Alzheimer’s drug trials have been fraught with failure. A study last year that made headlines reported more than 99% of all Alzheimer’s drugs have flopped in the past decade, and only one new medicine to mediate symptoms of the disease has been approved since 2004.
The problem is, scientists still don’t know what exactly causes Alzheimer’s disease, though a protein called amyloid beta is most often implicated. Scientists think that amyloid-beta proteins build up and form deposits, known as amyloid plaque, which are to blame for the characteristic cognitive declines of the disease. Most Alzheimer’s drugs tested in clinical trials have used amyloid beta as the pharmacological target. The study found that out of 221 trials of disease-modifying agents registered from 2002 to 2012, more than 65% – or 145 trials – involved experimental drugs that targeted amyloid beta.
The other target drug developers have been interested in is a protein called tau, which has been found in deposits in the brains of people with a variety of neurological diseases. But tau-related therapies have also failed, leading some researchers to speculate that the existence of these proteins may not be the major culprit behind this devastating condition after all – or, at the very least, other factors are at play.
A new study, published in the August issue of the journal Aging, hypothesizes that Alzheimer’s is not a single disease but that it exists in three distinct subtypes – inflammatory, noninflammatory and cortical. The paper’s author, Dr. Dale Bredesen, professor of neurology at the University of California, Los Angeles, came to the conclusion by conducting regular metabolic testing on a small sample of 50 Alzheimer’s patients over two years.
“Because the presentation varies from person to person, there has been suspicion for years that Alzheimer’s represents more than one illness,” said Bredesen, who also is the founding president of the nonprofit Buck Institute for Research on Aging, in a statement.
Bredesen used metabolic testing in hopes of spotting biomarkers, or indicators of disease, in patients presenting the telltale signs of Alzheimer's. The study classifies the inflammatory subtype as having high levels of C-reactive proteins, which are produced by the liver and increase when inflammation is present in the body. In this subtype, the serum albumin to globulin ratio – a common metabolic test – is also elevated. In the noninflammatory type, the study suggests these markers do not appear in heightened levels but other metabolic abnormalities are present.
The third or cortical subtype, as described by Bredesen, is fundamentally different from the other two types. According to the study, this type is associated with a significant zinc deficiency and may occur in a more widely distributed pattern across the brain.
“The important implications of this are that the optimal treatment may be different for each group, there may be different causes, and, for future clinical trials, it may be helpful to study specific groups separately,” Bredesen said.
Since Alzheimer’s disease has been classified as a neurodegenerative disorder – and with good reason, due to its symptoms – Bredesen said doctors don't typically conduct extensive metabolic evaluations. Still, the biomarkers described in Bredesen’s study have not been validated as indicators of Alzheimer's disease.
While advancing age is the main risk factor for Alzheimer’s, some studies have suggested that metabolic conditions, such as chronic inflammation, obesity, hypertension and elevated glucose levels, may also play a role in the neurodegenerative process. Bredesen's paper notes that metabolic disorders are present in patients with cognitive decline, often years prior to diagnosis of Alzheimer's disease. It’s true that many of these metabolic conditions – along with Alzheimer’s – are increasing in the United States, as well as in other developed countries. But it’s important to point out that this could just be a correlative effect, not a causative one.
Bredesen’s study raises the possibility that Alzheimer’s might not only be diverse but also have a metabolic connection – a provocative idea that could change the way scientists think about drug development. But until the findings can be supported by more research, this theory will remain just that – another Alzheimer’s theory.
