アルツハイマー病が脳の特定部位を損傷する原因解明の手がかりを得る(Study yields clues to why Alzheimer’s disease damages certain parts of the brain)

言語や視覚の問題など、稀な症状を説明するのに役立つ可能性があります。 Findings could help explain rare symptoms such as problems with language, vision

2022-11-16 ワシントン大学セントルイス

Red and orange areas on these heat maps of human brains show where the gene APOE is most active (top two brain images) and where tangles of the protein tau are most concentrated (bottom two brain images). APOE is the biggest genetic risk factor for Alzheimer’s, and tau tangles drive brain damage in the disease. The similarities in the two sets of maps suggested to researchers at Washington University School of Medicine in St. Louis that APOE plays a role in making certain brain areas particularly vulnerable to Alzheimer’s damage. (Image: Diana Hobbs)

<関連情報>

• https://source.wustl.edu/2022/11/study-yields-clues-to-why-alzheimers-disease-damages-certain-parts-of-the-brain/
• https://www.science.org/doi/10.1126/scitranslmed.abl7646

APOE ε4遺伝子型、アミロイドβ、および性別は、APOE mRNA高発現領域におけるタウを予測するために相互作用する。 APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression

Aylin Dincer,Charles D. Chen,Nicole S. McKay,Lauren N. Koenig,Austin McCullough,Shaney Flores,Sarah J. Keefe,Stephanie A. Schultz,Rebecca L. Feldman,Nelly Joseph-Mathurin,Russ C. Hornbeck,Carlos Cruchaga,Suzanne E. Schindler,David M. Holtzman,John C. Morris,Anne M. Fagan,Tammie L.S. Benzinger,Brian A. Gordon
Science Translational Medicine  Published:16 Nov 2022
DOI: 10.1126/scitranslmed.abl7646

The genetic of tau pathology

APOE ε4 allele is associated with increased risk of developing late-onset Alzheimer’s disease (AD). However, the relationship between the APOE ε4 allele and the major hallmarks of AD pathophysiology remains to be completely elucidated. Now, Dincer et al. used imaging data, cerebrospinal fluid, and mRNA from APOE ε4 carrier and noncarrier participants and showed that APOE ε4 influenced brain Aβ, tau, and CSF ptau₁₈₁. Moreover, APOE ε4 was associated with increased tau burden in regions with high APOE mRNA expression. The results suggest that the severity of brain pathology might be driven by gene expression. APOE status should be considered when evaluating disease progression and clinical trials.

Abstract

The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau₁₈₁). Three hundred fifty participants underwent imaging, and 270 had ptau₁₈₁. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau₁₈₁. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau₁₈₁. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.