CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response

Lena Duchateau, Fahri Küҫükali, Arne De Roeck, Mandy M J Wittens, Joke Temmerman, Ilse Weets, Maarten Timmers, Sebastiaan Engelborghs, Maria Bjerke, Kristel Sleegers

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Abstract

BACKGROUND: The Alzheimer's disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.

METHODS: The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aβ1-42, Aβ1-40, P-tau181, T-tau, sAPPα, sAPPβ, YKL-40, and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers and the Aβ ratio between AD patients with or without an ABCA7 PTC mutation or expansion using linear regression on INT-transformed data with APOE-status, age and sex as covariates.

RESULTS: Carriers of ABCA7 expansion mutations had significantly lower Aβ1-42 levels (P = 0.022) compared with non-carrier patients. The effect of the presence of ABCA7 mutations on CSF levels was especially pronounced in APOE ε4-negative carriers. In addition, VNTR expansion carriers had reduced Aβ1-40 (P = 0.023), sAPPα (P = 0.047), sAPPβ (P = 0.016), and YKL-40 (P = 0.0036) levels.

CONCLUSIONS: Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers.

Original languageEnglish
Article number195
Number of pages13
JournalAlzheimer's Research & Therapy
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2023

Bibliographical note

Funding Information:
The research was in part funded by Fund of Scientifc Research Flanders (FWO), special research fund of the University of Antwerp, an Alzheimer’s Association Research grant, and unrestrictive research grants from Janssen Pharmaceutica NV and ADx Neurosciences to the BIODEM lab, UAntwerp. LD is a recipient of a PhD fellowship of FWO

Funding Information:
The research was in part funded by Fund of Scientific Research Flanders (FWO), special research fund of the University of Antwerp, an Alzheimer’s Association Research grant, and unrestrictive research grants from Janssen Pharmaceutica NV and ADx Neurosciences to the BIODEM lab, UAntwerp. LD is a recipient of a PhD fellowship of FWO.

Publisher Copyright:
© 2023, The Author(s).

Keywords

  • ABCA7
  • Alzheimer Disease
  • Amyloid-β
  • CSF Biomarkers
  • Inflammation
  • PTC mutation
  • Tau
  • VNTR expansion

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