New Culprit Protein Linked to Cognitive Decline, Alzheimer's

Susan Jeffrey

July 25, 2014

COPENHAGEN, Denmark — Researchers have for the first time described a pathologic role for a third protein in the Alzheimer's disease process, in addition to the well-described β-amyloid and tau proteins.

In a postmortem study of 340 brains from participants identified after death as having AD, a protein called TDP-43 correlated strongly with cognitive impairment during life, as well as hippocampal and cortical atrophy, independent of amyloid deposition and particularly at lower Braak stages of AD pathology progression.

"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 Keith A. Josephs, MD, from the Mayo Clinic, Rochester, Minnesota, in a statement from the Alzheimer's Association. "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."

Dr. Joseph's colleague Jennifer L. Whitwell, PhD, associate professor of radiology also at the Mayo Clinic, discussed the results at a press conference here at the Alzheimer's Association International Conference (AAIC) 2014.

Dr. Jennifer Whitwell

Third Protein

Two proteins, β-amyloid and tau, are considered core pathologic markers that define AD, the authors note. However, in 2006, researcher first recognized that TDP-43, the 43-kDa TAR DNA–binding protein, could be present in an abnormal form in patients with frontotemporal dementia or amyotrophic lateral sclerosis, Dr. Whitwell said. "Since that time, we and others have found that TDP-43 is present in the brains of patients with Alzheimer's disease," she noted.

The aim of this study was to see whether TDP-43 contributes to the clinical and neuroimaging features of AD, including memory loss and hippocampal atrophy. The investigators addressed the question by using a cohort of 342 patients who had died and been given a pathologic diagnosis of intermediate-high probable AD with a Braak stage of IV to VI.

All patients had been classified as cognitively impaired or cognitively normal during life. Earlier this year, this group reported that 195, or 57%, of these brains had TDP-43 present, and those with the protein were 10 times more likely to have dementia during life than when it was absent.

Of these 342 patients, 133 had undergone 2 MRI before death, an average of about 3 years apart, which allowed the researchers to look at changes over time. The brains were assessed for the presence and distribution of TDP-43 and tau burden in the hippocampus and lateral temporal cortex, and tensor-based morphometry was used to measure rates of hippocampal and cortical atrophy.

When the authors looked at the hippocampus, the presence of TDP-43 was significantly associated with faster rates of hippocampal loss (multivariate P = .03), but none of other factors were, including tau in the hippocampus, amyloid burden, presence of Lewy bodies, or age at death.

In the cortex, both tau (P < .0001) and TDP-43 (P = .01) in the cortex were associated with the rate of cortical loss, as was the age at death (P = .002). "We actually found a stronger relationship with tau than with TDP-43, so both proteins seem to be important in the cortex," Dr. Whitwell noted.

After accounting for potential confounders, TDP-43 had a strong effect on cognition, memory loss, and hippocampal atrophy in AD, particularly at lower Braak stages. "We actually found these differences were greater at a slightly earlier stage in the disease, when people were at Braak stage IV, compared to stage V or VI," she noted. Portions of these results were recently published in June 2014 in Acta Neuropathologica.

"So the question then becomes, can we target TDP-43 in these subjects, and try to slow down these disease processes?" Dr. Whitwell said. "If we could remove the TDP-43, or prevent it from accumulating, then perhaps we could slow the rate of hippocampal loss," or other cognitive features of AD.

The researchers plan next to look at patients with AD in earlier stages of the disease, Dr. Whitwell said. "I think we want to go back and look at milder cases with less tau protein, and see when does TDP-43 start having an effect, and if we can get a sense of that from looking across the whole range from normal to very advanced AD," she told Medscape Medical News.

Rosetta Stone

Dr. Ralph Nixon

Ralph Nixon, MD, chair of the Alzheimer's Association Medical and Scientific Advisory Council, professor of psychiatry and cell biology, former director of the NYU Comprehensive Center on Brain Aging, the Silverstein Alzheimer's Institute at New York University School of Medicine, and director of research at the Center for Dementia Research at the Nathan S Kline Institute for Psychiatric Research, Orangeburg, New York, moderated a press conference featuring these results here.

"The TDP-43 findings in Alzheimer's come out of work that had been done previously in other diseases, ALS and frontotemporal dementia, that had implicated TDP-43 as part of the mechanism of neurodegeneration, so there's intensive interest in how it operates in those diseases," Dr. Nixon told Medscape Medical News.

"Finding this protein aggregating in Alzheimer's and also linking to worsening cognition I think is really telling us that number 1, it's probably important in Alzheimer's disease, but number 2, that there are mechanisms that are probably shared by a number of different diseases, and that you may have a number of different ways to get to that particular mechanism in different diseases. Once you do, they may share pathways beyond that, and that's hopeful for targets we haven't thought about."

Rather than considering disease-specific targets, he said, "we really need to be thinking about ones that might affect the process a little bit downstream, and have an impact on a number of different diseases. That's what excites me about it, is it really is — I wouldn't call it exactly a Rosetta stone, but it's one of these proteins that acts like a Rosetta stone in kind of tying together a bigger picture of how disease and neurodegeneration may impact a number of different diseases," Dr. Nixon said.

A new protein may also explain why targeting only amyloid or tau has not been entirely effective.

"I think most people in the field now think of Alzheimer's as a multifactorial disease that certainly involves amyloid and tau, but that may not be enough to explain all of the manifestations or, more importantly, to be able to create a treatment that would be totally effective even in a prevention mode, so that we need to be looking at these other proteins that may be required to produce the full spectrum of the pathology and pathogenesis," he said. "Unless we're targeting the entire spectrum we're probably diminishing our chances of having a treatment that would work totally effectively."

The study was funded by the National Institute on Aging. Dr. Whitwell and Dr. Josephs have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2014. Abstract DT-01-01. Presented July 16, 2014.

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