Clusters of a sticky protein – amyloid plaque – found in the brain signal mental decline years before symptoms appear, a new study finds.
Older adults with elevated levels of brain–clogging plaques – but otherwise normal cognition – experience faster mental decline suggestive of Alzheimer’s disease, according to a new study led by the Keck School of Medicine of USC that looked at 10 years of data.

Just about all researchers see amyloid plaques as a risk factor for Alzheimer’s. However, this study presents the toxic, sticky protein as part of the disease – the earliest precursor before symptoms arise.

“To have the greatest impact on the disease, we need to intervene against amyloid, the basic molecular cause, as early as possible,” said Paul Aisen, senior author of the study and director of the USC Alzheimer’s Therapeutic Research Institute (ATRI) at the Keck School of Medicine. “This study is a significant step toward the idea that elevated amyloid levels are an early stage of Alzheimer’s, an appropriate stage for anti–amyloid therapy.”

Notably, the incubation period with elevated amyloid plaques – the asymptomatic stage – can last longer than the dementia stage.

“This study is trying to support the concept that the disease starts before symptoms, which lays the groundwork for conducting early interventions,” said Michael Donohue, lead author of the study and an associate professor of neurology at USC ATRI.

The researchers likened amyloid plaque in the brain to cholesterol in the blood. Both are warning signs with few outward manifestations until a catastrophic event occurs. Treating the symptoms can fend off the resulting malady – Alzheimer’s or a heart attack – the effects of which may be irreversible and too late to treat.

“We’ve learned that intervening before the heart attack is a much more powerful approach to treating the problem,” Donohue said.

Aisen, Donohue and others hope that removing amyloid at the preclinical stage will slow the onset of Alzheimer’s or even stop it.

Researchers measured amyloid levels in 445 cognitively normal people in the United States and Canada via cerebrospinal fluid taps or positron emission tomography (PET) scans: 242 had normal amyloid levels and 202 had elevated amyloid levels. Cognitive tests were performed on the participants, who had an average age of 74.

Although the observation period lasted 10 years, each participant, on average, was observed for three years. The maximum follow–up was 10 years.

The elevated amyloid group was older and less educated. Additionally, a larger proportion of this group carried at least one copy of the ApoE4 gene, which increases the odds that someone will develop Alzheimer’s.

Based on global cognition scores, at the four–year mark, 32 percent of people with elevated amyloid had developed symptoms consistent with the early stage of Alzheimer’s disease. In comparison, only 15 percent of participants with normal amyloid showed a substantial decline in cognition.

Analyzing a smaller sample size at year 10, researchers noted that 88 percent of people with elevated amyloid were projected to show significant mental decline based on global cognitive tests. Comparatively, just 29 percent of people with normal amyloid showed cognitive decline.