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. 2024 Apr 23;102(8):e209219.
doi: 10.1212/WNL.0000000000209219. Epub 2024 Mar 25.

Explaining the Variability of Alzheimer Disease Fluid Biomarker Concentrations in Memory Clinic Patients Without Dementia

Vincent Bouteloup  1 , Isabelle Pellegrin  1 , Bruno Dubois  1 , Genevieve Chene  1 , Vincent Planche  1 , Carole Dufouil  1 ; MEMENTO Study Group  1
Collaborators, Affiliations

Explaining the Variability of Alzheimer Disease Fluid Biomarker Concentrations in Memory Clinic Patients Without Dementia

Vincent Bouteloup et al. Neurology. .

Abstract

Background and objectives: Patients' comorbidities can affect Alzheimer disease (AD) blood biomarker concentrations. Because a limited number of factors have been explored to date, our aim was to assess the proportion of the variance in fluid biomarker levels explained by the clinical features of AD and by a large number of non-AD-related factors.

Methods: MEMENTO enrolled 2,323 individuals with cognitive complaints or mild cognitive impairment in 26 French memory clinics. Baseline evaluation included clinical and neuropsychological assessments, brain MRI, amyloid-PET, CSF (optional), and blood sampling. Blood biomarker levels were determined using the Simoa-HDX analyzer. We performed linear regression analysis of the clinical features of AD (cognition, AD genetic risk score, and brain atrophy) to model biomarker concentrations. Next, we added covariates among routine biological tests, inflammatory markers, demographic and behavioral determinants, treatments, comorbidities, and preanalytical sample handling in final models using both stepwise selection processes and least absolute shrinkage and selection operator (LASSO).

Results: In total, 2,257 participants were included in the analysis (median age 71.7, 61.8% women, 55.2% with high educational levels). For blood biomarkers, the proportion of variance explained by clinical features of AD was 13.7% for neurofilaments (NfL), 11.4% for p181-tau, 3.0% for Aβ-42/40, and 1.4% for total-tau. In final models accounting for non-AD-related factors, the variance was mainly explained by age, routine biological tests, inflammatory markers, and preanalytical sample handling. In CSF, the proportion of variance explained by clinical features of AD was 24.8% for NfL, 22.3% for Aβ-42/40, 19.8% for total-tau, and 17.2% for p181-tau. In contrast to blood biomarkers, the largest proportion of variance was explained by cognition after adjustment for covariates. The covariates that explained the largest proportion of variance were also the most frequently selected with LASSO. The performance of blood biomarkers for predicting A+ and T+ status (PET or CSF) remained unchanged after controlling for drivers of variance.

Discussion: This comprehensive analysis demonstrated that the variance in AD blood biomarker concentrations was mainly explained by age, with minor contributions from cognition, brain atrophy, and genetics, conversely to CSF measures. These results challenge the use of blood biomarkers as isolated stand-alone biomarkers for AD.

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Conflict of interest statement

V. Bouteloup, I. Pellegrin, B. Dubois, and G. Chene have no conflict of interest to declare. During the past 3 years, V. Planche was a local unpaid investigator or sub-investigator for clinical trials granted by NovoNordisk, Biogen, TauRx Pharmaceuticals, Janssen, Green Valley Pharmaceuticals, and Alector. He received consultant fees for animal studies from Motac Neuroscience Ltd., outside the submitted work. C. Dufouil has no conflict of interest to declare. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Proportions of Variance Explained by Clinical Features of AD for Blood and CSF Biomarker Concentrations: The MEMENTO Cohort
Green: neuropsychological tests, blue: imaging, and red: genetic. Blood biomarkers: n = 2,257; CSF subsample: n = 305. Aβ = β-amyloid; p181-tau = 181-phosphorylated tau.
Figure 2
Figure 2. Proportions of the Variance Explained by Clinical Features of AD for Blood and CSF Biomarker Concentrations According to Amyloid Status: The MEMENTO Cohort
Green: neuropsychological tests, blue: imaging, and red: genetic. Blood biomarkers: Amyloid+ n = 234, Amyloid− n = 666; CSF subsample: Amyloid+ n = 88, Amyloid− n = 217. Aβ = β-amyloid; p181-tau = 181-phosphorylated tau.
See this image and copyright information in PMC

References

    1. Sperling RA, Aisen PS, Beckett LA, et al. . Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280-292. doi:10.1016/j.jalz.2011.03.003 - DOI - PMC - PubMed
    1. Planche V, Villain N. US Food and Drug Administration approval of aducanumab: is amyloid load a valid surrogate end point for Alzheimer disease clinical trials? JAMA Neurol. 2021;78(11):1307-1308. doi:10.1001/jamaneurol.2021.3126 - DOI - PubMed
    1. Tosun D, Veitch D, Aisen P, et al. . Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers. Brain Commun. 2021;3(2):fcab008. doi:10.1093/braincomms/fcab008 - DOI - PMC - PubMed
    1. Ni M, Zhu ZH, Gao F, et al. ; CANDI Consortium. Plasma core Alzheimer's disease biomarkers predict amyloid deposition burden by positron emission tomography in Chinese individuals with cognitive decline. ACS Chem Neurosci. 2023;14(1):170-179. doi:10.1021/acschemneuro.2c00636 - DOI - PubMed
    1. Moscoso A, Grothe MJ, Ashton NJ, et al. ; Alzheimer's Disease Neuroimaging Initiative. Time course of phosphorylated-tau181 in blood across the Alzheimer's disease spectrum. Brain. 2021;144(1):325-339. doi:10.1093/brain/awaa399 - DOI - PMC - PubMed