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. 2021 May;17(5):788-800.
doi: 10.1002/alz.12245. Epub 2021 Mar 4.

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum

Gemma Salvadó  1   2 , Marta Milà-Alomà  1   2   3   4 , Mahnaz Shekari  1   2   3 , Carolina Minguillon  1   2   4 , Karine Fauria  1   4 , Aida Niñerola-Baizán  5   6 , Andrés Perissinotti  5   6 , Gwendlyn Kollmorgen  7 , Christopher Buckley  8 , Gill Farrar  8 , Henrik Zetterberg  9   10   11   12 , Kaj Blennow  9   10 , Marc Suárez-Calvet  1   2   4   13 , José Luis Molinuevo  1 , Juan Domingo Gispert  1   2   3   6 ; ALFA study
Affiliations

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum

Gemma Salvadó et al. Alzheimers Dement. 2021 May.

Abstract

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages.

Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated.

Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent.

Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.

Keywords: Alzheimer; [18F]flutemetamol; biomarkers; glial activation; inflammation; modulation; neuronal injury; preclinical.

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Conflict of interest statement

JLM is currently a full time employee of H. Lundbeck A/S and priory has served as a consultant or at advisory boards for the following for‐profit companies, or has given lectures in symposia sponsored by the following for‐profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. GK is a full time employee of Roche Diagnostics GmbH. The remaining authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Age and Aβ interaction effects on CSF biomarkers. CSF biomarkers residuals, after adjusting by covariates (sex, education, and APOE‐ε4 status), are compared to global Aβ load measured as Centiloids. Light, medium and dark blue colors depict the three age groups (tertiles): below 60, between 60 and 64 and, above 64 years old, respectively. These groups were used for visualization purposes only. P‐value of each interaction effect is shown in the upper left corner. Statistically significant effects (P < .05) are shown in bold. x axis is depicted in logarithmic scale. Aβ, amyloid‐β; GFAP, glial fibrillary acidic protein; IL‐6, interleukin 6; NfL, neurofilament light; p‐tau, phosphorylated tau; sTREM2, soluble triggering receptor on myeloid cells 2 (TREM2); t‐tau, total tau
FIGURE 2
FIGURE 2
Sex and Aβ interaction effects on CSF biomarkers. CSF biomarkers residuals, after adjusting by covariates (age, education, and APOE‐ε4 status), are compared to global Aβ load measured as Centiloids. Colors represent the two sex groups, with women depicted in dark coral. P‐value of each interaction effect is shown in the upper left corner. Statistically significant effects (P < .05) are shown in bold. x axis is depicted in logarithmic scale. Aβ, amyloid‐β; GFAP, glial fibrillary acidic protein; IL‐6, interleukin 6; NfL, neurofilament light; p‐tau, phosphorylated tau; sTREM2, soluble triggering receptor on myeloid cells 2 (TREM2); t‐tau, total tau
FIGURE 3
FIGURE 3
Aβ mediated effects on CSF biomarkers. Models of mediation for CSF NfL (A,E), sTREM2 (B), GFAP (C,F) and YKL‐40 (D,G) with Aβ PET (upper part) and CSF Aβ (lower part). Models with CSF Aβ as independent variable only included Aβ positive participants (n = 109). The values of each path show the effect (SE). Total effect between Aβ load and each CSF biomarker is shown in dark green (path c); direct effect, after adjusting by mediators, is shown in light green (path c'); and indirect effects are shown in dark blue (path a1b1, mediation effect of p‐tau), in purple (path a2b2, mediation effect of NfL) and in light blue (path a1·d21·b2, mediation effect of p‐tau and NfL). All paths depicted are significant (P < .05), except for direct effect between Aβ and NfL that showed a trend to significance (P < .10, in italics). All paths are adjusted by covariates (age, sex, education, and APOE‐ε4 status). Aβ, amyloid‐β; GFAP, glial fibrillary acidic protein; IL‐6, interleukin 6; NfL, neurofilament light; p‐tau, phosphorylated tau; sTREM2, soluble triggering receptor on myeloid cells 2 (TREM2).
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References

    1. Jack CR, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013;12:207‐216. - PMC - PubMed
    1. Milà‐Alomà M, Suárez‐Calvet M, Molinuevo JL. Latest advances in cerebrospinal fluid and blood biomarkers of Alzheimer's disease. Ther Adv Neurol Disord 2019;12:1‐23. 10.1177/https. - DOI - PMC - PubMed
    1. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015;14:388‐405. - PMC - PubMed
    1. Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, Fagan AM, Hampel H, Mielke MM, Mikulskis A, O’Bryant S, Scheltens P, Sevigny J, Shaw LM, Soares HD, Tong G, Trojanowski JQ, Zetterberg H, Blennow K. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathologica 2018;136(6):821‐853. 10.1007/s00401-018-1932-x. - DOI - PMC - PubMed
    1. Palmqvist S, Insel PS, Stomrud E, et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease. EMBO Mol Med 2019;11:e11170. 10.15252/emmm.201911170. - DOI - PMC - PubMed

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