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Cardiac biomarkers are enzymes, proteins, and hormones released into the blood when cardiac cells are injured. They are powerful tools for triaging.
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Area of Science:

  • Neurodegenerative diseases
  • Alzheimer's disease (AD)
  • Parkinson's disease (PD)

Background:

  • Mixed pathologies, including Alzheimer's disease (AD) and alpha-synucleinopathy, contribute to diverse clinical presentations and disease progression.
  • The transcriptional risk effect of alpha-synucleinopathy on clinical outcomes in AD remains poorly understood.
  • A blood-based transcriptional risk score for Parkinson's disease (PD-TRS) was developed to assess alpha-synucleinopathy.

Purpose of the Study:

  • To investigate the association between blood-based PD-TRS and longitudinal cognitive function in individuals with AD.
  • To examine the relationship between PD-TRS and the presence of alpha-synuclein seeds in cerebrospinal fluid (CSF).
  • To evaluate the impact of PD-TRS on cognitive decline in relation to CSF alpha-synuclein seed levels.

Main Methods:

  • Prioritized target genes using PD genome-wide association study and expression quantitative trait locus data via Mendelian randomization.
  • Calculated PD-TRS using blood transcriptome data from two independent cohorts: ADNI (n=661) and ANMerge (n=665).
  • Performed association analyses of PD-TRS with longitudinal cognition and CSF alpha-synuclein seed amplification assay (SAA) positivity.

Main Results:

  • Higher PD-TRS was significantly associated with accelerated cognitive decline rates in both ADNI and ANMerge cohorts.
  • Elevated PD-TRS correlated with increased likelihood of alpha-synuclein SAA positivity in CSF within the ADNI cohort.
  • A significant interaction between PD-TRS and CSF SAA positivity was observed, with higher PD-TRS linked to faster cognitive decline specifically in SAA-positive individuals.

Conclusions:

  • Blood-based PD-TRS may serve as a biomarker for detecting CSF alpha-synuclein SAA positivity in AD.
  • PD-TRS shows potential in reflecting longitudinal cognitive decline associated with mixed alpha-synucleinopathy in AD.
  • This research advances the identification of a blood-based biomarker for assessing mixed pathologies in Alzheimer's disease.