ARTICLE IN BRIEF
In a longitudinal study examining subjects for TAR DNA-binding protein 43 (TDP-43), investigators found that memory loss was the most strongly impaired cognitive function associated with having TDP-43.
Plaques and tangles may define Alzheimer's disease, but a third protein, TAR DNA-binding protein 43 (TDP-43), may be a major contributor to memory loss in the disease, according to a new neuropathological study that was presented in Copenhagen at the Alzheimer's Association International Conference in July. But whether TDP-43 accumulation is in fact a central part of the Alzheimer's disease process, or represents an independent pathology, and whether its aggregation is a cause of neuronal death or is just its symptom, is still unclear.
TDP-43 aggregates are perhaps best known for their appearance in motor neurons in most forms of amyotrophic lateral sclerosis and in cortical neurons in a subset of patients with frontotemporal dementia. But their role in other forms of dementia has been increasingly recognized in recent years.
The current study, led by Keith Josephs, MD, a professor of neurology at the Mayo Clinic in Rochester, MN, examined the brains of 342 subjects enrolled in longitudinal studies of aging, who received a pathologic diagnosis of AD, based on the presence of amyloid plaques and tau tangles. Not all of the subjects had received a clinical diagnosis of cognitive impairment before death, Dr. Josephs noted, and his study was an attempt in part to understand what distinguished those whose cognition remained intact from those who became demented.
Overall, 57 percent of subjects stained positive for TDP-43. The distribution of pathology suggested a spreading pattern, beginning in the amygdala and progressing to the hippocampus, the frontal cortex, and the temporal cortex. This stereotypical pattern allowed Dr. Josephs to develop a five-stage system to classify the topographic extent of the pathology.
The most surprising finding came when the burden of TDP-43 was compared with cognitive performance before death. “In the TDP-43-positive group, 98 percent were cognitively impaired by the time they died,” Dr. Josephs said. “In contrast, in the group without TDP-43, 81 percent were cognitively impaired.”
“This is the biggest finding of the study,” Dr. Josephs told Neurology Today. Memory loss was the most strongly impaired cognitive function.
The results were significant after controlling for age at death, apolipoprotein E4 (APOE4) gene status, amyloid deposition, Lewy bodies, and hippocampal sclerosis. The effect was most significant for those at the earlier stages of AD, as defined by the Braak stage.
The absence of cognitive impairment in those with significant plaques and tangles has been attributed to “resilient cognition,” Dr. Josephs noted. It may be that instead that absence is a sign of lack of TDP-43, or that TDP-43 accumulation “overpowers” resilient cognition. TDP-43, which affects the hippocampus especially, has its most detrimental effect on memory.
“I think we have to consider the possibility that Alzheimer's disease is not just defined by amyloid-beta and tau, but by multiple proteins,” he said. The results of this study indicate that TDP-43 “is a key player in the Alzheimer's disease [AD] neurodegenerative process and should be considered a potential therapeutic target for the treatment of AD.”
There is little question that TDP-43 may be a valuable therapeutic target, but whether its aggregation is truly a part of Alzheimer's disease is a subject of controversy, according to experts who were not involved with the current study.
“The interesting question is how much of what we are seeing is really Alzheimer's disease, or whether it is an independent pathology,” said Peter Nelson, MD, PhD, a professor of neuropathology at the University of Kentucky in Lexington. There is a strong, and often misplaced, desire to attribute dementia to a single disease, he said, when the past several decades have shown repeatedly that the situation is much more complex. “The data are clear that Alzheimer's disease is a different disease from either hippocampal sclerosis or vascular diseases,” even though they may occur together in the same patient. “Occam's razor need not apply to the most complex object we know,” the human brain.
The emerging picture, he said, is that TDP-43 pathology is an independent, primarily late-life disease process, compared with the relatively earlier accumulation of plaques and tangles, driven by APOE. “There may be some downstream TDP-43 aggregation due to the AD pathology, as an endstage phenomenon, but there is good evidence from the Mayo group, from ours, and from others that there is a separate, independent TDP-43 disease, that is very important and highly prevalent in the elderly, that has a significant impact on cognition.”
“I think the findings are quite striking,” said Robert Wilson, PhD, a neuropsychologist at the Rush Alzheimer's Disease Center at the Rush University Medical Center in Chicago. But, he noted, there are many people with TDP-43 accumulations who don't have pathological Alzheimer's disease. “I am not convinced TDP-43 has a special relationship with Alzheimer's disease per se. That is one of the many big questions out there to answer about TDP-43.”
Working with Julie Schneider, MD, a professor of neurology and neuropathology at Rush, Dr. Wilson is conducting longitudinal studies of large cohorts of subjects, involving annual exams and brain autopsy at death. “One thing that is clear is that late-life cognitive impairment is rarely due to one thing,” Dr. Wilson said. Their work has shown that the most common cause of dementia “is not Alzheimer's disease, but Alzheimer's disease and something else.”
“We see a wide spectrum of pathology” in cognitively impaired individuals, he said. More than half have TDP-43 pathology, seen most prominently in people in their 80s or 90s. “Like the Mayo group, we find TDP-43 is related to memory and thinking quite strongly, even after controlling for Alzheimer's pathology, stroke, hippocampal sclerosis, and Lewy bodies. It has an independent association with cognitive decline and dementia in old age. We think of it as one more big player in late life dementia. It is second only to tangles in the effect on dementia.”
“In our studies, tangles are associated with decline in all cognitive areas, but not especially related to decline in memory. TDP-43, on the other hand, is very strongly related to decline in memory.” In that sense, he said, “one of the classical features of clinical Alzheimer's disease is probably mainly due to TDP-43.”
A major challenge at this point is to develop better imaging methods to identify the different protein aggregates during life, in order to understand when and how their accumulation affects cognitive processes. “The big challenge is teasing apart the signatures of different proteinopathies,” Dr. Wilson said. He added that a fundamental unanswered question remains: is TDP-43 accumulation itself toxic, or is it simply a sign of a dying neuron? The answer will shape therapeutic trials directed at TDP-43.
The other major challenge for therapy is to better understand whether reduction of plaques and tangles can, by themselves, improve cognition, or whether that effort would be meaningless without also reducing TDP-43 in those in whom it has accumulated. Said Dr. Nelson: “The key thing is to acknowledge these different patient groups exist. If you have a dirty sample in a clinical trial, you have no way of getting a signal for your therapeutic intervention.”
EXPERTS: ON TDP-43 IN ALZHEIMER'S DISEASE