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A Positive Amyloid PET Scan Identifies Subtle Cognitive Problems in Asymptomatic Adults

Article In Brief

PET scans done as part of the A4 study showed elevated amyloid burden and subtle cognitive deficits in adults who were asymptomatic for Alzheimer's disease.

The study was massive, complex, and controversial from the start. Could scientists use biomarkers—primarily PET to identify abnormal levels of amyloid-beta protein (Abeta)—in the brains of asymptomatic older people and treat half of them with an anti-amyloid antibody that targets the disease protein to stop or slow the development of cognitive problems characteristic of Alzheimer's disease?

The multisite prevention study is still ongoing, but researchers have published the first results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study in the April 6 online edition of JAMA Neurology.

The early findings suggest that about 30 percent of 4,486 people who had no signs of cognitive impairment at baseline—after an extensive battery of neurocognitive assessments— tested positive for Abeta on the PET scan. At the screening, everyone underwent blood tests to look for the most common AD risk gene, APOE4. The researchers found that amyloid-positive individuals performed slightly worse on the neurocognitive tests compared with those who did not have evidence of Abeta accumulating in their brains.

What's more, people who said they felt that their cognitive abilities were slipping—evidenced on a 15-item questionnaire—were more likely to also have higher Abeta levels, as were those with at least one APOE4 allele.


“This is clear evidence that we can identify people in the preclinical stages of Alzheimers who have elevated beta-amyloid in their brains.”—DR. REISA A. SPERLING

“This is clear evidence that we can identify people in the preclinical stages of Alzheimer's who have elevated beta-amyloid in their brains,” said Reisa A. Sperling, MD, a professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital.

“It was somewhat surprising that individuals testing amyloid-positive performed worse on many cognitive measures and were more likely to report a subjective change in how they function in their lives. This was striking because they did these cognitive and functional testing assessments a month before they had a PET scan.

“With the thousands of PET scans we were able to see significant differences between the two groups—those with a positive amyloid scan and those with a negative exam–and that suggests that amyloid is associated with a decrease in performance and subtle changes in cognitive function years before they have a clinically diagnosable cognitive impairment.”

This early finding does not address the ongoing controversy over whether Abeta or phosphorylated tau drives disease progression, she added.

“We just don't know what amyloid's role is in causing symptoms or not. But we can say what is associated with amyloid-beta and what isn't. We can't prove a causative role until you remove the toxic amyloid and that prevents the disease progression. But what this tells us is that there is a clear association between amyloid and a decrease in cognitive performance. It is certainly possible that amyloid-beta is one critical piece but we don't know whether it is the most important piece.”

Study Methods, Findings

The study, a collaborative effort between public and private funding sources—the National Institutes of Health, the Alzheimer's Association and Eli Lilly & Co—was novel at the time it was launched in 2014 when clinical trials focused on those already diagnosed with dementia.

Dr. Sperling and Paul Aisen, MD, founding director of the University of Southern California's Alzheimer Therapeutic Research Institute at the Keck School of Medicine, along with 65 other research centers in the US, Canada, Australia and Japan, recruited more than 4,000 people to participate in the prevention trial without evidence that they have, or will ever get, symptoms of the disease.

The researchers acknowledged that participants may have self-selected to enroll in the study for many reasons. Most had a close family member with AD, and worried about their own risk. Others were just worried that they would learn they had the sticky peptide associated with the neurodegenerative disease.


“The A4 study was able to show that people with a positive amyloid PET scan had poorer cognitive performance, and it will be important to understand how this changes over time.”—DR. RANDALL BATEMAN

If they had an abnormal amyloid scan, they would be enrolled in the treatment arm of the study and have a 50/50 chance of getting the active drug. The problem was, and still is, they wouldn't know whether the drug—solanezumab—was doing anything to reverse the pathology in their brains or protect it from further damage, or have an effect on their cognition, during the four and a half years they will be on it.

In this new paper in JAMA Neurology, scientists reported on the screening demographics, APOE genotyping, lifestyle variables, self and partner assessments on functional changes, cognitive testing, and the florbetapir amyloid PET scan data collected a month after the initial screening. The researchers administered the Mini-Mental State Examination (MMSE), along with other neurocognitive screening tests.

The average age of the study participants was 71 years (65-85 at start of study) and there were 2647 woman and 1839 men. Almost 30 percent of them–1323–were classified as amyloid-positive.

Dr. Sperling said that those who were amyloid positive were slightly older than those who came in as amyloid-negative, and they found no differences in sex, education, marital or retirement status, or other lifestyle factors like diet and exercise. Those who were amyloid-positive had a higher rate of family members with dementia (74 percent versus 68 percent in those who were amyloid-negative) and 58 percent of the amyloid positive people had at least one copy of the APOE4 allele compared to 25 percent of those who were amyloid-negative. The amyloid-positive individuals showed worse performance on the Preclinical Alzheimer Cognitive Composite and they reported noticing more cognitive changes on a 15-item Cognitive Function Index than the amyloid-negative individuals.

Those who met the cut-off for a positive result were enrolled into a secondary prevention study to test the anti-amyloid drug, solanezumab, developed by Eli Lilly & Co. By the time researchers announced discouraging results from a phase 3 study in patients with mild Alzheimer's at the end of 2016—it did not alter the clinical picture for patients on the drug compared to those on a placebo—half of the A4 study individuals were already taking the experimental monoclonal antibody, delivered in a monthly infusion.

