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Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen’s kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure‐1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure‐1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure‐2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure‐2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [¹⁸F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [¹⁸F]flortaucipir (ADNI), [¹⁸F]MK‐6240 (CPAS), and [¹⁸F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([¹⁸F]flortaucipir) and AIBL ([¹⁸F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [¹⁸F]flortaucipir and [¹⁸F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([¹⁸F]PI‐2620) are underway.

Importance Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. Objective To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. Design, Setting, and Participants This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. Interventions Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. Main Outcomes and Measures Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer’s Disease Rating Scale (iADRS) and Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. Results Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score ( R 2 , 0.73 [95% CI, 0.37-0.97]) and CDR-SB score ( R 2 , 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 ( R 2 , 0.86 [95% CI, 0.73-0.97]), p-tau181 ( R 2 , 0.88 [95% CI, 0.77-0.97]), and GFAP ( R 2 , 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL ( R 2 , 0.03 [95% CI, 0.00-0.54]). Conclusions and Relevance The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. Trial Registration ClinicalTrials.gov Identifier: NCT04437511

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Objective The objective of this study was to determine the predictive value of amyloid‐positron emission tomography (PET) versus the plasma ratio of phosphorylated tau at threonine 217 (p‐tau217) to non‐phosphorylated tau217 (%p‐tau217) for tau‐PET transitions (T− to T+). The added value of combining plasma amyloid‐β 42 and amyloid‐β 40 (Aβ42/40) and %p‐tau217 into an amyloid probability score (APS2) was also assessed. Methods Mayo Clinic Study of Aging (MCSA) participants had plasma markers measured at via mass spectrometry (MS), an amyloid‐PET scan, and a tau‐PET (meta‐temporal region of interest [ROI]) negative scan (standardized uptake value ratio [SUVR] <1.29) at the index (baseline) date, along with one or more follow‐up tau‐PET scans. The BioFINDER‐2 cohort was used for validation. Cox proportional hazards models adjusted for age, sex, and apolipoprotein ( APOE ) ε4 were used to assess predictors, with scaling to the interquartile range (IQR) for comparability of hazard ratios (HR). Results Among 255 tau‐PET negative MCSA participants (median age: 71.9 years), 37 converted to tau‐PET positive (median follow‐up time: 3.81 years). Higher %p‐tau217 (HR: 1.52 [95% CI: 1.28–1.80]), amyloid‐PET centiloid (HR: 1.47 [95% CI: 1.20–1.79]), and APS2 (HR: 1.62 [95% CI: 1.22–2.16]) predicted tau‐PET conversion. However, Aβ42/40 (HR: 0.94 [95% CI: 0.54–1.66]) was not associated with tau‐PET conversion. In the BioFINDER‐2 cohort (605 tau‐negative, median age: 70.2), 33 converted to tau‐positive (median follow‐up time: 2 years), with higher %p‐tau217 (HR: 1.80 [95% CI: 1.50–2.17]), amyloid‐PET centiloid (HR: 2.29 [95% CI: 1.77–2.97]), and lower Aβ42/40 (HR: 2.38 [95% CI: 1.17–4.83]) predicting conversion. Interpretation In two cohorts, %p‐tau217 was associated with tau‐PET conversion, comparable to amyloid‐PET. APS2 also predicted conversion in the MCSA cohort, whereas Aβ42/40 predicted conversion in the BioFINDER‐2 cohort, which had more individuals with cognitive impairment. ANN NEUROL 2025;98:1249–1260

