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Observational Study
. 2025 May 1;82(5):506-515.
doi: 10.1001/jamaneurol.2025.0142.

Cognitive Phenotyping and Interpretation of Alzheimer Blood Biomarkers

Vincent Bouteloup  1   2 , Nicolas Villain  3   4 , Jean Sebastien Vidal  5   6 , Fernando Gonzalez-Ortiz  7   8 , Idil Yuksekel  3 , Cristiano Santos  8 , Susanna Schraen-Maschken  9 , Isabelle Pellegrin  10   11 , Sylvain Lehmann  12 , Kaj Blennow  3   7   8 , Geneviève Chêne  1   2 , Olivier Hanon  5   6 , Carole Dufouil  1   2 , Vincent Planche  13   14 ; MEMENTO and the BALTAZAR Study Groups
Collaborators, Affiliations
Observational Study

Cognitive Phenotyping and Interpretation of Alzheimer Blood Biomarkers

Vincent Bouteloup et al. JAMA Neurol. .

Abstract

Importance: Blood phosphorylated tau 217 (p-tau217) showed good performance in predicting brain amyloidosis. However, the importance of detailed cognitive phenotyping in patients without dementia when interpreting p-tau217 results remains unclear.

Objective: To assess whether accuracy, negative predictive value (NPV), and positive predictive value (PPV) in predicting brain amyloidosis using p-tau217 varies across clinical presentations in patients without dementia.

Design, setting, and participants: The study design included 2 observational, prospective cohort studies: The Cohort of Outpatients From French Research Memory Centers in Order to Improve Knowledge on Alzheimer's Disease and Related Disorders (MEMENTO), with enrollment from 2011 to 2014 and 5 years of follow-up, and the Biomarker of Amyloid Peptide and Alzheimer's Disease Risk (BALTAZAR) cohort study, with enrollment from 2010 to 2015 and 3 years of follow-up. Both are multicenter cohorts conducted in French memory clinics. Participants without dementia were included for analysis if they had baseline blood p-tau217 measurement and a known amyloid status through cerebrospinal fluid amyloid β (Aβ)-42/Aβ-40 ratio or positron emission tomography. They presented with either subjective cognitive impairment (SCI), mild cognitive impairment (MCI) with a common Alzheimer disease (AD) phenotype (cAD-MCI: amnestic syndrome of hippocampal type, posterior cortical atrophy, or logopenic primary progressive aphasia), or MCI with uncommon AD or other phenotypes (uAD-MCI). Data were analyzed from May to September 2024.

Exposures: Blood p-tau217 concentrations.

Main outcomes and measures: Brain amyloidosis probabilities were derived from p-tau217 logistic regressions including age, gender, and APOE genotype. Published and internally developed cut points with 90% sensitivity and specificity were used.

Results: A total of 776 participants from the MEMENTO cohort (N = 2323 participants) and 193 participants from the BALTAZAR cohort (N = 1040) were included in this analysis. In the MEMENTO cohort (median [IQR] age, 71 [65-76] years; 444 female [57%]), brain amyloidosis prevalence was 16.5% (20 of 121) in SCI, 45.9% (78 of 170) in cAD-MCI, and 24.5% (119 of 485) in uAD-MCI. Area under the receiver operating characteristic curve for predicting brain amyloidosis with p-tau217 models was 0.78 (95% CI, 0.66-0.89), 0.91 (95% CI, 0.86-0.95), and 0.87 (95% CI, 0.84-0.91) in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. External cut points resulted in a PPV of 60.0%, 90.0%, and 74.5% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPV ranged from 84.2% to 90.2%. With internally developed cut points, PPVs were 52.6%, 84.0%, and 72.3% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPVs were high (91.7%-94.6%) in all subgroups. Rates of incident dementia strongly increased with the probability of brain amyloidosis in the cAD-MCI subgroup. Replicated analyses in the BALTAZAR cohort provided similar results.

