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New Alzheimer's Disease Genes Linked Through Transcriptome-Wide Study

NEW YORK – In a transcriptome-wide study, researchers have tied two novel genes to Alzheimer's disease, underscoring the role of the hippocampus in the neurodegenerative condition.

The hippocampus — which has a role in learning and memory — is one of the first brain regions affected by Alzheimer's disease and, as the condition progresses, shrinks in size. This suggested to Tianjin Medical University General Hospital's Chunshui Yu that the hippocampus is particularly vulnerable to the effects of Alzheimer's disease and that a transcriptome-wide analysis of the brain region might be able to identify disease-linked genes.

He and his colleagues examined changes in gene expression in the hippocampuses of individuals with Alzheimer's disease. As they reported in PLOS Genetics on Thursday, the researchers identified two dozen genes, including two not previously linked to the condition, that appear to have an effect on Alzheimer's disease through the hippocampus. The expression of these genes was further associated with the loss of neurons and shrinkage of the hippocampus during disease progression.

"The abnormal expression of these genes in hippocampal tissue resulted from genetic mutations [and] may affect the normal development of the hippocampus and/or neuron-related biological processes, which may compromise the structure and function of the hippocampus and therefore raise the risk of AD," Yu, who is at the Tianjin Key Laboratory of Functional Imaging, said in an email.

By combining genomic and transcriptomic data on 111 hippocampal samples with data from two GWAS meta-analyses, the researchers uncovered three dozen genes with significant associations between hippocampal expression and Alzheimer's disease. The two meta-analyses included 455,258 individuals and 63,926 individuals, respectively. 

Through fine-mapping, the researchers homed in on 24 genes that appeared to affect Alzheimer's disease through their expression in the hippocampus. While some of these, like APOE, have previously been linked to Alzheimer's disease, others like PTPN9 and PCDHA4 had not. 

PTPN9 belongs to the protein tyrosine phosphatase family, while PCDHA4 is a member of the protocadherin alpha gene family. Functional analyses suggest that PTPN9 is involved in neurogenesis and dephosphorylation and that PCDHA4 has a role in establishing complex brain network connections. Previous studies suggested knocking down PTPN9 leads to severe neurodevelopmental disorders in mice, while knocking down protocadherin alpha proteins like those encoded by PCDHA4 also affect mouse learning and memory. This suggested to the researchers that PTPN9 and PCDHA4 may affect hippocampus-dependent Alzheimer's disease development.

The researchers additionally validated the genes they identified using the Alzheimer's Disease Neuroimaging Initiative (ADNI) neuroimaging dataset. That dataset included 599 individuals with Alzheimer's disease and 317 cognitively normal individuals. In all, they confirmed that the expression of seven genes in the hippocampus varied between the groups.

Based on imaging data, hippocampal size also correlated with the expression of the 24 disease-linked genes, though the expression of the genes QPCTL and ERCC2 had the greatest effect. Further, the researchers noted that their expression levels in other brain tissues — caudate nucleus accumbens, and putamen — did not appear to correlate with tissue volume, suggesting they have a greater influence on the hippocampus. QPCTL, they noted, interacts with APP, and ERCC2 was linked to a network module tied to many disease-related pathways. 

Yu said he and his colleagues are next going to validate the relationship between the two new genes they uncovered and Alzheimer's disease, study how they affect hippocampal structure and function, and search for ways to prevent hippocampal damage by changing how they are regulated.

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