Abstract INTRODUCTION Plasma biomarkers’ utility for predicting incident mild cognitive impairment (MCI) remains unclear. We evaluated associations of plasma Alzheimer's disease (AD) biomarkers and amyloid positron emission tomography (PET) with transitions from cognitively unimpaired (CU) to MCI in the Mayo Clinic Study of Aging (MCSA) and BioFINDER‐2 studies. METHODS Associations of continuous baseline plasma biomarker levels and amyloid PET Centiloid with progression to MCI, adjusting for age, sex, and education, were evaluated with Cox proportional hazards models. RESULTS The study included 381 MCSA and 584 BioFINDER‐2 participants. Amyloid PET and percent phosphorylated to non‐phosphorylated tau217 (%p‐tau217) were strong predictors of progression to MCI in both cohorts: hazard ratios of 1.49 and 1.23 in the MCSA and 1.72 and 1.65 in BioFINDER, respectively. Amyloid beta 42/40 was a significant predictor in BioFINDER‐2 only (hazard ratio 2.20). DISCUSSION Plasma %p‐tau217 was associated with progression from CU to MCI in both cohorts, although differences in biomarker associations may be related to differences in the two cohorts. Highlights Mass‐spectrometry‐based plasma phosphorylated tau217 was associated with cognitively unimpaired to mild cognitive impairment (MCI) progression. Plasma amyloid beta 42/40 was a significant predictor in BioFINDER but not the Mayo Clinic Study of Aging (MCSA). Amyloid positron emission tomography (PET) was the strongest predictor of progression to MCI in the MCSA. Plasma had added value to amyloid PET in BioFINDER but not the MCSA. Biomarker performance may vary with cohort and biomarker measurement differences.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract INTRODUCTION Biomarkers play a crucial role in understanding Alzheimer's disease (AD) pathogenesis and treatment effects. However, comparing biomarker measures without standardization and appreciating their magnitude relative to the disease can be challenging. METHODS To address this issue, we propose the CentiMarker approach, similar to Centiloid, which provides a standardized scale between normal (0) and nearly maximum abnormal AD (100) ranges. We applied this scale to cerebrospinal fluid (CSF) biomarkers in dominantly inherited AD and sporadic AD cohorts. RESULTS CentiMarkers facilitated the interpretation of disease abnormality, demonstrating comparable changes and distributions of AD biomarkers across disease stages. CentiMarkers make the treatment effect more comparable than their original scales across various biomarkers. DISCUSSION The versatility of CentiMarkers makes it a valuable tool for standardized biomarker comparison in AD research, enabling informed cross‐study comparisons and contributing to accelerated therapeutic development. Adoption of the CentiMarker scale could enhance biomarker reporting and advance our understanding of AD. Highlights Comparing fluid biomarkers without appreciating their magnitude relative to the disease can be challenging. We propose a CentiMarker metric to standardize biomarker measures from normal (0) and nearly maximum abnormal AD (100) ranges. CentiMarkers make the treatment effect more comparable across various biomarkers than when using the original scales.

Importance Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence in adults without AD indicates that females exhibit higher tau deposition than age-matched males, particularly in the setting of elevated β-amyloid (Aβ), but the evidence for sex differences in tau accumulation rates is inconclusive. Objective To examine whether female sex is associated with faster tau accumulation in the setting of high Aβ (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOE ε4 carrier status and tau accumulation. Data Sources This meta-analysis used data from 6 longitudinal aging and AD studies, including the Alzheimer’s Disease Neuroimaging Initiative, Berkeley Aging Cohort Study, BioFINDER 1, Harvard Aging Brain Study, Mayo Clinic Study of Aging, and Wisconsin Registry for Alzheimer Prevention. Longitudinal data were collected between November 2004 and May 2022. Study Selection Included studies required available longitudinal [ 18 F]flortaucipir or [ 18 F]-MK-6240 tau-PET scans, as well as baseline [ 11 C] Pittsburgh Compound B, [ 18 F]flutemetamol or [ 18 F]florbetapir Aβ-PET scans. Recruitment criteria varied across studies. Analyses began on August 7, 2023, and were completed on February 5, 2024. Data Extraction and Synthesis In each study, primary analyses extracted estimates for the sex (female or male) and the sex by baseline Aβ-PET status (high or low) association with longitudinal tau-PET using a series of mixed-effects models. Secondary mixed-effects models extracted the interaction estimate for the association of sex by APOE ε4 carrier status with longitudinal tau-PET. Study-specific estimates for each mixed-effects model were then pooled in a meta-analysis, and the global fixed effect (β) and total heterogeneity ( I 2 ) across studies were estimated. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures Seven tau-PET outcomes that showed cross-sectional sex differences were examined across temporal, parietal, and occipital lobes. Results Among 6 studies assessed, there were 1376 participants (761 [55%] female; mean [range] age at first tau scan, 71.9 [46-93] years; 401 participants [29%] with high baseline Aβ; 412 APOE ε4 carriers [30%]). Among individuals with high baseline Aβ, female sex was associated with faster tau accumulation localized to inferior temporal (β = −0.14; 95% CI, −0.22 to −0.06; P = .009) temporal fusiform (β = −0.13; 95% CI, −0.23 to −0.04; P = .02), and lateral occipital regions (β = −0.15; 95% CI, −0.24 to −0.06; P = .009) compared with male sex. Among APOE ε4 carriers, female sex was associated with faster inferior-temporal tau accumulation (β = −0.10; 95% CI, −0.16 to −0.03; P = .01). Conclusions and Relevance These findings suggest that sex differences in the pathological progression of AD call for sex-specific timing considerations when administrating anti-Aβ and anti-tau treatments.