How do amyloid PET and CSF biomarker tests influence eligibility for FDA‑approved Alzheimer’s therapies?
Executive summary
FDA‑approved anti‑amyloid therapies for early symptomatic Alzheimer’s disease require evidence of brain amyloid pathology before initiation, and clinicians most commonly rely on amyloid PET imaging or cerebrospinal fluid (CSF) biomarker assays to provide that evidence [1] lecanemab-leqembi" target="blank" rel="noopener noreferrer">[2]. Both modalities are accepted in practice, have high concordance overall, but important performance limits, discordant cases, and evolving blood tests complicate real‑world eligibility decisions [3] [4] [5].
1. Why a biomarker matters: a gatekeeper for anti‑amyloid drugs
Since the arrival of disease‑modifying, amyloid‑targeting drugs, regulatory guidance and clinical practice demand biomarker confirmation of amyloid pathology before these treatments are started; this requirement exists because the therapies target amyloid and exposing amyloid‑negative patients to risks (including ARIA) without likely benefit is clinically unacceptable [1] [2] [6]. The FDA’s labeling for drugs such as lecanemab does not prescribe a single diagnostic tool, but the prescribing information explicitly requires confirmation of beta‑amyloid plaques, with amyloid PET and CSF assays named as typical ways to demonstrate that pathology [2].
2. Amyloid PET and CSF: complementary tests that serve the same gatekeeping role
Amyloid PET imaging visualizes fibrillar amyloid plaques in the brain and has long been treated as a reference standard against which fluid biomarkers are judged, while CSF assays measure analyte ratios (for example Aβ42/Aβ40 or p‑tau/Aβ42) that correlate strongly with amyloid PET status and are now available as FDA‑approved CSF platforms [5] [4] [3]. In routine clinical workflows, either a positive PET or a positive CSF ratio can establish the “A+” status used to determine eligibility for anti‑amyloid therapy, and many memory clinics use the two interchangeably depending on availability, patient preference, and comorbidities [3] [4].
3. Accuracy, discordance, and the problem of borderline results
Overall agreement between PET and CSF is high—studies report ~90% concordance for many automated assays—but discordant and intermediate results are not rare, prompting recommendations for confirmatory testing or clinical adjudication when results are borderline [5] [7] [4]. False positives or negatives have practical consequences: a false positive could expose an amyloid‑negative person to risk and cost, while a false negative could deny a potentially beneficial therapy; consequently, specialists emphasize minimizing false positives and often pursue additional testing (e.g., PET when CSF is borderline) before prescribing [3] [4].
4. Blood tests are shifting the landscape but do not yet replace PET/CSF for many clinicians
Rapid advances in plasma biomarkers (p‑tau and Aβ ratios) and recent FDA clearances/authorizations for specific blood tests have created scalable first‑line screening options that reduce the need for immediate PET or lumbar puncture, particularly to rule out amyloid in symptomatic patients [5] [8] [9]. Guideline panels and specialty societies, however, urge caution: some workgroups in 2025 noted blood measures are promising but still evolving in clinical validation and recommended their use alongside confirmatory testing and clinical judgment [10] [11]. Regulatory and expert voices also point out that many blood tests were validated against amyloid PET rather than autopsy, and that progressive reliance on non‑gold‑standard comparators can erode diagnostic certainty [12].
5. Practical implications: access, workflow, and monitoring
In practice, CSF and PET availability, cost, patient comorbidities, and local expertise determine which test is used to establish eligibility; CSF assays are less expensive and permit testing for alternative causes of cognitive decline, while PET is useful when CSF is inconclusive or discordant and for treatment monitoring in some settings [4] [3] [13]. Health systems and specialty clinics are building pathways—including registries such as ALZ‑NET—to collect real‑world data on who receives therapy and how biomarkers predict outcomes, recognizing that biomarker confirmation is both a clinical necessity and an operational bottleneck [13].
6. Tensions, incentives, and unanswered questions
There is a clear tension between the desire to widen access with cheaper blood screens and the imperative to avoid inappropriate treatment; industry and diagnostic companies have incentives to promote scalable assays, while clinicians and regulators emphasize rigorous validation and the risk of a degrading “gold standard” effect when tests are validated only against PET [12] [1]. Available reporting documents performance characteristics and practical guidance, but gaps remain: long‑term outcomes tied to different biomarker pathways, optimal algorithms for resolving discordance, and equitable access to confirmatory testing are questions that current sources flag but do not fully answer [7] [10] [6].