APOEε4 potentiates amyloid β effects on longitudinal tau pathology

Nat Aging. 2023 Oct;3(10):1210-1218. doi: 10.1038/s43587-023-00490-2. Epub 2023 Sep 25.


The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aβ effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the living human brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / genetics
  • Amyloid beta-Peptides* / metabolism
  • Apolipoprotein E4* / genetics
  • Heterozygote*
  • Humans
  • Magnetic Resonance Imaging
  • Positron-Emission Tomography
  • tau Proteins / genetics


  • Amyloid beta-Peptides
  • tau Proteins
  • Apolipoprotein E4

Supplementary concepts

  • Alzheimer disease type 2