Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer’s disease

Abstract

Background: To assess the effects of apolipoprotein E (ApoE) ε4 genotype on amyloid-β (Aβ) and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum.Methods: Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for the partial-volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.Results: The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.Conclusions: Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on the Aβ burden depending on the existing amyloidosis and may enhance vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

“…Accumulation of protein Tau is also likely to play a role as a study showed an increase of tau PET uptake in the entorhinal cortex and hippocampus among ε4carriers independently of Aβ load [37]. Poorer cognition has been related to tau PET accumulation, even among Aβ-negative ε4 carriers [38], suggesting that the APOE ε4 allele may enhance the vulnerability to progressive tau accumulation in the AD spectrum [39].…”

Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer’s and Lewy body neuropathology

“…Interestingly, in PET studies among asymptomatic APOE ε4 carriers, the largest correlation between the cerebral metabolic rate for glucose and APOE ε4 status was noted in the parietotemporal regions of the brain [ 37 ]. The parietotemporal cortex was noted as having the highest degree of tau accumulation on 8 F-flortaucipir PET among APOE ε4 carriers compared to non-carriers regardless of the amyloid positive status [ 38 ]. Even though the specific mechanism of this parietotemporal vulnerability is unclear, one could speculate that regional neuronal energy metabolism vulnerabilities not unlike the posterior cingulate in AD are possible leading to early regional synaptic loss [ 39 ].…”

Vascular risk is not associated with PET measures of Alzheimer’s disease neuropathology among cognitively normal older adults

“…The discrepancy might be due to differences in sample composition: although both studies assessed vascular risk with the Framingham 10-year CVD risk score, Rabin et al found a wider range (4% - 74%) of CVD risk in their sample compared to ours (4% - 51%). Additionally, their sample consists of a higher percentage of APOE e4 carriers (31% vs. 26%), who on average have been shown to have greater vascular risk (Mielke et al, 2011) and AD neuropathology (Baek et al, 2020).…”