TDP-43: Yet another protein implicated in Alzheimer's

Alzheimer's disease is characterized by the hallmark pathology of beta-amyloid plaque and tau protein tangles, but there appears to be a new protein on the block in the development of the neurodegenerative disease. It is called TAR DNA binding protein of 43kDa (TDP-43), according to research presented during the 2014 international conference of the Alzheimer's Association (AAIC).

Keith Josephs, MD, from the the Mayo Clinic in Rochester, Minn., and colleagues tested TDP-43 to see if it had an impact on memory and cognition independent of the pathology of tau and amyloid in the brain. Results of the study confirmed a correlation between cognitive decline and loss of memory and amounts of TDP-43 in the brain. Researchers were able to verify this link from the autopsy data of 342 subjects who had undergone significant cognitive testing and had received Alzheimer's diagnoses clinched by tau deposition in the patients' cortices.

The subjects underwent a thorough evaluation of TDP-43, and its development, distribution and density were all noted. In the end, an increase in any one of these factors was associated with loss of memory, poor cognition and a diminishing hippocampus. MRI was also used to assess brain atrophy. The researchers were able to conclude that 195 of the participants were 10 times more likely to suffer cognitive decline by the time of their death compared to those who did not have TDP-43 deposition.

“These findings show that TDP-43 amplifies memory loss and hippocampal atrophy in Alzheimer's disease, and also appears to overpower what has been termed ‘resilient cognition' in Alzheimer's, where subjects remain cognitively normal in spite of high levels of Alzheimer's brain changes,” said Josephs in a statement. “This suggests that TDP-43 is a key player in the Alzheimer's neurodegenerative process, and should be considered a potential therapeutic target for treatment of the disease.”

A relatively TDP-43-free brain may be a clue to why some patients with ample tau and amyloid pathology do not appear to be suffering from dementia. More research is needed to appreciate the true role that the protein plays in the scheme of Alzheimer's disease.