2019 ended on a high note for Alzheimer’s research. Just before the new year, the pharma company Biogen released clinical trial data suggesting that its drug, aducanumab, could successfully remove amyloid from the brain—one of the trademark proteins behind Alzheimer’s disease.
Understandably, the drug has gotten a lot of attention: It’s been a bleak few decades for Alzheimer’s research, whose history is pock-marked with clinical trial failures. If approved by the US Food and Drug Administration, aducanumab would be the first new treatment for the disease in over a decade.
But a new study from researchers at the University of California San Diego highlights the need for dementia research to go beyond amyloid—and beyond Alzheimer’s disease alone. Focusing on one drug target for one form of dementia won’t address the growing number of dementia cases that will develop as the population ages.
Researchers led by Kelsey Thomas, a neuropsychologist at UCSD, tracked the cognitive function of 747 senior participants over four years, including 305 people who were cognitively normal and 298 with mild cognitive impairment (a term for people who are cognitively impaired, but don’t yet have dementia). In an attempt to pick out even earlier signs of dementia, they also identified 153 people showing “objective subtle cognitive decline”—a new classification meaning these individuals were technically cognitively normal, but made the kinds of mistakes on functional assessments that indicated they weren’t totally healthy, either.
Every year, they reassessed participants’ cognition and amyloid levels. Those who had objective subtle cognitive decline developed amyloid faster than those who were in the cognitively normal group over time, and a larger percentage of them were diagnosed with MCI or dementia by the study’s end. It’s hard to say whether these differences were statistically meaningful; the group was small, and on average started with slightly more amyloid than those who were cognitively normal. But one way of interpreting the data is that they were indeed on the path to developing Alzheimer’s—even if amyloid wasn’t the first sign of the disease.
“In terms of the timing, the pathologies may not be the same in everyone,” says Thomas. For some, Alzheimer’s may indeed be primarily driven by the formation of amyloid. In these cases, a drug like aducanumab may treat all of a person’s cognitive decline. But earlier cognitive changes could instead be the result of buildups of tau, or changes in blood vessel structure. That’ll be the subject of a future study, because finding those changes requires a different kind of brain imaging.
But Alzheimer’s may not be the only condition present in this trial. “There are lots of reasons that people have cognitive impairment that have nothing to do with Alzheimer’s disease,” says Suzanne Schindler, a neurologist studying Alzheimer’s disease at Washington University at St. Louis. Strokes, medication interactions, or even other forms of dementia like vascular dementia or LATE could also cause the mental errors picked up in the objective subtle cognitive decline group.
Importantly, Thomas’ work suggests that there’s another way to measure cognition that’s more sensitive than traditional assessments. By picking out people who were otherwise cognitively normal but had objective subtle decline, her team found a group that seemed to be more likely to develop cognitive problems later on. If clinicians can flag these people early, there’s a better chance of being able to intervene with the right treatments—like the potentially forthcoming aducanumab—early on.
Studying these earliest changes could give researchers clues about how other forms of dementia develop over time, too. If people in these earliest stages go on to develop Alzheimer’s, there could be other cognitive changes that put them at risk for developing it in the first place.