Yu Meichen, Risacher Shannon L, Nho Kwangsik T, Wen Qiuting, Oblak Adrian L, Unverzagt Frederick W, Apostolova Liana G, Farlow Martin R, Brosch Jared R, Clark David G, Wang Sophia, Deardorff Rachael, Wu Yu-Chien, Gao Sujuan, Sporns Olaf, Saykin Andrew J
medRxiv. 2023 Aug 16:2023.08.12.23294017. doi: 10.1101/2023.08.12.23294017.
Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We studied the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies leveraging two large independent cohorts (n = 715) of participants along the AD continuum. We identified several AD susceptibility genes and gene modules in a gene co-expression network with expression profiles related to regional vulnerability to Aβ and tau pathologies in AD. In particular, we found that the positive -to-tau association was only seen in the AD cohort, whereas patients with AD and frontotemporal dementia shared similar positive -to-tau association. Some AD candidate genes showed sex-dependent negative gene-to-Aβ and gene-to-tau associations. In addition, we identified distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. Finally, we proposed a novel analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations. Taken together, our study identified distinct gene expression profiles and biochemical pathways that may explain the discordance between regional Aβ and tau pathologies, and filled the gap between gene-to-pathology associations and cognitive dysfunction in individual AD patients that may ultimately help identify novel personalized pathogenetic biomarkers and therapeutic targets.
We identified replicable cognition-related associations between regional gene expression profiles and selectively regional vulnerability to amyloid-β and tau pathologies in AD.
在阿尔茨海默病（AD）中，β淀粉样蛋白（Aβ）和tau蛋白在不同的神经元系统中积累。虽然尚不清楚为何某些脑区比其他脑区更容易受到Aβ和tau病理变化的影响，但基因表达可能起了作用。我们利用两个大型独立队列（n = 715）的处于AD连续病程中的参与者，研究了全脑基因表达谱与区域对Aβ（基因与Aβ关联）和tau（基因与tau关联）病理变化易感性之间的关联。我们在一个基因共表达网络中鉴定出了几个AD易感性基因和基因模块，其表达谱与AD中区域对Aβ和tau病理变化的易感性相关。特别地，我们发现正向基因与tau关联仅在AD队列中出现，而AD患者和额颞叶痴呆患者具有相似的正向基因与tau关联。一些AD候选基因表现出性别依赖性的负向基因与Aβ及基因与tau关联。此外，我们鉴定出了与基因与Aβ关联以及基因与tau关联相关的不同生化途径。最后，我们提出了一个新的分析框架，将鉴定出的基因与病理关联与个体水平上AD的认知功能障碍联系起来，提示了基因与病理关联的潜在临床意义。综上所述，我们的研究鉴定出了不同的基因表达谱和生化途径，这些可能解释了区域Aβ和tau病理变化之间的不一致性，并填补了个体AD患者中基因与病理关联和认知功能障碍之间的空白，这最终可能有助于识别新的个性化致病生物标志物和治疗靶点。
我们在区域基因表达谱与AD中对淀粉样β蛋白和tau病理变化的选择性区域易感性之间鉴定出了可重复的与认知相关的关联。
