Prof George Perry: Perspectives on Alzheimer’s Disease Research – Part 2
Are amyloid plaques the best therapeutic target?
21 Jan 2016
With over 1000 publications, Prof George Perry is recognized worldwide as an expert in the field of Alzheimer’s disease research. As Dean of the College of Sciences at the University of Texas at San Antonio, he is Professor of both biology and chemistry, holds a Semmes Foundation Distinguished University Chair in Neurobiology and also serves as Editor-in-Chief for the Journal of Alzheimer’s Disease. In the first part of this interview he discussed his research into the role of oxidative stress in Alzheimer’s disease. In part two of this exclusive interview, Prof Perry talks about his concerns for the future of Alzheimer’s research. Amyloid-β plaques are a hallmark of Alzheimer’s disease pathology and removal of this protein is undergoing testing in several clinical trials as a potential treatment. However, Prof Perry believes that this approach will be unsuccessful, “There is still more work to be done, the data we have are correlational, but we think that amyloid-β may be a protective response in the brain and not a causative response.”
Amyloid-β accumulation as a protective response
Trials of antibodies targeting amyloid-β are not working, as it is the wrong target; amyloid-β is a protective response, so it makes no sense to remove it.
Prof. George Perry University of Texas at San Antonio
Although this is controversial, Prof Perry points out that in vitro data have shown amyloid-β to function as an antioxidant and that in vivo studies have found an inverse relationship between the amount of amyloid-β deposition and the level of oxidative damage. He states, “I think that Alzheimer’s disease is fundamentally a metabolic abnormality, which results in all sorts of consequential changes, of which amyloid-β accumulation is one of those responses.” However, this is in contradiction to numerous studies, both in vitro and in vivo, that suggest amyloid-β plaques are a causative factor in Alzheimer’s disease. Prof Perry highlights that Alzheimer’s animal models, the majority of which overexpress amyloid-β, represent a protective response being evoked out of biological context, “like inducing inflammation when you are normal.” Under these abnormal conditions it is unlikely that a protective outcome would be observed, regardless of the normal function of the protein. Furthermore, his hypothesis does not argue that amyloid-β is always having a positive effect but posits that the current simplistic view of plaques being causative is naive. This idea could be paralleled by human risk gene data, where the risk mutations predispose carriers to greater accumulation of amyloid-β, regardless of physiological state.
Concern about therapeutic targets & early diagnosis
Many studies are underway to test treatments that clear amyloid-β from the brain and Prof Perry’s views differ considerably from many other Alzheimer’s disease researchers, “Trials of antibodies targeting amyloid-β are not working, as it is the wrong target; amyloid-β is a protective response, so it makes no sense to remove it.”
Prof Perry advocates taking a much broader view of Alzheimer’s pathology. He does not necessarily believe that oxidative stress is the single causative factor but given its role as an early change, it and other upstream mechanisms warrant closer scrutiny. He also points out that amyloid-β accumulation is associated with normal aging, which can be considered a form of natural degeneration. He suggests that the function of amyloid-β does not change, rather, as we age, and our physiology begins to unravel, that the plaques become more apparent. Despite an increased drive for earlier diagnosis of Alzheimer’s disease, this remains a very difficult proposition pre-mortem, and the post-mortem brain pathology of patients and the unaffected becomes indistinguishable with advanced age. Furthermore, the amount of neuronal degeneration varies massively among patients, independently of disease stage. Prof Perry commented that we may never cure Alzheimer’s disease and what use is early diagnosis without a successful treatment? He counsels the greater importance of maintaining health in old age and refers to studies showing that lifestyle changes alone had a huge impact on Alzheimer’s disease course, “Tremendous progress has been made using lifestyle interventions, with the extent of disease being reduced by between 50–90%.”
Tremendous progress has been made using lifestyle interventions, with the extent of disease being reduced by between 50–90%.
Prof. George Perry University of Texas at San Antonio
Prof Perry is concerned that the current mode of thinking is constraining progress in Alzheimer’s research and a massive shake-up in hypotheses and attitudes is needed. “The field is very focused around vaccines for amyloid-β. In fact, if amyloid-β deposition is a protective effect, intervention earlier is likely to have detrimental effects.” Prof Perry highlights how some initial amyloid-β removal trials reported no improvement or worsening of patients’ conditions and vascular bleeding as an adverse outcome. In Alzheimer’s patients, amyloid-β is deposited in blood vessel walls, therefore its removal could result in vessel breakage. As Prof Perry warns, “removal of amyloid-β without understanding its biological context could make the situation worse.”
Future perspectives
So what does Prof Perry advocate as the best future strategy? “To go beyond amyloid-β removal and try to understand what amyloid-β is doing in the brain, whether we would want to increase or decrease its levels or modify its function”, he explains. He believes that looking more closely at mitochondrial function and calcium levels could be the key to identifying new therapeutic approaches but maintains that lifestyle changes could still be the most successful treatment strategy, as he says, “Big clues are being given from the lifestyle intervention studies, which make such a difference.”
Read about the key role of oxidative stress in Alzheimer’s disease in part one of this interview.