An method devised by researchers at Washington University School of Medicine in St. Louis estimates when someone who is prone to acquire Alzheimer’s disease but has no cognitive symptoms will begin exhibiting indications of Alzheimer’s dementia. It utilizes data from an amyloid positron emission tomography (PET) scan, which measures brain levels of the main Alzheimer’s protein amyloid beta. The method is published in the journal Neurology and may be seen online. Amyloid quietly accumulates in the brains of individuals who may ultimately acquire Alzheimer’s dementia for up to two decades before the first symptoms of confusion and forgetfulness emerge.. Using Amyloid PET scans, which are currently extensively used in Alzheimer’s research, is an algorithm that may help predict when symptoms would start appearing. The program estimates how far a person has advanced toward dementia — and how much time is left before cognitive impairment comes in — based on their age and data from a single amyloid PET scan.
Professor of neurology and senior author Suzanne Schindler, MD, PhD, stated, “When I inform cognitively normal people with positive findings from amyloid PET scans, the first question is usually, ‘How long do I have before I develop dementia?'” “There was a time when my only response was, “You’re at greater risk of dementia in the next five years.” Nevertheless, what does it imply? People want to know when symptoms will appear, not simply whether they are more likely to acquire them.” Amyloid PET scans from 236 Alzheimer’s disease participants were examined by Schindler and colleagues at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University. At the start of the research, the participants had an average age of 67. For each individual, there were two MRI scans performed at a minimum, with an average interval of 412 years between scans. The quantity of amyloid in each participant’s brain at each time point was estimated using a commonly used measure known as the standard uptake value ratio (SUVR) applied to the images.
Over 1,300 clinical evaluations of 180 individuals were also accessible by the researchers. The evaluations took place every one to three years on average. When the study started, most individuals had normal cognitive abilities, thus the researchers were able to identify when a participant’s cognitive abilities began to deteriorate via the use of repeated evaluations. Schindler worked for years to find out how to utilize amyloid PET scan data to predict when symptoms might emerge. One of her most important discoveries was that amyloid buildup has a tipping point, and each person is different in when they reach that threshold. Amyloid buildup follows a predictable path after this turning point. This “tipping moment” may happen to anybody at any age, according to Schindler. “It may never happen,” he said. “However, once you’ve over that threshold, you’ll begin to build dangerously high amounts of the protein amyloid, which is linked to dementia. As long as we know how much amyloid a person has right now, we can figure out when they reached the tipping point and how long it will be until they start to show symptoms.”
Cognitive symptoms were longer to emerge in research participants who hit the tipping point earlier in life. At the tipping point of 50, participants usually take almost 20 years to acquire symptoms; at the tipping point of 80, participants take less than 10 years to develop symptoms. The brains of individuals with Alzheimer’s who died when they were young usually appear healthy apart from the disease, Schindler said. As a result of having dwindled cognitive reserves due to aging, older individuals are more susceptible to amyloid-induced cognitive impairment. Because it just needs one brain scan and the person’s age, this new method has a lot of potential. The model can predict the development of symptoms plus or minus many years using this information. Researchers found an excellent connection between anticipated age of symptoms and actual diagnosis, with an R-squared value of above 0.90 (no correlation) to 1 in this research (perfect correlation).
Age is the second most important risk factor for Alzheimer’s disease, followed by the genetic variation APOE4. Alzheimer’s disease is twice as common in individuals who have one copy of the variation as in the general population, and carrying two copies increases your risk by ten times. Researchers found that individuals with the high-risk variation had an earlier onset of the disease, but once the tipping point had been reached, they had the same course as everyone else. Schindler asserted that APOE4 seems to have a seeding function. “When amyloid levels are low, below the tipping point, individuals with APOE4 observe an increase in amyloid whereas those without APOE4 experience no change. As a result, those who have the APOE4 gene are more likely to reach a critical mass. People with two APOE4 alleles are approximately 10 years ahead of those without alleles when it comes to survival. APOE4 carriers and noncarriers are the same beyond that point.”
PET brain scans for amyloid are too costly for regular clinical usage, costing approximately $6,000 to the patient out-of-pocket. However, by simplifying clinical trials, this approach may help speed up medication development. “Most clinical trial participants do not acquire symptoms throughout the studies,” Schindler said of the experiments aimed at slowing or preventing Alzheimer’s symptoms. “That takes a lot of time and effort on both sides, with no real benefit to either the volunteers or the researchers. We might speed up the discovery of new treatments by conducting clinical trials exclusively on individuals who are expected to acquire symptoms in the next few years.”
Journal Reference: Suzanne Schindler, Yan Li, Virginia D. Buckles, Brian Andrew Gordon, Tammie L.S. Benzinger, Guoqiao Wang, Dean Coble, William E. Klunk, Anne M. Fagan, David Holtzman, Randall J. Bateman, John C Morris, Chengjie Xiong. Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET. Neurology, 2021; 10.1212/WNL.0000000000012775 DOI: 10.1212/WNL.0000000000012775