Neurology · Medical Literature
Clinico-biological trajectories stratified by combined tau biomarkers in preclinical Alzheimer's disease.
Abstract
Tau pathology biomarkers provide prognostic indicators of neurodegeneration and cognitive decline in Alzheimer's disease (AD), making them crucial to early patient stratification for disease-modifying interventions. Plasma p-tau217 indexes early tau pathophysiology, whereas FDA/EMA-approved [18F]flortaucipir PET (tau-PET) visual assessments indicate advanced neurofibrillary tangle pathology. Here, we identified concordant and discordant profiles based on combined plasma p-tau217 status and tau-PET visual assessments in cognitively unimpaired amyloid-β (Aβ)-positive older adults and investigated whether these profiles delineate distinct longitudinal trajectories of Aβ and tau accumulation, neurodegeneration, and cognitive decline. We included 330 cognitively unimpaired Aβ-PET-positive participants (72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) from the A4 Study, who underwent plasma p-tau217 and tau-PET at baseline. Plasma positivity (T1 +) followed A4 core criteria as previously reported (≥ 0.28 U/mL), while tau-PET positivity (T2 +) was determined by three expert visual readers with strong inter-rater agreement (κ = 0.954). Participants were stratified as T1[- / +]T2[- / +] at baseline and were followed for 5.0 ± 1.7 years. Baseline and longitudinal differences in regional Aβ- and tau-PET SUVR, MRI-measured gray-matter (GM) volume, and cognitive performance were examined using ANCOVA and mixed-effects models. All models accounted for treatment, with additional sensitivity analyses excluding treated participants. At baseline, 57% were negative-concordant (T1 - T2 - : n = 187), 24% were discordant (T1 + T2 - : n = 53; T1 - T2 + : n = 27), and 19% were positive-concordant (T1 + T2 + : n = 63). T1 + T2 + profile constituted the highest-risk state, showing the greatest baseline cortical Aβ burden, the strongest neocortical tau progression (fronto-temporo-parietal pattern; p(FDR) < 0.05), marked baseline atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline (PACC: d = -1.84, p < 0.001). Consistently, T1 + T2 + exhibited the highest hazard of progression to more advanced clinico-biological stages over follow-up (HRClinical = 3.03, HRBiological = 9.98; p < 0.001). Discordant profiles showed comparatively limited progression, suggesting earlier or low-tau states. Results were essentially unchanged after excluding treated participants. Integrating plasma p-tau217 with tau-PET visual assessment reveals clinically meaningful tau-biomarker heterogeneity in preclinical AD. Our findings highlight the value of combining these biomarkers to refine early risk prediction and support prioritization strategies for prevention trials. The frequency of discordance also motivates refining tau-PET visual assessments beyond binary classification (e.g., ordinal/semi-quantitative staging) to better capture subtle early tau signal.
Clinical relevance
In cognitively unimpaired, amyloid-β-positive older adults, do combined concordant and discordant profiles of plasma p-tau217 and tau-PET visual assessment define distinct longitudinal trajectories of amyloid-β accumulation, neurofibrillary tau progression, neurodegeneration, and cognitive decline? __SNAPSHOT__ {"studyDesign":"Prospective longitudinal cohort study using data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study — a completed Phase 3, double-blind, placebo-controlled multicenter trial — with biomarker stratification analyses applied post-hoc to a tau-PET subsample","setting":"Multicenter; 67 sites across the United States, Australia, Canada, and Japan (A4 Study infrastructure); cognitively unimpaired community-dwelling older adults","sampleSize":"n=330 (negative-concordant T1−T2−: n=187 [57%]; discordant T1+T2−: n=53 [16%] and T1−T2+: n=27 [8%]; positive-concordant T1+T2+: n=63 [19%])","population":"Cognitively unimpaired Aβ-PET-positive adults aged 65–85 years (mean 72.2 ± 4.8 years; 58% female; 48% randomized to receive solanezumab) who had both plasma p-tau217 and [18F]flortaucipir tau-PET available at baseline; all were in NIA-AA Stage 1 (asymptomatic Alzheimer's disease)","intervention":"Baseline biomarker stratification into four tau profile groups defined by plasma p-tau217 positivity (T1+: ≥0.28 U/mL; Lilly immunoassay) and tau-PET visual read positivity (T2+: consensus of three expert visual readers; Fleiss κ=0.953 [0.923–0.981]) in the context of universal Aβ-PET positivity","comparator":"The T1−T2− (negative-concordant) group served as the reference category for longitudinal trajectory analyses; the four profiles were compared with one another","primaryOutcome":"Longitudinal clinico-biological trajectories including: Aβ accumulation (Aβ-PET), neocortical tau progression (tau-PET), gray matter (GM) volume loss on MRI, and cognitive decline assessed by the Preclinical Alzheimer Cognitive Composite (PACC); additionally, hazard of progression to more advanced clinico-biological AD stages","followUp":"Median approximately 7.4 years for PACC (median 12 assessments per participant) and cortical GM MRI (median 6 scans per participant); tau-PET and Aβ-PET follow-up durations not separately reported in the available abstract","fundingSource":"Public-private partnership: National Institute on Aging (NIA/NIH), Eli Lilly and Company, Alzheimer's Association, GHR Foundation, Foundation for the NIH, and additional philanthropic sources"}
Key findings
Four tau profile groups were identified at baseline: 57% were negative-concordant (T1−T2−; n=187), 16% were plasma-positive/tau-PET-negative (T1+T2−; n=53), 8% were plasma-negative/tau-PET-positive (T1−T2+; n=27), and 19% were positive-concordant (T1+T2+; n=63). The dual-positive (T1+T2+) group constituted the highest-risk state and demonstrated the greatest baseline cortical Aβ burden, the strongest neocortical tau progression in a fronto-temporo-parietal distribution (p[FDR] <0.05), marked baseline cortical atrophy with accelerated longitudinal GM loss in overlapping regions, and the fastest cognitive decline on the PACC (Cohen's d = −1.84, p <0.001 vs. reference). The T1+T2+ group further exhibited the highest hazard of progression to more advanced clinico-biological AD stages over follow-up (HRClinical = 3.03; HRBiological = 9.98; both p <0.001 vs. T1−T2−). Discordant profiles (T1+T2− and T1−T2+) showed comparatively limited longitudinal progression, consistent with interpretation as earlier or low-tau pathological states. Between-group comparisons for discordant profiles vs. T1−T2− are not fully enumerated in the available abstract text. Confidence intervals for the hazard ratios and PACC effect size are not reported in the abstract. No new safety or adverse event data were generated, as this was a secondary analysis of the completed A4 Study. Results were reported as essentially unchanged in sensitivity analyses excluding the 48% of participants who received solanezumab.
