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

Abstract

ImportanceFor 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.ObjectiveTo 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 ParticipantsThis 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 MeasuresMediation 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).ResultsThe 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 RelevanceThe 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.

The influence of APOEε4 on the pTau interactome in sporadic Alzheimer’s disease

“…This observation aligns with our proteomics findings and further support an effect of APOE ε4 on pTau cellular transport and relocation toward axonal endings and synapses. Tau pathology progresses from neuron to neuron through synaptic connections [ 16 , 28 , 83 , 88 , 93 ]; we hypothesize that the spreading of pathological pTau species is accelerated in APOE ε4/ε4 carriers, in accordance with recent clinical observations [ 8 , 75 ]. In vivo experiments support an Aβ-independent influence of APOE ε4 on Tau-pathology spreading, by demonstrating an exacerbation of Tau pathology in PS19 mice expressing human A POE ε4/ε4 [ 74 ], but a recent study questions this scenario [ 21 ].…”

Association of a pace of aging epigenetic clock with rate of cognitive decline in the Framingham Heart Study Offspring Cohort

“…We conducted exploratory analyses to evaluate sensitivity of associations between pace of aging and cognitive decline to modification by ADRD risk factors: cognitive reserve, sex, and APOE4 carrier status 37,40,43,44,45,46 . Cognitive reserve was not directly observed in our study.…”