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. 2020 Apr 1;77(4):470-479.
doi: 10.1001/jamaneurol.2019.4421.

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

Joseph Therriault  1   2   3 , Andrea L Benedet  1   2   3 , Tharick A Pascoal  1   2   3 , Sulantha Mathotaarachchi  1 , Mira Chamoun  1   2 , Melissa Savard  1 , Emilie Thomas  1   2 , Min Su Kang  1   2   3 , Firoza Lussier  1   2   3 , Cecile Tissot  1   2   3 , Marlee Parsons  1   2   3 , Muhammad Naveed Iqbal Qureshi  1   2 , Paolo Vitali  1   2 , Gassan Massarweh  3   4 , Jean-Paul Soucy  2   3 , Soham Rej  5 , Paramita Saha-Chaudhuri  6 , Serge Gauthier  1   2   5 , Pedro Rosa-Neto  1   2   3   5
Affiliations

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

Joseph Therriault et al. JAMA Neurol. .

Abstract

Importance: Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial.

Objective: To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age.

Design, setting, and participants: This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study.

Main outcomes and measures: A main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio.

Results: The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001).

Conclusions and relevance: Our results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gauthier has received honoraria for serving on the scientific advisory boards of Alzheon, Axovant, Lilly, Lundbeck, Novartis, Schwabe, and TauRx and on the Data Safety Monitoring Board of a study sponsored by Eisai and studies run by the Alzheimer’s Disease Cooperative Study and by the Alzheimer’s Therapeutic Research Institute. Dr Mathotaarachchi reported personal fees from Enigma Biomedical Group outside the submitted work. Dr Soucy reported grants from CIHR during the conduct of the study. Dr Rej reported grants from Satellite Healthcare outside the submitted work. Dr Gauthier reported personal fees from TauRx, Alzheon, Axovant, Lilly, Lundbeck, Novartis, Schwabe, and Boeringher; other support from IntelGenx, Eisai, the Alzheimer’s Disease Cooperative Study, the Alzheimer’s Therapeutic Research Institute, and Banner-Health; and grants from from Weston Brain Institute, CIHR, FQRS, and the National Institutes of Health outside the submitted work.

Figures

Figure 1.
Figure 1.. Association of Medial Temporal Tau Positron Emission Tomography With Apolipoprotein E ε4 (APOEε4) Independent of Amyloid-β
T-statistical parametric maps were corrected for multiple comparisons using a random field theory cluster threshold of P < .001, overlaid on the Alzheimer's Disease Neuroimaging Initiative reference template. Age, sex, clinical diagnosis, and amyloid-β standardized uptake value ratio were used as covariates the model. A, Voxelwise analyses revealed that APOEε4 carriership was associated with increased fluorine 18–labeled [18F] MK6240 in the bilateral entorhinal cortex and hippocampus. B, Voxelwise analyses revealed that APOEε4 carriership was associated with increased [18F]flortaucipir in the bilateral entorhinal cortex.
Figure 2.
Figure 2.. Associations Between Medial Temporal Tau Positron Emission Tomography (PET) and Neocortical Amyloid PET Stratified by Apolipoprotein E ε4 (APOEε4) Genotype
A, Clusters that remained significant after multiple comparisons correction with random field theory at P < .001 were used to extract tau-PET standardized uptake value ratio (SUVR) values in the TRIAD cohort (left) and ADNI cohort (right). B, Scatterplots displaying associations between medial temporal tau PET and neocortical amyloid PET stratified by APOEε4 genotype in TRIAD (left) and ADNI (right). Density plots are provided along the x and y axes to visualize the distribution of the data for neocortical amyloid PET and medial temporal tau PET SUVR, respectively. In the TRIAD cohort, APOEε4 carriership was associated with medial temporal fluorine 18–labeled [18F] MK6240 SUVR (t = 4.42; β = 0.33; 95% CI, 0.19-0.49). In the ADNI cohort, APOEε4 carriership was significantly associated with medial temporal [18F]flortaucipir SUVR (t = 4.527; β = 0.13; 95% CI, 0.08-0.19).
Figure 3.
Figure 3.. Association Between Medial Temporal Tau Positron Emission Tomography (PET) and Apolipoprotein E ε4 (APOEε4) Stratified by Cognitive Status
A, In cognitively unimpaired participants (n = 124), APOEε4 carriership was associated with fluorine 18–labeled [18F] MK6240 standardized uptake value ratio (SUVR) in the bilateral entorhinal cortex and hippocampus. In cognitively impaired participants (n = 100), APOEε4 carriership was associated with increased [18F]MK6240 in the bilateral hippocampus. B, In cognitively unimpaired patients (n = 157), APOEε4 carriership was associated with [18F]flortaucipir SUVR in the left entorhinal cortex. In cognitively impaired patients (n = 109), APOEε4 carriership was associated with increased [18F]flortaucipir in the bilateral entorhinal cortices and hippocampus. Age, sex, and amyloid-β SUVR were used as covariates in each model. Results remained similar when using partial volume–corrected PET data. CU indicates cognitively unimpaired; CI, cognitively impaired.
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