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

Abstract

Background: To assess effects of apolipoprotein E (ApoE) ε4 genotype on 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 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 Aβ burden depending on the existing amyloidosis and enhances vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

Population pharmacokinetics and standard uptake value ratio of aducanumab, an amyloid plaque–removing agent, in patients with Alzheimer’s disease

“…This could be attributed to fewer number of ApoE ε4 carrier homozygote subjects relative to ApoE ε4 carrier heterozygotes (1‐copy of ApoE ε4 allele) and noncarriers within the population. Based on literature evidence, physiological relevance, along with the significant improvement in OFV, both homozygote and heterozygote carriers (as well as noncarriers) were included as covariates, despite the large CI for carrier homozygote 10–12 …”

“…Based on literature evidence, physiological relevance, along with the significant improvement in OFV, both homozygote and heterozygote carriers (as well as noncarriers) were included as covariates, despite the large CI for carrier homozygote. [10][11][12] The relevance of these associated covariates is shown in Figure 3a and Figure 3b. Overall, it can be inferred that, except for age, all other identified covariates had a minimal effect on PK-PD parameters (Baseline, E max , and K out ) or as measured using ∆SUVR at steady-state.…”

Effects of amyloid and APOE4 on medial temporal lobe subregions in cognitively unimpaired elderly

“…However, it is important to note that this work was performed using standard T1 isotropic 1 mm 3 images, where subfields were not investigated. Recently, several studies showed higher MTL tau-PET uptake in APOE ε4 carriers in comparison to non-carriers (Ramanan et al, 2019; Baek et al, 2020; Pereira et al, 2020; Therriault et al, 2020; La Joie et al, 2021; Salvadó et al, 2021). Note that while the APOE ε4 allele is thought to promote tau pathology, the mechanism underlying these effects may be indirect, mediated by APOE effects on microglia (Serrano-Pozo et al, 2021).…”

Aging the Brain: Multi-Region Methylation Principal Component Based Clock in the Context of Alzheimer’s Disease

“…One limitation, however, is that our dataset shows an enrichment of APOE ε4 carriers with MCI and dementia over cognitively normal counterparts. Regardless, this may reflect APOE ε4 carriers' increased neuropathological burden [57,58],…”