APOE\u03b54 is the most well-established genetic risk factor for sporadic Alzheimer\u2019s disease and is associated with cerebral amyloid-\u03b2. However, the association between APOE\u03b54 and tau pathology, the other major proteinopathy of Alzheimer\u2019s disease, has been controversial. Here, we sought to determine whether the relationship between APOE\u03b54 and tau pathology is determined by local interactions with amyloid-\u03b2. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer\u2019s disease subjects: (1) 211 participants who underwent tau-PET with [18F]MK6240 and amyloid-PET with [18F] AZD4694, (2) 264 individuals who underwent tau-PET with [18F]Flortaucipir and amyloid-PET with [18F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [18F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOE\u03b54 and amyloid-\u03b2 on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOE\u03b54 and amyloid-\u03b2, rather than the sum of their independent effects, was related to increased tau load in Alzheimer\u2019s disease-vulnerable regions. The interaction between one APOE\u03b54 allele and amyloid-\u03b2was related to increased tau load, while the interaction between amyloid-\u03b2and two APOE\u03b54 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 APOE\u03b54 genotype involves mechanisms associated with both amyloid-\u03b2 and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.<\/p>\n","protected":false},"author":19,"featured_media":0,"template":"","meta":{"_acf_changed":false},"studies-relation":[],"class_list":["post-4438","ccna_publication","type-ccna_publication","status-publish","hentry"],"acf":[],"yoast_head":"\n