By Rohan Shah
“Alzheimer’s strips you of who you are. It robs you of your identity,” said Ryan Watts of Denali Therapeutics, a neurodegeneration-focused start up company, in an interview only astoundingly last year. Almost incredulously, even after decades of research and billions worth of investment, the greatest medical minds in the US are still incapable of curing this demonic disease.
With the advent of biotechnology in the early 1990s, scientists finally gained a small window into the molecular underpinnings of the disease. Sparked by new biological insights and technologies, the scientific community rallied behind the Amyloid and Tau hypotheses. The Amyloid hypothesis postulated that extracellular beta-amyloid plaques caused the pathology; the Tau hypothesis suggested that the disease arose from Tau protein tangles within nerve cell bodies. Fundamentally, both prevailing hypotheses held that extracellular plaques or tangles, caused neuron failure that ultimately caused the disease.
Unfortunately, both theories have failed to treat Alzheimer’s in humans. Although the theories are supported by scientific experiments, these approaches have not translated into clinical relevance. Just last week, Eli Lily, a celebrated expert in the the field of neurological disorders, released his Phase III clinical trial data on candidate solanezumab—an experimental drug once heralded as the cure for Alzheimer’s. To the despair of patients and scientists, the trial, which enrolled 2,100 patients and absorbed two billion dollars, failed miserably and dealt a critical blow to the Amyloid hypothesis.
Regrettably, this new data is not surprising to most working in the pharmaceutical field. No drug so far has shown that removing beta-amyloid plaques or Tau tangles slows Alzheimer’s progression. Lily’s study has simply added to the long list of failures in cures for neurodegeneration. For example in the period between 2002 and 2012, only one compound out of 244 has successfully been approved for the treatment of dementia. Yet, even this approved compound had a pathetic success rate of 0.4%.
More importantly than the medical significance of the study, Eli Lily’s disappointing results have crippled the confidence of the entire pharmaceutical industry. Investors are afraid to finance developments on drugs that counter neurodegeneration. Venture capitalists have refused to back start-ups for new medical companies that primarily treat Alzheimer’s patients. Flagship research centers such as the Banner Institute have allowed grant money to chiefly areas in biology which are more likely to offer returns on their investments, such as cancer immunotherapy and hepatitis.
However, this despair and subsequent neglect belie the important tenet that society cannot afford to neglect Alzheimer’s disease. According to the Alzheimer’s Association, nearly 5.1 million Americans are currently living with the disease and the societal cost has recently surpassed 250 billion dollars. In other words, one in five Medicare dollars is spent on the disease; this proportion can jump to one in three by 2050. Unless research dramatically advances, Alzheimer’s is projected to cost the nation more than one trillion dollars by 2050 and bankrupt the US healthcare system; the US literally cannot afford to treat its citizens stricken with Alzheimer’s. Therefore despite prior failures, researchers must continue to dive and do so courageously into the unknown of Alzheimer’s.
In order to study the disease afresh, medical professionals aim to understand neurodegeneration instead of producing treatments. Supporting this shift in thinking, Derek Lowe, a prominent medicinal chemist, said, “Our level of ignorance is cripplingly high. Researchers are still arguing, with great vigor, about the amyloid hypothesis. There’s a lot of crucial information that we’re missing. We are seeing a return to the drawing board.” To that end, those involved in biotechnology are delving into the core genetic problems behind the disease instead of racing toward therapeutics. Leading companies such as Denali Therapeutics are resolving the relationship between “degenogenes” and specific intracellular changes that drive disease progression. Others are examining clinical trials on a specific risk-prone population in Columbia, which are elucidating important risk factors that may cause Alzheimer’s.
It is no secret that Alzheimer’s is unrelenting, the challenge daunting, and the mysteries extraordinary. Yet, comprehending the mechanisms behind Alzheimer’s is no longer an option but a societal need. Although researchers may lose more battles at the hands of the complex human biology behind the disease, they must remain strong. They must “beat on, boats against the current, borne back ceaselessly.”