Conclusions and relevance: Results from 2 clinical cohorts suggest that amyloid prevalence varied across cognitive phenotypes and was associated with the diagnostic performance of blood p-tau217 models to determine brain amyloidosis. Comprehensive cognitive phenotyping beyond the basic characterization of SCI, MCI, or dementia should accompany the use of blood biomarkers in clinical practice to avoid misdiagnosis due to false positives.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Villain reported receiving grants from Lion’s Club, Fondation pour la Recherche sur l’Alzheimer, Fondation Claude Pompidou, and Fondation ICM, Union Nationale pour les Intérêts de la Médecine (UNIM), Banque Publique d’Investissement; serving as principal investigator or subinvestigator of AriBio, GSK, Biogen, Roche, Eisai, Johnson & Johnson, Alector, UCB Pharma, Novo Nordisk, Novartis, unpaid lectures for Janssen; unpaid expert from Eli Lilly, and unpaid lectures for Servier Foundation outside the submitted work. Dr Blennow reported having served as a consultant and on advisory boards for AbbVie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi, and Siemens Healthineers; serving on data monitoring committees for Julius Clinical and Novartis; giving lectures, producing educational materials, and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and being a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this article. Dr Chene reported receiving grants from the Ministry of Research during the conduct of the study. Dr Hanon reported receiving personal fees from Eli Lilly during the conduct of the study. Dr Planche reported receiving personal fees from Motac Neurosciences for animal studies; grants from Fondation Recherche Alzheimer, Agence Nationale de la Recherche, and PSP France for animal studies; and during the past 3 years, serving as a local unpaid investigator or subinvestigator for clinical trials granted by Novo Nordisk, Biogen, TauRx Pharmaceuticals, Janssen, Green Valley Pharmaceuticals, and Alector. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prediction of Amyloid Positivity (A+) in Different Cognitive Phenotypes Using Blood Phosphorylated Tau 217 (p-Tau217), the MEMENTO and BALTAZAR Studies
A, External cut points (validation in the MEMENTO cohort). Colored horizontal lines (42%, 70%) represent the cut points defined in BioFINDER-1 and BioFINDER-2 studies for a sensitivity and a specificity at 90%. The MEMENTO cohort was used as a validation sample. B, Cut points developed in the MEMENTO study (replication in the BALTAZAR cohort). Colored horizontal lines (15%, 42%) represent the cut points developed in the MEMENTO cohort for a sensitivity and a specificity at 90%. Light orange and light blue bands represent the 95% CI of the cutoff lines. These cut points were then applied on the BALTAZAR replication sample. Each plot represents the probability of being A+ for an individual. Probabilities were derived from a logistic model with age, sex, APOE genotype and log(p-tau217) as predictors, fitted independently of the cognitive phenotype and separately for the MEMENTO and BALTAZAR cohorts. Orange dots represent the individuals who developed dementia within the follow-up period. Individuals above the upper cut point line (in orange) were considered A+, and those below the lower cut point line (in blue) were considered amyloid negative (A−). Individuals with a probability between the 2 cut point lines had intermediate probability and would require additional examination (lumbar puncture or amyloid positron emission tomography). AD, Alzheimer disease; BALTAZAR, Biomarker of Amyloid Peptide and Alzheimer’s Disease Risk study; cAD-MCI, MCI with common AD phenotype; MCI, mild cognitive impairment; MEMENTO, The Cohort of Outpatients From French Research Memory Centers in Order to Improve Knowledge on Alzheimer’s Disease and Related Disorders study; SCI, subjective cognitive impairment; uAD-MCI, MCI with an uncommon AD/other phenotype.
Figure 2.
Figure 2.. Incidence of Dementia at 3 and 5 Years for Individuals With Mild Cognitive Impairment (MCI) According to Amyloid Positivity Probability
The probability of amyloid positivity is provided for cut points developed in The Cohort of Outpatients From French Research Memory Centers in Order to Improve Knowledge on Alzheimer’s Disease and Related Disorders (MEMENTO) study. AD indicates Alzheimer disease; BALTAZAR, Biomarker of Amyloid Peptide and Alzheimer’s Disease Risk study; cAD, common AD phenotype; uAD, uncommon AD/other phenotypes; PY, person-year.
Figure 3.
Figure 3.. Brain Amyloid Determination Based on Blood Phosphorylated Tau 217 (p-Tau217) Regarding the Cognitive Phenotype of Individuals Attending a Memory Clinic
AD indicates Alzheimer disease; MCI, mild cognitive impairment; SCI, subjective cognitive impairment.
See this image and copyright information in PMC

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