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Cited by 241Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.

Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum

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Milà‐Alomà, Marta, Salvadó, Gemma, Gispert, Juan Domingo, Vilor‐Tejedor, Natalia, Grau‐Rivera, Oriol, Sala‐Vila, Aleix, Sánchez‐Benavides, Gonzalo, Arenaza‐Urquijo, Eider M., Crous‐Bou, Marta, González‐de‐Echávarri, José Maria, Minguillon, Carolina, Fauria, Karine, Simon, Maryline, Kollmorgen, Gwendlyn, Zetterberg, Henrik, Blennow, Kaj, Suárez‐Calvet, Marc, Molinuevo, José Luis, for the ALFA study·2020·Alzheimer's & Dementia
DOI 10.1002/alz.12131PMC PMC7586814
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Abstract

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys ® immunoassays to measure cerebrospinal fluid (CSF) amyloid‐β (Aβ)42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α‐synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum . Results: CSF t‐tau, p‐tau, and neurogranin increase throughout aging only in Aβ‐positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p‐tau and p‐tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p‐tau; t‐tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum .

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FIGURE 1 Comparison of cerebrospinal fluid (CSF) biomarkers between AT groups. Dot and box plots depicting the levels of each CSF biomarker in each of the AT groups. The box plots depict the median (horizontal bar), interquartile range (IQR, hinges), and 1.5 × IQR (whiskers). Because our goal is to assess CSF biomarkers in the Alzheimer's continuum, we did not include the A–T+ group (ie, non‐AD pathologic change) in the analyses, but this group is included in the figure for the sake of completeness. P‐values were assessed by a one‐way analysis of covariance adjusted by age and sex, followed by Tukey corrected pair‐wise post hoc comparisons
FIGURE 1 Comparison of cerebrospinal fluid (CSF) biomarkers between AT groups. Dot and box plots depicting the levels of each CSF biomarker in each of the AT groups. The box plots depict the median (horizontal bar), interquartile range (IQR, hinges), and 1.5 × IQR (whiskers). Because our goal is to assess CSF biomarkers in the Alzheimer's continuum, we did not include the A–T+ group (ie, non‐AD pathologic change) in the analyses, but this group is included in the figure for the sake of completeness. P‐values were assessed by a one‐way analysis of covariance adjusted by age and sex, followed by Tukey corrected pair‐wise post hoc comparisonsCC BY-NC-ND · PubMed Central
FIGURE 2 Association of cerebrospinal fluid (CSF) biomarkers with age. Scatter plots representing the associations of each of the CSF biomarkers with age in the A–T– (ie, normal AD biomarkers) and the A+T* (ie, Alzheimer's continuum) groups. Each point depicts the value of the CSF biomarker of an individual and the solid lines indicate the regression line for each of the groups. The standardized regression coefficients (β) and the P‐values are shown and were computed using a linear model adjusting for age, sex, and apolipoprotein E (APOE)‐ε4. Additionally, we also computed the “Aβ42/40 x age” interaction term. All P‐values are corrected for multiple comparisons using the FDR approach
FIGURE 2 Association of cerebrospinal fluid (CSF) biomarkers with age. Scatter plots representing the associations of each of the CSF biomarkers with age in the A–T– (ie, normal AD biomarkers) and the A+T* (ie, Alzheimer's continuum) groups. Each point depicts the value of the CSF biomarker of an individual and the solid lines indicate the regression line for each of the groups. The standardized regression coefficients (β) and the P‐values are shown and were computed using a linear model adjusting for age, sex, and apolipoprotein E (APOE)‐ε4. Additionally, we also computed the “Aβ42/40 x age” interaction term. All P‐values are corrected for multiple comparisons using the FDR approachCC BY-NC-ND · PubMed Central
FIGURE 3 Cerebrospinal fluid (CSF) biomarker trajectories. The graphs represent the z‐scores changes of each CSF biomarker using the mean and the standard deviation of that CSF biomarker in the A–T– group as a reference. The resulting z‐scores are shown as a function of CSF Aβ42/40 (A) p‐tau (B) or p‐tau/Aβ42 (C) using a robust local weighted regression method. The solid lines depict the trajectory of each CSF biomarker. The dashed lines depict the cutoff for CSF Aβ42/40, p‐tau, and p‐tau/Aβ42, respectively. The horizontal axis direction of CSF Aβ42/40 (A) was inverted.
FIGURE 3 Cerebrospinal fluid (CSF) biomarker trajectories. The graphs represent the z‐scores changes of each CSF biomarker using the mean and the standard deviation of that CSF biomarker in the A–T– group as a reference. The resulting z‐scores are shown as a function of CSF Aβ42/40 (A) p‐tau (B) or p‐tau/Aβ42 (C) using a robust local weighted regression method. The solid lines depict the trajectory of each CSF biomarker. The dashed lines depict the cutoff for CSF Aβ42/40, p‐tau, and p‐tau/Aβ42, respectively. The horizontal axis direction of CSF Aβ42/40 (A) was inverted.CC BY-NC-ND · PubMed Central

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Authors
Milà‐Alomà, M., Salvadó, G., Gispert, J. D., Vilor‐Tejedor, N., Grau‐Rivera, O., Sala‐Vila, A., Sánchez‐Benavides, G., Arenaza‐Urquijo, E. M., Crous‐Bou, M., González‐de‐Echávarri, J. M., Minguillon, C., Fauria, K., Simon, M., Kollmorgen, G., Zetterberg, H., Blennow, K., Suárez‐Calvet, M., Molinuevo, J. L., & study, F. T. A.
Affiliations
  • Universitat Pompeu Fabra (ES)
  • Pasqual Maragall Foundation (ES)
  • Barcelonaβeta Brain Research Center (BBRC) Pasqual Maragall Foundation Barcelona Spain
  • Harvard University (US)
  • F. Hoffmann-La Roche AG (CH)
  • Roche Diagnostics GmbH Penzberg Germany
  • Sahlgrenska University Hospital (SE)
Corresponding author
Suárez‐Calvet, Marc
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2020-06-23
Volume
16
Issue
10
Pages
1358-1371
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.12131
PMC
PMC7586814
OpenAlex
W3037038790
Cited by
241
References
51
Citations by year
2026: 30 · 2025: 45 · 2024: 53 · 2023: 34 · 2022: 41 · 2021: 33 · 2020: 5
FWCI
17.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by-nc-nd)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
“la Caixa” Foundation (ID 100010434)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
preclinical Alzheimer's disease
MeSH terms
Aged, Alzheimer Disease, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Nerve Degeneration, Neuroglia, Synapses, Biomarkers, Amyloid beta-Peptides, tau Proteins, Prodromal Symptoms

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