Associations Between APOE Variants, Tau and α-Synuclein.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Neurodegenerative diseases, or proteinopathies, are defined by misfolded protein aggregates like amyloid-β (Aβ), tau, and α-synuclein.
• Co-pathologies involving these proteins are common in Alzheimer's disease (AD), Parkinson's disease (PD), and related disorders, complicating diagnosis and prognosis.
• The apolipoprotein E (APOE) ε4 allele is a significant genetic risk factor, yet its precise role in linking tau and α-synuclein pathology remains unclear.

Purpose of the Study:

• To review current experimental evidence on the relationships between APOE variants and tau and α-synuclein.
• To highlight knowledge gaps in understanding these proteinopathies and their underlying mechanisms.
• To inform future research directions for improved diagnosis and patient stratification.

Main Methods:

• Analysis of clinical studies using fluid biomarkers (CSF, plasma) and positron emission tomography (PET) imaging.
• Review of basic experimental studies in cellular/molecular biology and animal models.
• Focus on recent advances and identification of limitations, such as the lack of α-synuclein PET tracers.

Main Results:

• Evidence suggests complex associations between APOE variants and tau/α-synuclein biomarkers.
• Co-pathologies frequently occur, contributing to disease heterogeneity and diagnostic challenges.
• Current research is limited by the absence of in vivo α-synuclein imaging and scarce comparative tau PET studies.

Conclusions:

• Understanding the interplay between APOE, tau, and α-synuclein is critical for elucidating neurodegenerative disease mechanisms.
• Multimodal research combining imaging, fluid biomarkers, and genetics is essential.
• Further investigation will aid in differential diagnosis and clinical trial patient stratification.