A recently recognized pathologic protein in the brain may play a larger role in the development of clinical Alzheimer鈥檚 disease dementia than previously recognized, according to a study by researchers at 海角原创. The findings of the study of nearly 1,000 older adults were published in the Sept. 30 issue of the journal, Brain.
鈥淭his finding could help researchers to understand the cause of memory loss and lead to new ways to approach studying Alzheimer鈥檚 disease,鈥 said , study author and epidemiologist with the . 鈥淥ur study found that when the main characteristic pathologies of Alzheimer鈥檚 disease, plaques and tangles, were mixed with a pathologic protein called TDP-43 in the brain, the combination was more likely to result in diagnosed Alzheimer鈥檚 dementia than plaques and tangles alone.鈥
The abnormal protein, TDP-43 (short for hyperphosphorylated transactive response DNA-binding protein 43), previously has been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS, sometimes called Lou Gehrig鈥檚 disease). In recent years, TDP-43 also has been found in the brains of persons with other diseases, but most recently in Alzheimer鈥檚 disease.
Mixed pathologies increase Alzheimer鈥檚 risk
The hallmark pathologies of Alzheimer鈥檚 disease are the accumulation of the protein beta-amyloid (called plaques) and an abnormal form of the protein tau (called tangles). However, research from the Rush Alzheimer鈥檚 Disease Center and other groups has shown that the majority of people with clinical Alzheimer鈥檚 dementia also develop other disease pathologies in their brains as well, such as small strokes or protein deposits called Lewy bodies.
This combination, called "mixed pathologies," increases the risk for developing diagnosed Alzheimer鈥檚 dementia above and beyond just having plaques and tangles in the brain.
鈥淭he clinical disease that we call 鈥楢lzheimer鈥檚 disease鈥 is looking more and more like the result of the accumulation of a number of disease processes in the brain of older persons,鈥 James said. The majority of people with diagnosed Alzheimer鈥檚 dementia actually have mixed pathologies in their brains 鈥 not just the plaques and tangles that are the known hallmarks of Alzheimer鈥檚 disease.
鈥淚n particular, mixed Alzheimer鈥檚 and TDP-43 pathologies appear to be an under-recognized yet common form of mixed pathologies that contributes to the development of clinical Alzheimer鈥檚 dementia,鈥 James said. 鈥淭his is one of the first studies to examine TDP-43 and Alzheimer鈥檚 disease in the context of mixed pathologies.鈥
TDP-43 found in two-thirds of those with Alzheimer鈥檚 dementia
The Brain paper built on previous research by examining whether TDP-43 was associated with an increased likelihood of a diagnosis of Alzheimer鈥檚 dementia in people both with and without pathologic Alzheimer鈥檚 disease. The new study examined brain pathology, drawing on tissue samples from 946 deceased older men and women who had been enrolled in one of two cohort studies by the Rush Alzheimer鈥檚 Disease Center, the Rush or the . Participants in both studies agree to donate their brains to research after their death.
TDP-43 was present in the brains of about half of the participants and in two-thirds of the brains of persons who had been diagnosed with Alzheimer鈥檚 dementia while alive. More than a third of the participants had mixed Alzheimer鈥檚 (plaques and tangles) and TDP-43 pathologies in their brain. Mixed Alzheimer鈥檚 and TDP-43 pathologies were associated with a higher likelihood of diagnosed Alzheimer鈥檚 dementia at death than plaques and tangles alone.
鈥淭hese data are exciting, because an improved understanding of the TDP-43 protein has potential to guide alternative treatment strategies for Alzheimer鈥檚 disease,鈥 James said.
