How should clinicians integrate Centiloid values with tau PET and CSF biomarkers to estimate individual dementia risk?
Executive summary
Clinicians should use Centiloid (CL) values as a standardized continuous measure of brain amyloid burden and interpret them alongside tau PET and CSF biomarkers in a staged, complementary framework: low CLs can identify early amyloid accumulation, intermediate "gray-zone" CLs predict early mesial temporal tau and elevated CSF p‑tau, and high CLs mark advanced amyloid with greater likelihood of neocortical tau and clinical decline [1] [2] [3]. Integration requires moving beyond binary A+/A− calls toward magnitude staging (e.g., CL cut‑points around ~12–22 and ~30–68 in published work), combined with tau PET regional patterns and CSF p‑tau/tau ratios to estimate individualized near‑term dementia risk, while acknowledging assay, tracer and cohort limitations [3] [4] [2] [5].
1. Why Centiloids matter—and why a number is not a diagnosis
The Centiloid scale standardizes amyloid PET across tracers so 0 CL approximates young amyloid‑negative controls and 100 CL reflects typical mild‑moderate AD dementia, enabling cross‑site comparison of amyloid burden [1]. Multiple studies show CL magnitude correlates with downstream tau PET and CSF changes: lower CL thresholds (~12–22 CL) detect early aggregation linked to early mesial temporal tau and CSF p‑tau elevations, whereas higher thresholds (e.g., CL ≈30–68) correspond to more widespread tau and risk of clinical progression [4] [3] [2].
2. Use a three‑level amyloid staging as the backbone for risk estimation
Several recent analyses recommend moving from binary amyloid positivity to at least three meaningful CL levels—low/“gray‑zone”/high—because the gray zone carries distinct biomarker and prognostic profiles that affect short‑term risk estimates [2]. Practically, clinicians can treat CL < ~12 as likely absent or minimal amyloid, CL between roughly 12–30 as early/gray‑zone with potential for rising CSF p‑tau and regional tau PET later, and CL > ~30–68 as increasingly established amyloid with higher probability of neocortical tau and cognitive decline [4] [3] [2].
3. Weigh tau PET regionally and CSF markers as complementary, not redundant
Tau PET provides spatial staging—mesial temporal versus neocortical deposition—that refines prognosis beyond amyloid magnitude, with neocortical tau signaling higher immediate dementia risk [6] [7]. CSF Aβ42 (and Aβ42/Aβ40) behave as state markers reflecting presence of amyloid pathology and can precede PET, while CSF p‑tau181 (and emerging p‑tau isoforms) often track early tau‑related processes and predict later tau PET positivity in Aβ‑positive but tau‑PET‑negative individuals [5] [8] [9]. Therefore, combine CL magnitude with regional tau PET and CSF p‑tau to move from population risk to individualized short‑term prognosis [7] [5].
4. Practical algorithm for clinicians in the current evidence base
Begin with CL quantification when amyloid PET is available and place the value into a magnitude stage (e.g., <12, 12–30, >30), then assess tau PET: mesial temporal tau in an intermediate CL suggests elevated 3–5 year risk whereas neocortical tau at higher CL predicts imminent clinical decline [4] [3] [2]. If tau PET is unavailable, use CSF p‑tau and Aβ42/Aβ40: elevated p‑tau with gray‑zone CL increases suspicion for evolving tau pathology and raises near‑term risk estimates [8] [5].
5. Caveats, discordance, and hidden assumptions
Concordance between PET and CSF is high but not perfect; discordant CSF+/PET− cases can have low CLs (e.g., 12–19 CL) or alternative pathologies like frontotemporal or vascular disease, so clinical context and imaging remain essential [10]. Centiloid pipelines and tau PET quantification platforms are still being standardized and not universally approved for clinical use in all regions, creating variability that must temper deterministic risk claims [5] [11]. Finally, emerging therapies can change biomarker trajectories differently across fluids and PET—PET Centiloids may remain altered longer than plasma/CSF changes—so treatment context affects interpretation [7].
6. How to communicate risk to patients: probabilistic, staged, and transparent
Risk estimates should be framed probabilistically: a higher CL plus neocortical tau PET or elevated CSF p‑tau increases the likelihood of progression but does not guarantee dementia, and gray‑zone results merit closer longitudinal monitoring rather than binary prognostication [2] [3] [5]. Clinicians and centers should report CL as a continuous value with the chosen cut‑points and explain limitations of assays, potential discordance, and planned follow‑up biomarker or cognitive surveillance [1] [5].