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[Preprint]. 2024 Jun 13:2024.06.12.24308824.
doi: 10.1101/2024.06.12.24308824.

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology

Rik Ossenkoppele  1   2   3 , Gemma Salvadó  1 , Shorena Janelidze  1 , Alexa Pichet Binette  1 , Divya Bali  1 , Linda Karlsson  1 , Sebastian Palmqvist  1   4 , Niklas Mattsson-Carlgren  1   5   6 , Erik Stomrud  1   4 , Joseph Therriault  7   8 , Nesrine Rahmouni  7   8 , Pedro Rosa-Neto  7   8 , Emma M Coomans  2   3 , Elsmarieke van de Giessen  3   9 , Wiesje M van der Flier  2   3   10 , Charlotte E Teunissen  3   11 , Erin M Jonaitis  12   13 , Sterling C Johnson  12   13 ; PREVENT-AD Research Group; Sylvia Villeneuve  14   15 , Tammie L S Benzinger  16   17 , Suzanne E Schindler  17   18 , Randall J Bateman  17   18   19 , James D Doecke  20 , Vincent Doré  20   21 , Azadeh Feizpour  21   22 , Colin L Masters  22 , Christopher Rowe  21   22 , Heather J Wiste  23 , Ronald C Petersen  24 , Clifford R Jack Jr  25 , Oskar Hansson  1   4
Affiliations

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology

Rik Ossenkoppele et al. medRxiv. .

Abstract

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

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Conflict of interest statement

DECLARATION OF INTERESTS R.O. has received research support from Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. He has given lectures in symposia sponsored by GE Healthcare and serves on advisory boards for Asceneuron and Bristol Myers Squibb. SP has acquired research support (for the institution) from ki elements / ADDF and Avid. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Biogen, Esai, Lilly, and Roche. Research programs of WF have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003) in the context of Onderzoeksprogramma Dementie, part of the Dutch National Dementia Strategy. TAP-dementia receives co-financing from Avid Radiopharmaceuticals and Amprion. Gieskes-Strijbis fonds also contributes to TAP-dementia. WF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. WF is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. EvdG has performed contract research for Heuron Inc. and Roche. EvdG has a consultancy agreement with IXICO and Life Molecular Imaging for reading PET scans. CET has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had consultancy/speaker contracts for Eli Lilly, Merck, Novo Nordisk, Olink and Roche. SES has served as a consultant to Eisai and Novo Nordisk and has received speaker fees from Eli Lilly and Medscape. She has analyzed biomarker data provided by C2N Diagnostics. JT has served as a consultant for the Neurotorium educational platform and for Alzheon. PR-N has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. CCR has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Enigma/Mellieur Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. RJB laboratory research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Avid Radiopharmaceuticals, Janssen, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, Coins for Alzheimer’s Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly, and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Meyers Squibb, Hoffman La Roche), and the Tracy Family SILQ Center; having equity ownership interest in C2N Diagnostics and receiving income based on technology licensed by Washington University to C2N Diagnostics; and receiving income from C2N Diagnostics for serving on the scientific advisory board. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. SCJ has served in the past two years on advisory boards for Enigma Biomedical and ALZPath. The other authors report no competing interests.

Figures

Figure 1.
Figure 1.. Plasma p-tau217 and Tau-PET prediction of future cognitive decline
a, d, Scatterplots showing the association between cognitive change over time on the mPACC5 and the tau biomarkers (Quartile 1-3 vs Quartile 4) across all participants (a) and Aβ+ participants (d) only. The shadow area indicated the 95% confidence interval. b, e, Explained variance (R2, inside the bar plot) and model fit (corrected Akaike criterion, outside the bar plot) for various models predicting longitudinal change on the mPACC5 across all participants (b) and Aβ+ (d) participants only. Errorbars represent the 95% CI. c, f, Partial explained variance (R2) for combined biofluid and neuroimaging models predicting longitudinal change on the mPACC5 across all participants (c) and Aβ+ (f) participants only. **p<0.01, ***p<0.001.
Figure 2.
Figure 2.. Plasma p-tau217 and Tau-PET prediction of progression to mild cognitive impairment
a, c, Survival curves for progression to mild cognitive impairment (Quartile 1-3 vs Quartile 4) across all participants (a) and Aβ+ (c) participants only, including a table of total number of participants available at each time point. The dashed line in c indicates the time point at which 50% of a group had progressed to MCI, and the shadow area indicated the 95% confidence interval. b, d, Model fit (corrected Akaike criterion) for various models predicting future clinical progression to mild cognitive impairment across all participants (b) and Aβ+ (d) participants only. Errorbars represent the 95% CI. * p<0.05, **p<0.01, ***p<0.001.
Figure 3.
Figure 3.. A two-step recruitment approach for clinical trials in preclinical Alzheimer’s disease using the mPACC as outcome measure
a, conceptual framework of a sequential two-step recruitment strategy of a clinical trial in preclinical Alzheimer’s disease using a cognitive endpoint. b, the obtained sample size reduction using sample selection based on different percentiles (75th, 50th and 25th) of baseline plasma p-tau217 levels in step 1 followed by the selection based on the same percentiles (75th, 50th and 25th) of the Tau-PETMTL measurement in step 2 with mPACC5 as the primary endpoint. Note that 100% in step 2 refers to the participants selected by plasma p-tau217 in step 1. Errorbars represent the 95% CI. c shows the calculated sample size reductions for various plasma p-tau217 and Tau-PETMTL quartile combinations
Figure 4.
Figure 4.. Clinical trial sample size reductions through a two-step recruitment strategy when using clinical progression to mild cognitive impairment as an outcome measure
a, the obtained sample size reduction using sample selection based on different percentiles (75th, 50th and 25th) of baseline plasma p-tau217 levels in step 1 followed by the selection based on the same percentiles (75th, 50th and 25th) of the Tau-PETMTL measurement in step 2 with clinical progression to mild cognitive impairment as the primary endpoint. Note that 100% in step 2 refers to the participants selected by plasma p-tau217 in step 1. Errorbars represent the 95% CI. b shows the calculated sample size reductions for various plasma p-tau217 and Tau-PETMTL quartile combinations.
Figure 5.
Figure 5.. Characterization of different plasma p-tau217/Tau-PETMTL groups on relevant trial measures
This figure shows how different group compositions based on their baseline plasma p-tau217 and Tau-PETMTL levels are related to various relevant trial metrics, including the proportion of Aβ+ individuals (a), annual mPACC5 slope (b), proportion of initially cognitively unimpaired individuals that progress to mild cognitive impairment during a 4-year trial (c), and the proportion of individuals from the entire population that fall within the group definitions described on the x-axis (d). Errorbars in b represent the 95% CI.
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