CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology.
• Genetic factors, including cytochrome P450 (CYP) gene polymorphisms, are increasingly recognized for their role in AD pathogenesis.
• Understanding the genetic underpinnings of Aβ accumulation is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the association between CYP polymorphisms and Aβ pathology in individuals with Alzheimer's disease.
• To examine this relationship across the spectrum of clinical AD using both in vivo and postmortem data.
• To explore the impact of identified genetic associations on cognitive function.

Main Methods:

• A candidate-gene approach was employed, analyzing 28 single nucleotide polymorphisms across 5 CYP genes.
• Amyloid-beta (Aβ) load was measured using in vivo [18F]florbetapir PET SUVR in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.
• Significant findings were validated using plasma and cerebrospinal fluid (CSF) Aβ levels, Aβ/p-tau ratios, and postmortem brain Aβ measurements.

Main Results:

• A significant association was found between the CYP2C19 gene variant rs4388808 and reduced Aβ PET SUVR (p=0.0006).
• Carriers of the minor allele (MA) of rs4388808 exhibited lower Aβ load in specific brain regions, higher CSF Aβ, and an elevated Aβ/p-tau ratio.
• Postmortem analysis confirmed lower Aβ load in MA carriers, who also demonstrated better global cognition mediated by Aβ levels.

Conclusions:

• The CYP2C19 polymorphism rs4388808 is associated with reduced Aβ pathology in Alzheimer's disease.
• The minor allele of rs4388808 demonstrates a protective effect against Aβ accumulation and may influence cognitive function.
• Further research is warranted to elucidate the precise biological mechanisms underlying this protective genetic association.