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APOEε4 potentiates the relationship between amyloid-β and tau pathologies
Joseph Therriault1,2,3, Andrea L Benedet1,2,3, Tharick A Pascoal1,2,3
1Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
Molecular Psychiatry
|March 13, 2020
Summary
The presence of APOEε4 combined with amyloid-β, not their individual effects, increases tau pathology in Alzheimer's disease. This interaction explains the genetic risk for dementia.
Area of Science:
- Neuroscience
- Genetics
- Radiology
Background:
- APOEε4 is a significant genetic risk factor for Alzheimer's disease (AD), linked to amyloid-β (Aβ) deposition.
- The relationship between APOEε4 and tau pathology, another key AD hallmark, remains debated.
- Understanding these interactions is crucial for elucidating AD pathogenesis and developing targeted therapies.
Purpose of the Study:
- To investigate whether APOEε4 influences tau pathology through interactions with amyloid-β.
- To assess the combined effect of APOEε4 genotype and amyloid-β burden on tau accumulation in the brain.
- To explore the implications for Alzheimer's disease risk and therapeutic strategies.
Main Methods:
- Analysis of three independent cohorts comprising cognitively unimpaired, mild cognitive impairment, and Alzheimer's disease participants.
- Utilized PET imaging ([18F]MK6240, [18F]Flortaucipir for tau; [18F]AZD4694, [18F]Florbetapir for amyloid-β) and lumbar puncture data.
- Employed voxel-wise regression models to evaluate the interactive effects of APOEε4 and amyloid-β on tau load, controlling for age and diagnosis.
Main Results:
- The interaction between APOEε4 and amyloid-β, not their independent effects, significantly correlated with increased tau load in AD-vulnerable brain regions.
- Carrying one APOEε4 allele in combination with amyloid-β was associated with higher tau accumulation.
- Individuals with two APOEε4 alleles and amyloid-β exhibited a more extensive pattern of tau aggregation.
Conclusions:
- The elevated dementia risk associated with APOEε4 genotype is mediated by synergistic mechanisms involving both amyloid-β and tau pathologies.
- These findings support a model where APOEε4 exacerbates AD progression through combined effects on Aβ and tau.
- Results may inform the design of future therapeutic trials targeting amyloid or tau pathways in Alzheimer's disease.
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