For the past 25 years, the scientific community's perception of Alzheimer's disease has been dominated by the "amyloid cascade hypothesis." The hypothesis is that Alzheimer's disease is caused by an abnormal accumulation of B-amyloid proteins in the brain, a phenomenon that eventually destroys nerve cells and synapses, with the consequences of dementia. There is considerable evidence to support this hypothesis.
First, "plaques" containing amyloid protein are a classic marker of Alzheimer's disease (another marker is tau protein tangles). In 1906, Alois Alzheimer (the discoverer of Alzheimer's disease) found exactly this protein in the brain slice of patient zero. Second, if there is a defect in the amyloid precursor protein (APP) due to genetic factors, the entire family will be deeply affected by early-onset Alzheimer's disease. Third, if mice are genetically engineered to produce large amounts of amyloid, they will show memory problems; When amyloid accumulation stops, memory performance gets better.
There is much more evidence than that. This has led to billions of dollars in research grants and pharmaceutical companies looking to develop therapies for amyloid. However, studies of more than a dozen drug candidates have failed one after another. The most recent failure was in April 2019, when in a very early trial of Alzheimer's disease, the otherwise promising amyloid antibody (aducanumab) did not perform better than placebo.
At the same time, researchers working on non-amyloid proteins are left out in the cold, making it difficult to get funding and publish papers. Science journalist Sharon Begley, who has spent more than a year reporting on these missed opportunities, notes that current support for the amyloid hypothesis has blocked the way to explore other directions.
Genetic and other evidence suggest that inflammation and immunomodulatory abnormalities have equally great an impact on Alzheimer's disease, and that these two causative factors have the potential to be targeted for drug therapy. The situation is similar for vascular tissue. Other possible causative factors include altered lipid processing in the brain, changes in glucose levels, abnormal folding of proteins, and obstruction of brain-gut bacteria communication.
Viruses can also have an effect. Whether or not this dizzying series of paths interacts and how they work is unknown. Sam Gandy, director of the Cognitive Health Center at mount Sinai Icahn School of Medicine, said, "I don't think there may be a way to linearly integrate these pathogenic mechanisms and sort out the causal and sequential relationships."
Every path can be the target of disease intervention. "We may not be able to choose just one system," says Mary Sano, who also works at the Icahn School of Medicine at Mount Sinai, "and there are as many interventions to try." "Gandy and his colleagues are tracking a lot of targets. In an article published in 2018, they demonstrated that in the brains affected by Alzheimer's disease, genes from the herpes simplex virus are overexpressed, which may affect human genes associated with dementia. "We are still trying to understand the outcome," Gandy said. They also experimented with another molecule called "BCI-838," which promotes the formation of synapses in the hippocampus. In pharyngeal-tooth modeled Alzheimer's disease, "BCI-838" has been shown to improve brain function.
Protecting synapses is likely to be a key point in defeating Alzheimer's disease. According to a 2019 analysis, a total of 96 drugs entered clinical trials targeted Alzheimer's disease. 60% of these target pathways are no longer amyloid. "Right now, that diversity is very important," said Richard Hodes, head of the American Institute on Aging (NIA). The NIA is the leading public funding provider of Alzheimer's disease research. In October 2019, the NIA announced an additional $73 million for drug development to increase drug diversity.
However, the NIA has not yet given up on anti-amyloid drugs. Holtz believes that such drugs are likely to be shown to delay dementia in young people at high risk of early onset alzheimer's (people with genetic mutations or those with Down syndrome); And for people with the more common type of Alzheimer's disease, fighting amyloid may not be as important. These people tend to have blood vessel damage in addition to plaques and tangles in their brains, which may also be accompanied by other age-related changes.
Article excerpt from Global Science