By 2018, the study team decided that they would increase the study dose four-fold. The trial is double-blinded so none of the investigators know who is on active drug, and who is not. Scientists at the US Food and Drug Administration agreed that it could be done.

Solanezumab binds to soluble monomeric Abeta, where other anti-amyloid monoclonal antibodies in development target insoluble forms. The A4 scientists hope that targeting soluble Abeta at a very early preclinical stage could have a benefit, and “the only way to know is to continue the trial,” said USC's Dr. Aisen.

The study team also added tau-PET imaging in a subset of patients. They have baseline data on 390 individuals and will do another three tau-PET scans throughout the trial. The scientists also invited some of the individuals with a negative amyloid scan to join a study called LEARN. They have been following 500 people to see whether this group will help shed some light about elevated amyloid and its association with early preclinical changes in cognitive performance.

The scientists said that there are limitations to the study. Those who signed on to be in the prevention trial were “highly educated, generally healthy, and able to visit tertiary medical centers,” they wrote in the paper. Questions on lifestyle were collected with brief questionnaires and human recall is often faulty in assessing such behaviors over a few months, let alone a lifespan. The researchers knew going in that those individuals that signed on to such an intensive prevention trial were highly motivated, which could lead to selection bias in the data.

Challenges Ahead: COVID-19

Now, another challenge looms over the study: How to keep it going in the middle of the COVID-19 pandemic? The researchers have been figuring out ways to put a hold on the delivery of the drug without hurting the integrity of the data. At the same time, they are about to embark on a new study called AHEAD 3-45, “an even more ambitious project,” said Dr. Aisen.

They will recruit even younger patients in the late-50s, and utilize another anti-amyloid drug called BAN2401 that targets and removes beta amyloid plaques. “We think removing plaques preclinically is a powerful approach,” said Dr. Aisen. What they learned from the A4 study was that it was a long and expensive recruitment process.

This time, said Dr. Aisen, they will streamline recruitment through an NIH-funded project called the Trial-Ready Cohort for Preclinical/prodromal Alzheimer's disease (TRC-PAD), which includes an online observational study called the Alzheimer's Prevention Trial (APT) Web study. This online registry is open to people interested in clinical trials for dementia. The minimum age is 50, and around 30,000 people have already signed on to the registry. They want to identify 1,400 people for the A3-45 study.

“Our best chance is by intervening before people have irreversible brain damage,” said Dr. Sperling. “And we hope treating before symptoms develop will be the answer.”

Expert Commentary

“The A4 study tells us a lot of important things,” said Randall Bateman, MD, the Charles F. and Joanne Knight distinguished professor of neurology at Washington University School of Medicine, who directs the Dominantly Inherited Alzheimer's Network (DIAN) observational study and also the DIAN Trials Unit (DIAN-TU), the first clinical trial in AD gene carriers in the preclinical stages of disease.

“The A4 study tells us that we can enroll for a sporadic Alzheimer's prevention study based on amyloid status. There was uncertainty about how well such a study design would do. It also tells us about the properties of the people signing up for a prevention clinical trial. Although Alzheimer's disease is a feared disease, it was not clear whether people without clinical signs of dementia would sign up to be in a clinical trial that includes years of monthly infusions, brain scans, and ongoing tests.”

“The A4 study was able to show that people with a positive amyloid PET scan had poorer cognitive performance, and it will be important to understand how this changes over time,” he added.

“It's a very important study,” added Howard Fillit MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation. His organization is supporting 25 clinicals trials on potential AD medicines.

“It shows that amyloid is an important biomarker for Alzheimer's and that it is possible with careful neurocognitive testing to pick up subtle deficits. It gives us a vision of what the world of Alzheimer's will look like five years from now. The problem is: What can we do about it? As we follow this study population into the clinical treatment phase, we will have to see what happens.”

David M. Holtzman, MD, FAAN, professor and chairman of neurology at Washington University School of Medicine, added: “This is in many ways what we would have expected. People positive for beta-amyloid are probably having some cognitive dysfunction even though from the family members and clinician's impression, they still seem cognitively normal. These differences in cognition suggest that amyloid-related pathways are leading to some subtle cognitive changes and that over the next several years there will be cognitive decline in the amyloid-positive individuals.”

He said it will be “very interesting to see how much the people on the active drug progress over the time course of this study compared to those on a placebo dose.”


Dr. Sperling has served as a consultant and received compensation from AC Immune, Biogen, Eisai, Janssen, Neurocentria, Roche, Takeda; her husband has consulted and received compensation from AC Immune, Janssen, and Novartis. Dr. Bateman serves as a principal investigator in research partially sponsored by Eli Lilly and Company and Hoffman-LaRoche for the DIAN-TU study. He receives lab research funding from the Tau SILK Consortium (Eli Lilly and Company, AbbVie, and Biogen) and receives additional research funding from the DIAN Pharma (Eli Lilly and Company/Avid Radiopharmaceuticals, Hoffman-La Roche/Genentech, Biogen, Eisai, Janssen, and United Neuroscience). Dr. Holtzman is an inventor on patents for solanezumab; if it is approved, he will receive part of the net sales of the drug from Eili Lilly and Co., which has licensed the patents related to solanezumab from Washington University. Dr. Fillit has no disclosures.

Link Up for More Information

• Sperling RA, Donohue MC, Raman R, et al. Association of factors with elevated amyloid burden in clinically normal older individuals JAMA Neurology 2020. Epub 2020 Apr 6.