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Effects of Alzheimer's disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach. | LitMetric

AI Article Synopsis

  • This study explores the impact of newly identified genetic risk factors for Alzheimer's disease (AD) on its development and related biomarkers.* -
  • Researchers assessed 12 AD risk loci and created a polygenic risk score combining 22 key loci to analyze their relationships with cerebrospinal fluid (CSF) biomarkers and neurofibrillary pathology.* -
  • Findings suggest that these genetic factors contribute to amyloid-β pathology in CSF, potentially linked to increased γ-secretase activity, with APOE-ε4 showing a strong association with CSF Aβ42 levels.*

Article Abstract

Background: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis.

Objective: To investigate the individual and combined risk effects of the newly identified AD loci.

Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex.

Results: Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction.

Conclusions: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

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Source
http://dx.doi.org/10.3233/JAD-140777DOI Listing

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