Practice implications
This study establishes that combining plasma p-tau217 and FDA/EMA-approved tau-PET visual assessment delineates four biologically meaningful risk strata among cognitively unimpaired Aβ-positive older adults. Dual tau biomarker positivity (T1+T2+) identifies a high-risk subgroup (~19% of Aβ-positive individuals) with an approximately 3-fold higher clinical progression hazard and nearly 10-fold higher biological progression hazard relative to dual-negative individuals — findings with potential clinical relevance for patient selection in disease-modifying trials and, eventually, in clinical practice. The ~24% of participants with discordant profiles may represent intermediate biological stages, a finding with implications for biomarker staging frameworks and trial eligibility design. The study does not establish what practice-changing diagnostic thresholds should be adopted in clinical care, as it was performed in a trial-enriched, amyloid-positive-only cohort at research-capable academic sites. Patients with diverse racial/ethnic backgrounds, lower educational attainment, or comorbid conditions were not adequately represented in the A4 Study population. The findings apply specifically to cognitively unimpaired Aβ-positive adults and cannot be generalized to symptomatic patients or Aβ-negative individuals. Solanezumab treatment did not affect the primary conclusions (unchanged results in sensitivity analysis), strengthening internal validity. Since only the abstract is available for this review, full statistical details, covariate adjustments, confidence intervals for most outcomes, and subgroup analyses cannot be fully evaluated. __LIMITATIONS__ Restricted cohort: All 330 participants were Aβ-PET-positive and cognitively unimpaired at enrollment in the A4 Study, a highly enriched research population; findings may not generalize to primary care or diverse community settings,Limited racial/ethnic and socioeconomic diversity: The A4 Study enrolled predominantly non-Hispanic White participants, limiting generalizability across populations,Partial trial confounding: 48% of participants received solanezumab; though sensitivity analyses excluding treated participants were reportedly negative, residual treatment effects on biomarker trajectories cannot be fully excluded,Small subgroup sizes: The T1−T2+ (n=27) and T1+T2− (n=53) discordant subgroups are small, limiting statistical power for between-group comparisons within discordant strata,Biomarker positivity thresholds: Plasma p-tau217 positivity was defined using a single a priori cut-off (≥0.28 U/mL); alternative thresholds may reclassify a non-trivial proportion of participants and alter group compositions,Tau-PET visual read subjectivity: Although inter-rater reliability was high (Fleiss κ=0.953), visual read-based tau-PET classification is not uniformly available outside specialized academic centers and differs from quantitative SUVR methods,Surrogate biomarker endpoints: Tau-PET and Aβ-PET trajectories are imaging biomarkers; their translation to patient-level clinical outcomes (e.g., dementia incidence) requires further confirmation,Missing confidence intervals and full statistical tables: These key measures are not provided in the available abstract, precluding full assessment of precision and clinical significance for most outcomes,Follow-up duration heterogeneity: Cognitive follow-up was up to 7.4 years, but PET imaging follow-up duration is not separately reported in the abstract, making direct comparison of effect sizes across modalities uncertain,Industry co-sponsorship: Eli Lilly and Company co-funded the A4 Study and manufactures the p-tau217 immunoassay used; potential conflicts of interest cannot be fully assessed from the abstract alone __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In cognitively unimpaired Aβ-positive older adults, concordant positivity of both plasma p-tau217 and visual tau-PET (present in ~19% of the cohort) identifies a high-risk subgroup with markedly accelerated neocortical tau accumulation, gray matter loss, cognitive decline (Cohen's d = −1.84), and an approximately 10-fold higher hazard of biological stage progression compared with dual-negative individuals. Discordant profiles (~24%) represent intermediate-risk states consistent with earlier-stage tau pathophysiology. These findings support using combined tau biomarker profiling for precision risk stratification in preclinical AD trials but require validation in more diverse, real-world populations before informing routine clinical practice.