The amyloid cascade hypothesis has misled the pharmaceutical industry

Abstract

The pharmaceutical industry has invested a great deal of time and finance in the development of therapeutics targeting amyloid generation, signalling and plaque stability. This has been based on the amyloid cascade hypothesis which states that abnormal amyloid precursor protein processing and the formation of amyloid plaques is the central process in the development of the symptoms of Alzheimer's disease. However, most clinical trials in this area have been disappointing; therefore the attendees of the Models of Dementia: the Good, the Bad and the Future meeting were given the opportunity to openly debate the proposal 'the amyloid cascade has misled the pharmaceutical industry', with the main contributions from Professor John Hardy and Professor John Mayer. The present article is a representation of the debate.

Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury

“…Pharmaceutical strategies aiming at these different amyloidogenic events are being developed for AD treatment and prevention. As many anti-Aβ therapies fail to reverse or slow down neurological and cognitive declines in clinical trials, earlier drug administration is considered to be essential, although some call for a better understanding of the amyloid pathogenic process and its role in AD etiology (Pimplikar, 2009; Struble et al, 2010; D’Alton and George, 2011; Panza et al, 2011; No authors listed, 2011). …”

The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence

“…Returning to the amylоid cascade hypоthesis, which was originally postulated for the genetic form of the disease [21], it should be kept in mind that detection of APP and presenilin gene mutations [125] in the genetic form of AD was the only strong evidence underlying the amyloid hypothesis [116]. However, there was no evidence proving that amyloids are the only cause of this disease, especially its sporadic form [123], in which there are no such gene mutations, but instead increased amyloid synthesis which leads to accumulation, aggregation and amyloid plaque formation, characteristic of genetic disease.…”

“…A review of the literature sheds no light on when or by whom the role of genetic mutations was first considered in the pathоgenesis of sporadic form of AD. Apparently confusion has arisen concerning the hypothesis: it was proposed only for the genetic form of AD, and all anti-amyloid preparations were tested on transgenic mice, using the so-called genetic mouse models of AD, but clinical trials only recruited patients with sporadic disease [21], without mutations in the abovementioned genes. Further, despite the fact that all types of transgenic models perfectly imitate the amyloid aspect of AD [126], the relationship postulated by the amyloid cascade hypothesis between enhanced amyloid formation and accumulation of hyperphosphorylated tau protein, memory impairment, and neuronal death, is not generally confirmed, using transgenic models [127][128][129].…”

“…The "amyloid cascade hypothesis" [20] has greatly influenced research over the last twenty years with considerable effort devoted to designing new anti-amyloid drugs, and although there is still no cure for AD [21,22], this hypothesis remains the most prevalent. Nevertheless, the key points of the hypothesis suggesting a central role for amyloid plaques in disease development and considering the brain and its age-related changes independently of the blood flow are paradoxical rather than convincing.…”

“Amyloid” — Historical Aspects

“…Several hypotheses have been proposed [33], of which the "amyloid cascade hypothesis" by John Hardy and Gerald Higgins [34] has maybe got the greatest attention. The theory has recently also been criticized [35] as many therapeutic attempts based on it have failed [36].…”