APOEε4 potentiates the relationship between amyloid-β and tau pathologies

Abstract

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the other major proteinopathy of Alzheimer's disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with [ 18 F]MK6240 and amyloid-PET with [ 18 F] AZD4694, (2) 264 individuals who underwent tau-PET with [ 18 F]Flortaucipir and amyloid-PET with [ 18 F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [ 18 F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer's disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.

Synergy between amyloid-β and tau in Alzheimer’s disease

“…Several additional processes likely modulate A-tau interactions, including vascular changes (Box 3), ageing (Box 4), lipid metabolism, myelination, vesicle trafficking, autophagy, proteasome function, endosomal transport and mitochondrial function, since at least some experimental data are suggestive of both independent and interacting effects of A or tau on each of these processes. Indeed, lipid-metabolism related genes are related to the spread of both A and tau pathology in human AD 35 , and recent tau/A-PET revealed a synergistic interaction between APOE4 status and A levels on tau burden in the brain, as well as levels of p-tau in CSF, with the strongest effects seen in homozygous APOE4 carriers 110 . The LDL-receptor-related-protein 1 (LRP1) appears ideally positioned to modify A-tau synergy, since it can not only bind tau and mediate its neuronal uptake and spread, but also interact directly with APP, A and APOE4, thereby regulating A production and clearance 111,112 .…”

CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

“…In humans, APOE4 carriers display a higher level of neurodegeneration for a similar level of amyloid pathology [11,63] and seem to progress faster to more advanced stages of the disease [67]. A PET-study in humans also demonstrated a combined effect of APOE status and amyloid load on tau pathology and spreading [61]. Importantly, recent work identified a protective APOE mutation in a human autosomal dominant AD setting.…”

Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment

“…A global neocortical [ 18 F]AZD4694 SUVR was estimated for each study participant by averaging the [ 18 F]AZD4694 SUVR from the precuneus, prefrontal, orbitofrontal, temporal, parietal, anterior, and posterior cingulate cortices. [ 18 F]MK6240 SUVRs were calculated in a Braak stage I–II region of interest (ROI) comprising the entorhinal cortex and hippocampus 16 , 17 as well as a temporal meta-ROI comprising the entorhinal cortex, hippocampus, fusiform, parahippocampal, inferior temporal, and middle temporal cortices. 18 …”

“…[ 18 F]MK6240 SUVRs were calculated in a Braak stage I-II ROI comprising the entorhinal cortex and hippocampus as reported in 16,17 , as well as a temporal meta-ROI comprising the entorhinal cortex, hippocampus, fusiform, parahippocampal, inferior temporal and middle temporal cortices 18 .…”