Scientists at the Mayo Clinic have discovered a possible new link between an abnormal protein in the brain and the onset of Alzheimer’s disease, a breakthrough that could open new avenues to understanding the disease and finding effective treatments.
Abnormal forms of the protein, which assists DNA in coding and building new proteins inside the cell, appear to increase the atrophy of regions of the brain important to memory. And it could be a trigger of some kind, perhaps independently initiating the onset of Alzheimer’s-related dementia when combined with two other proteins whose abnormalities have long been implicated in the disease.
The findings are to be presented Wednesday during the six-day Alzheimer’s Association International Conference in Copenhagen. Scientists were also expected to unveil other research, such as the results of a Massachusetts study that used sophisticated brain scans to identify the disease in its earliest stages, and a Scandinavian study showing that people at risk of getting Alzheimer’s can improve their odds of staying healthy through lifestyle changes, including exercise, nutrition and mentally stimulating activities.
Alzheimer’s is an incurable, progressive, brain-killing disease and the leading cause of dementia. It affects 1 in 9 Americans 65 or older and 1 in 3 among those 85 or older. The conference is unfolding as the United States and other nations step up efforts to fight a disease that is on pace to spread as populations age.
Until now, scientists have focused almost entirely on beta-amyloid, whose fragments create sticky plaques found inside the brains of people with Alzheimer’s, and tau, which forms tangles. Both proteins are believed to damage and kill brain cells in ways that are not fully understood.
The discovery that a third protein may contribute to Alzheimer’s came about through the Mayo Clinic team’s investigation of a biological agent that had been identified several years ago as having a role in two other neurodegenerative diseases. The abnormal protein was first linked to the development of prefrontal lobe dementia and amyotrophic lateral sclerosis (ALS), which is commonly known as Lou Gehrig’s disease. Both diseases involve progressive nerve damage in the brain.
Keith A. Josephs, a physician who led the research, said his team examined the brains of 342 cadavers of people who were determined to have Alzheimer’s based on the extent of tau tangles and beta-amyloid plaques in their brains. They searched for the presence, amount and distribution of the TAR DNA binding protein of 43kD, or TDP-43, in brain tissue.
In healthy brain tissue, the binding protein helps to unlock chemical messages from a cell’s DNA and transmit them to the cell’s RNA, which creates new proteins from the code.
The researchers found that 195 of the test subjects, or 57 percent, had the abnormal form of binding protein in their brains. After controlling for other variables, such as beta-amyloid and tau deposits, age, and genetic risk, the researchers determined that people with the TDP-43 protein were 10 times as likely to be cognitively impaired at death than those without the TDP-43 deposits. Those with TDP-43 also had faster rates of brain tissue loss over time than those without TDP-43.
Josephs said in an interview that the presence of the abnormal protein may act as some sort of trigger or catalyst, or compound the effects of tau, in the onset of dementia. That is because in some cases, people can remain cognitively normal despite elevated levels of beta-amyloid or tau in the brain tissue or other Alzheimer’s-related changes, a condition known as “resilient cognition.” But when TDP-43 is added to the mix, these people’s brain tissue appears to deteriorate more and their cognitive functions weaken.
“Once you throw TDP-43 on top of everything else, you don’t see that resilience anymore,” Josephs said.
Josephs said the four-year study built on his previous work on prefrontal-lobe dementia. The condition, also known as frontotemporal dementia, involves areas of the brain near the forehead that are operative in emotions, language and behavior.
People who suffer from degeneration in the frontal temporal lobes can undergo profound personality changes and encounter difficulties with language.
The condition, which can strike people in their 60s, is less well known than Alzheimer’s. Josephs said the significance of the TDP-43 protein might have been overlooked until now because researchers into prefrontal-lobe dementia have tended to work in isolation from those investigating Alzheimer’s.
“It’s like you’re blindfolded holding the trunk and I’m blindfolded holding the tail and we don’t know it’s an elephant,” he said.
In other research presented Wednesday, a team of researchers from the Karolinska Institutet in Sweden and the National Institute for Health and Welfare in Finland studied 1,260 people, ages 60 to 77, at risk for Alzheimer’s to see whether modifications in diet, physical exercise and mental stimulation and close management of their cardiac health could influence their cognitive health. The two-year study found that members of the group who received intervention performed significantly better on cognitive and memory tests.
A team from Massachusetts General Hospital investigated whether advanced brain scans could be used in the search for the tau protein on living patients as a reliable way to identify and diagnose Alzheimer’s in people before cognitive impairment sets in.
The researchers, taking advantage of recent advances in positron emission tomography (PET) imaging, used a radioactive imaging agent that binds with tau to scan the brains of 56 participants. The subjects were cognitively normal people with a median age of 72 who had undergone annual memory testing for three years. The study found that participants who had higher tau levels in areas of the brain that are critical to memory were linked to worsening performance on memory tests.
“These preliminary data suggest that tau in these brain areas is related to memory decline in normal older individuals,” Keith A. Johnson, a physician who took part in the study, said in a statement. “This study demonstrates the potential for PET technology to be used for early detection and to help pick participants for prevention trials and treatment trials that target tau.”