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Original Investigation
November 6, 2023

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

Author Affiliations
  • 1Institute for Stroke and Dementia Research, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  • 2Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  • 3Eli Lilly and Company, Indianapolis, Indiana
  • 4Department of Nuclear Medicine, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  • 5Munich Cluster for Systems Neurology, Munich, Germany
  • 6German Center for Neurodegenerative Diseases, Munich, Germany
  • 7Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden
JAMA Neurol. Published online November 6, 2023. doi:10.1001/jamaneurol.2023.4038
Key Points

Question  Do apolipoprotein E ε4 (ApoE4) carriers show accelerated amyloid-related tau spreading?

Findings  In this cohort study of 2 longitudinal tau positron emission tomography samples (N = 367), ApoE4 carriers showed an acceleration of amyloid-mediated tau spreading at a lower amyloid threshold compared to ApoE4 noncarriers, controlling for age and sex.

Meaning  ApoE4 carriage was associated with earlier amyloid-induced tau spreading, indicating that the timing of therapeutic windows in antiamyloid therapies may need special consideration in ApoE4 carriers compared to noncarriers to successfully attenuate tau spreading.


Importance  For the Alzheimer disease (AD) therapies to effectively attenuate clinical progression, it may be critical to intervene before the onset of amyloid-associated tau spreading, which drives neurodegeneration and cognitive decline. Time points at which amyloid-associated tau spreading accelerates may depend on individual risk factors, such as apolipoprotein E ε4 (ApoE4) carriership, which is linked to faster disease progression; however, the association of ApoE4 with amyloid-related tau spreading is unclear.

Objective  To assess if ApoE4 carriers show accelerated amyloid-related tau spreading and propose amyloid positron emission tomography (PET) thresholds at which tau spreading accelerates in ApoE4 carriers vs noncarriers.

Design, Setting, and Participants  This cohort study including combined ApoE genotyping, amyloid PET, and longitudinal tau PET from 2 independent samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 237; collected from April 2015 to August 2022) and Avid-A05 (n = 130; collected from December 2013 to July 2017) with a mean (SD) tau PET follow-up time of 1.9 (0.96) years in ADNI and 1.4 (0.23) years in Avid-A05. ADNI is an observational multicenter Alzheimer disease neuroimaging initiative and Avid-A05 an observational clinical trial. Participants classified as cognitively normal (152 in ADNI and 77 in Avid-A05) or mildly cognitively impaired (107 in ADNI and 53 in Avid-A05) were selected based on ApoE genotyping, amyloid-PET, and longitudinal tau PET data availability. Participants with ApoE ε2/ε4 genotype or classified as having dementia were excluded. Resting-state functional magnetic resonance imaging connectivity templates were based on 42 healthy participants in ADNI.

Main Outcomes and Measures  Mediation of amyloid PET on the association between ApoE4 status and subsequent tau PET increase through Braak stage regions and interaction between ApoE4 status and amyloid PET with annual tau PET increase through Braak stage regions and connectivity-based spreading stages (tau epicenter connectivity ranked regions).

Results  The mean (SD) age was 73.9 (7.35) years among the 237 ADNI participants and 70.2 (9.7) years among the 130 Avid-A05 participants. A total of 107 individuals in ADNI (45.1%) and 45 in Avid-A05 (34.6%) were ApoE4 carriers. Across both samples, we found that higher amyloid PET–mediated ApoE4-related tau PET increased globally (ADNI b, 0.15; 95% CI, 0.05-0.28; P = .001 and Avid-A05 b, 0.33; 95% CI, 0.14-0.54; P < .001) and in earlier Braak regions. Further, we found a significant association between ApoE4 status by amyloid PET interaction and annual tau PET increases consistently through early Braak- and connectivity-based stages where amyloid-related tau accumulation was accelerated in ApoE4carriers vs noncarriers at lower centiloid thresholds, corrected for age and sex.

Conclusions and Relevance  The findings in this study indicate that amyloid-related tau accumulation was accelerated in ApoE4 carriers at lower amyloid levels, suggesting that ApoE4 may facilitate earlier amyloid-driven tau spreading across connected brain regions. Possible therapeutic implications might be further investigated to determine when best to prevent tau spreading and thus cognitive decline depending on ApoE4 status.

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