A new study presenting the first data from a long-running US government trial is suggesting high levels of amyloid proteins in the brains of cognitively normal older adults can be an effective presymptomatic sign of early stage Alzheimer’s disease.
Over the last few decades, the amyloid hypothesis has guided the majority of research into an Alzheimer’s disease treatment. The idea is that a build up of toxic amyloid proteins in the brain, called plaques, is the primary degenerative driver behind the disease.
Unfortunately a near-constant parade of failed clinical trials testing anti-amyloid drugs has caused many researchers to begin doubting the amyloid hypothesis. From neuroinflammation to bacterial infection, a broad number of alternative hypotheses are currently being investigated, however, some scientists suspect anti-amyloid treatments could still work, as long as they commence before major degenerative symptoms appear.
“A major issue for amyloid-targeting Alzheimer’s disease clinical trials, and one that is being addressed with the A4 study, is that previous trials may have been intervening too late in the disease process to be effective,” explains Richard Hodes, director of the National Institute on Aging, the major funding body behind this new research. “A4 is pioneering in the field because it targets amyloid accumulation in older adults at risk for developing dementia before the onset of symptoms.”
The A4 trial, also known as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease study, began in 2014 and was designed to explicitly investigate whether an anti-amyloid intervention could slow Alzheimer’s-related cognitive decline if started before clinical symptoms appear.
The trial is testing a drug called solanezumab, which has disappointingly failed in a number of large clinical trials over recent years. Unlike the A4 study, those failed trials targeted patients with mild or severe Alzheimer’s symptoms.
“In 2014, A4 was a first-of-its-kind study because it used amyloid PET to identify cognitively normal people with high levels of brain amyloid,” says Laurie Ryan, a NIA researcher. “Before the availability of amyloid PET, other amyloid-targeting clinical trials may have been testing therapies in some people who didn’t have amyloid.”
The A4 trial is designed to run until late 2022, so treatment efficacy data is still some time away. But, a newly published study in JAMA Neurology is demonstrating high amyloid levels can be an effective presymptomatic sign of Alzheimer’s.
“Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function,” the researchers conclude in the published study. “These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.”
One of the big challenges many Alzheimer’s researchers currently face is identifying those patients at the earliest stage of the disease. If prospective treatments prove to be most effective when administered before cognitive decline is apparent, as some scientists are beginning to suggest, then clinical trials must have techniques to best identify those high-risk subjects. Even if alternatives to anti-amyloid treatments are being trialled, high amyloid levels may be a useful biomarker to identify those early-stage subjects.
“A4 demonstrates that prevention trials can enroll high risk individuals — people with biomarkers for Alzheimer’s who are cognitively normal,” says Ryan. “Ultimately, precision medicine approaches will be essential. Alzheimer’s disease is never going to have a one-size-fits-all treatment. We’re likely to need different treatments, even combinations of therapies, for different individuals based on their risk factors.”
The new research was published in the journal JAMA Neurology.
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