Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

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  • Additional Information
    • Corporate Authors:
      Alzheimer’s Disease Neuroimaging Initiative (ADNI)
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101266600 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1326 (Electronic) Linking ISSN: 17501326 NLM ISO Abbreviation: Mol Neurodegener Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, 2006-
    • Subject Terms:
      Alzheimer Disease*/cerebrospinal fluid ; tau Proteins*/cerebrospinal fluid ; Amyloid Precursor Protein Secretases*/cerebrospinal fluid ; Amyloid Precursor Protein Secretases*/metabolism ; Amyloid beta-Peptides*/cerebrospinal fluid ; Neurogranin*/cerebrospinal fluid ; Aspartic Acid Endopeptidases*/cerebrospinal fluid ; Biomarkers*/cerebrospinal fluid; Humans ; Aged ; Male ; Female ; Middle Aged ; Aged, 80 and over
    • Abstract:
      Background: Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy.
      Methods: This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts.
      Results: As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts.
      Conclusions: The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.
      (© 2024. The Author(s).)
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    • Contributed Indexing:
      Keywords: Alzheimer’s disease; Amyloid; BACE1; Cerebrospinal fluid; Neurodegeneration; Neurogranin; Tau proteinopathy
    • Accession Number:
      0 (tau Proteins)
      EC 3.4.- (Amyloid Precursor Protein Secretases)
      0 (Amyloid beta-Peptides)
      132654-77-4 (Neurogranin)
      EC 3.4.23.46 (BACE1 protein, human)
      EC 3.4.23.- (Aspartic Acid Endopeptidases)
      0 (Biomarkers)
      0 (MAPT protein, human)
    • Publication Date:
      Date Created: 20241008 Date Completed: 20241009 Latest Revision: 20241011
    • Publication Date:
      20241011
    • Accession Number:
      PMC11460012
    • Accession Number:
      10.1186/s13024-024-00755-3
    • Accession Number:
      39380095