Given that APOE ?4 and education have opposing influences on the onset of cognitive impairment and both strongly influence FDG metabolism in the elderly, we hypothesized that these effects may be mediated through independent influences on tau deposition and the relationship of tau with FDG metabolism.

Analyze the association of APOE ?4 and education with regional tau deposition and the impact of tau on FDG metabolism in older adults.

We identified 325 individuals 65 years old and over (53% male, 90% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging who underwent amyloid (PiB-PET), tau (AV1451-PET), and FDG-PET neuroimaging and APOE allele typing.  Regional tau burden and FDG metabolism was estimated for 43 atlas-defined regions.  Association tests utilized APOE ?4 status (presence vs. absence) and education (total years; high vs. low using a cutoff of 14 years) as predictors and regional tau burden and regional FDG/tau ratio as outcomes.  Age, sex, and composite vascular risk were used as primary covariates, with global amyloid burden as an additional covariate for secondary analyses.

Although APOE ?4 was associated with higher tau (p<0.001, Cohen’s d=0.42) and lower FDG/tau ratio (p=0.01, d=0.33) in the entorhinal cortex in the population, these associations were completely attenuated after additionally controlling for amyloid burden.  We identified no significant effects of education on any phenotype.  Global amyloid burden was the strongest driver of tau levels in AD-signature regions.  Age and regional tau were the strongest drivers of hypometabolism in most regions.

In this study, we identified no independent effect of APOE ?4 or education on tau accumulation.  Our results suggest that tau deposition is largely related to amyloid burden, and that effects of APOE ?4 and education on cognitive impairment are likely not mediated by direct effects on tau pathophysiology.