studies was 62.6 to 85.9 years, men comprised 33.8% to 60%, and APOE ε4 carrier prevalence ranged from 27.1% to 56.2%.

Diagnostic accuracy varied widely across assays, with pooled sensitivity ranging from 49.31% to 91.41%, and specificity from 61.54% to 96.72%. Tests meeting at least 90% sensitivity and 75% specificity were acceptable as triaging tools that could rule out AD pathology when negative, but would require confirmatory testing when positive. Tests meeting at least 90% for both sensitivity and specificity were deemed suitable as a confirmatory replacement for CSF or PET.

The panel issued 2 conditional recommendations concerning patients with objective cognitive impairment in specialized memory-care settings:

1. Use a high-sensitivity blood-based biomarker test as a triaging tool
2. Use a high-sensitivity, high-specificity blood-based biomarker test as a confirmatory diagnostic tool

A good practice statement emphasized that blood-based biomarker testing should follow a comprehensive clinical evaluation and be interpreted within the broader clinical context, with careful consideration of the pretest probability of AD.

Potential benefits include reduced invasiveness, improved patient acceptance, and increased diagnostic equity. Risks include false positives or negatives, inappropriate use in non-specialist settings, and variability in assay performance.

Limitations include low certainty for most tests, heterogeneity in study designs, lack of data on cost-effectiveness, and underrepresentation of primary care settings. The panel also noted that many commercially available blood-based biomarker tests do not yet meet accuracy thresholds, and real-world clinical performance workflows may differ from trial conditions.

The guideline is intended as a living document, with planned updates as new evidence emerges, particularly on multi-threshold testing strategies and biomarker combinations.

“…[T]hese 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,” the study authors concluded.

Disclosures: This research was supported by the Alzheimer’s Association.