Alzheimer's Imaging Consortium.

Area of Science:

• Neuroscience
• Genetics
• Biomarkers

Background:

• Alzheimer's disease (AD) progression is influenced by genetic factors like Apolipoprotein E ε4 (ApoE4).
• ApoE4 is linked to earlier tau pathology at lower amyloid-beta (Aβ) levels, but mechanisms are unclear.
• Investigating how ApoE4 accelerates Aβ-related tau aggregation is crucial for treatment strategies.

Purpose of the Study:

• To assess how ApoE4 accelerates Aβ-related tau aggregation.
• To determine if ApoE4 promotes Aβ-driven phospho tau (p-tau) secretion or p-tau dependent tau aggregation.
• To investigate the allele dose-dependent effect of ApoE4 on tau pathology.

Main Methods:

• Analysis of APOE-genotyped participants from ADNI and A4 cohorts.
• Integration of fluid biomarkers (plasma ptau217, CSF ptau181) and PET imaging (tau-PET, amyloid-PET).
• Linear regression models to assess interactions between amyloid burden, ApoE4 dosage, and tau markers/accumulation rates.

Main Results:

• ApoE4 allele dosage did not moderate the relationship between amyloid-PET and plasma or CSF p-tau levels.
• A significant ApoE4 allele dose effect was observed in moderating the relationship between plasma ptau217 and tau-PET accumulation, independent of amyloid burden.
• The strongest effect of ApoE4 on tau accumulation was seen in individuals with two ApoE4 alleles.

Conclusions:

• ApoE4 exerts an allele dose-dependent effect on p-tau induced tau aggregation, accelerating tau spread at lower Aβ levels.
• Attenuating soluble p-tau in ApoE4 carriers may mitigate tau fibrilisation and delay dementia onset.
• Personalised therapeutic approaches targeting ApoE4 carriers show potential for Alzheimer's disease treatment.