The interaction of APOE genotype and amyloid‐β PET predicts PET but not CSF measures of tauopathy in regions of high APOE mRNA expression

Abstract

AbstractBackgroundThe apolipoprotein E (APOE) ε4 allele is the most well‐established genetic risk factor for late‐onset Alzheimer disease (AD). The ε4 allele is strongly linked with cerebral β‐amyloidosis whereas its relationship with tauopathy is less established. Here we investigate the relationship between APOE ε4 carrier status, regional amyloid‐β‐ (Aβ) and tau‐ positron emission topography (PET), APOE mRNA expression patterns, and cerebrospinal fluid phosphorylated tau (CSF ptau).Method350 participants from the Knight Alzheimer Disease Research Center (mean age = 69.7) underwent tau‐PET ([18F]‐flortaucipir) and Aβ‐PET ([18F]‐florbetapir) imaging. Tau‐ and Aβ‐ PET data were converted to standardized uptake value ratios (SUVRs). APOE ε4 carrier status was defined by the presence of at least one ε4 allele. CSF ptau data was available for 270 of the participants. Linear regression models were used to predict regional Aβ‐ and tau‐PET levels from APOE ε4 carrier status. Additional models were used to predict regional tau‐PET and CSF ptau from the interaction of APOE genotype and global Aβ‐PET. Age and sex were included as covariates in all models. Regional APOE mRNA expression was derived from the Allen Human Brain Atlas (Fig. 3G).ResultStrong associations were found between elevated regional tau‐ and Aβ‐ PET levels and APOE ε4 carrier status (Fig. 1A, B). There was a significant interaction between APOE genotype and global Aβ‐PET predicting tau‐PET levels specifically in the entorhinal, amygdala, and superior temporal regions (Fig 1C), but not CSF ptau (Fig. 2). The spatial pattern of APOE mRNA expression was significantly associated to the spatial pattern of APOE ε4 genotype exerted on regional tau‐PET, but less so for regional Aβ‐PET (Fig. 3).Conclusion APOE ε4 genotype exerts influence on tauopathy above its effect on Aβ. These effects occur in regions of the brain that have high APOE mRNA expression, suggesting potential local tissue vulnerability to tauopathy. The lack of an interaction in CSF ptau may be due to different roles soluble and aggregated forms of the tau protein play in AD pathophysiology.