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January 31, 2023; 100 (5) Research ArticleOpen Access

Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort

Vincent Planche, Vincent Bouteloup, Isabelle Pellegrin, Jean-Francois Mangin, Bruno Dubois, Pierre-Jean Ousset, Florence Pasquier, Frederic Blanc, Claire Paquet, Olivier Hanon, Karim Bennys, Mathieu Ceccaldi, Cédric Annweiler, Pierre Krolak-Salmon, Olivier Godefroy, David Wallon, Mathilde Sauvee, Claire Boutoleau-Bretonnière, Isabelle Bourdel-Marchasson, Isabelle Jalenques, Genevieve Chene, Carole Dufouil, and the MEMENTO Study Group
First published October 19, 2022, DOI: https://doi.org/10.1212/WNL.0000000000201479
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Abstract

Background and Objective Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints.

Methods The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aβ42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period.

Results Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aβ42/40 was less efficient than CSF Aβ42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A “clinical” reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86–0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aβ42/40. A “research” reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89–0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aβ42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances.

Discussion In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.

Glossary

Aβ=
β-amyloid peptide;
AD=
Alzheimer disease;
AUC=
area under the curve;
ApoE=
apolipoprotein E;
CDR=
Clinical Dementia Rating;
eGFR=
estimated glomerular filtration rate;
MCI=
mild cognitive impairment;
NfL=
neurofilament light chain;
ROC=
receiver operating characteristic;
SCC=
subjective cognitive complaint;
SUVR=
standard uptake value ratio;
TMT=
Trail Making Test

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • The Article Processing Charge was funded by the authors.

  • Submitted and externally peer reviewed. The handling editors were Brad Worrall, MD, MSc, FAAN, and Andrea Schneider, MD, PhD.

  • CME Course: NPub.org/cmelist

  • Received May 16, 2022.
  • Accepted in final form September 13, 2022.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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