Scientists and clinicians have been aware of Alzheimer's disease, the most common cause of dementia, for decades, but there is still a lot we don’t know about what causes it. One major challenge is that it affects the human brain, which we cannot study directly. But researchers have now found genetic changes in the brains of Alzheimer’s patients that happen to DNA that alter how genes are regulated. This work may show why Alzheimer’s can vary so significantly from one patient to another. The findings have been reported in Nature Communications.
A buildup of aberrant proteins in the brain, known as amyloid plaques, and tau tangles are hallmarks of Alzheimer’s. Brain cells shrink and die, impacting cognition. The disease can eventually lead to death.
In this study, researchers were able to assess post-mortem brain tissue that had been donated by 472 Alzheimer’s patients and unaffected individuals. The investigators analyzed the methylation patterns on the genomes of the cells in this tissue. Methylation is an epigenetic mark, which can have a dramatic effect on gene expression without altering the sequence of DNA.
The work showed that in Alzheimer’s patients, there are epigenetic changes that alter the function of a type of cell called oligodendrocytes, which produce an insulation for neurons called myelin. This insulation keeps neural signals moving properly and is essential to proper neurological function. Most of the methylation changes that were identified in this study affected the tau protein.
"Our team has previously shown that oligodendrocytes are affected in Alzheimer's and another tau-related disease, progressive supranuclear palsy (PSP)," noted senior study author Nilüfer Ertekin-Taner, MD, Ph.D., a physician-scientist and chair of Neuroscience at Mayo Clinic. "These new results further highlight that problems in oligodendrocytes and myelin are central to [Alzheimer’s]. They also point to specific molecular pathways, particularly epigenetic changes, that could be targeted in future therapies."
This work also revealed novel Alzheimer’s-linked genes, such as LDB3.
The genetic data that was used in this work is now freely available to other researchers, as the Multiomic Atlas of AD Brain Endophenotypes, and the team made a search tool for it.
"While our study findings are impactful by themselves, we did not want to stop there and sought to make both our data and results available to the research community in a way that also protects donor identities," said Ertekin-Taner. "We wanted to do this because relatively few groups have the expertise to analyze such big data and derive biological insights."
Sources: Mayo Clinic, Nature Communications
