Recent research published in Alzheimer’s disease and dementia This suggests that older adults with early biological signs of Alzheimer’s disease experience markedly different rates of cognitive decline. Many of these people remain mentally sharp for years, but a smaller number rapidly lose their memory and thinking skills. The study, funded in part by the National Institutes of Health, shows that this variation is not well predicted by existing medical tests, providing evidence that clinical trials testing new treatments may need to reconsider their selection of participants.
Alzheimer’s disease develops in the brain long before memory problems become apparent to patients or their families. This early stage is known as preclinical Alzheimer’s disease. During this long period of time, abnormal proteins slowly begin to accumulate in the brain.
One of these key proteins is called amyloid beta, which forms sticky plaques between brain cells. Another protein involved in the disease process is called tau. Tau normally helps stabilize the internal structure of healthy brain cells.
In Alzheimer’s disease, tau becomes abnormal and forms destructive tangles within cells. Scientists can measure the presence of these proteins using special brain scans and blood tests. These measurements help doctors identify patients in the preclinical stages of the disease.
Medical professionals conduct special studies known as secondary prevention trials to test drugs at this very early stage. The goal of these prevention trials is to stop the disease before it causes significant memory loss, or slow its progression. Previously, these clinical trials typically grouped older adults simply based on the presence of amyloid plaques.
A basic assumption in the medical field was that everyone with these plaques was on a similar path to memory loss. However, in real-world clinical settings, scientists have found that the rate of cognitive decline varies widely from person to person. Some older people with amyloid buildup appear to maintain their cognitive abilities well for a long time, while others deteriorate rapidly.
“Most studies look at averages across participants, so it can appear that everyone is slowly getting worse at the same rate,” says Michael Donahue, professor of neurology and associate director of biostatistics at the University of Southern California’s Epstein Family Alzheimer’s Disease Treatment and Research Institute at the Keck School of Medicine. Donohue is the corresponding author of this paper. “However, we found that this approach masks large differences between people, suggesting that Alzheimer’s disease is more variable than often suggested.”
To better understand these different pathways, researchers investigated whether certain biological markers could predict a person’s trajectory. They also investigated how this natural variation affects the underlying mathematics for successful clinical trials.
To investigate these different pathways, the authors analyzed data from two large parallel studies in older adults aged 65 to 85 years. The first is anti-amyloid treatment research in asymptomatic Alzheimer’s disease, a clinical trial testing specific treatments. They also included data from a related study in people who did not have elevated amyloid levels.
At the beginning of the study, all participants were considered completely cognitively free. The total sample included exactly 1,629 people. The average age of the participants was approximately 71 years, and approximately 60 percent of the group was female.
Of this group, 1,110 participants had elevated levels of amyloid beta in their brains, while the remaining 519 participants did not. Researchers tracked participants’ memory and thinking skills for up to seven years. Median follow-up for the entire group was just 6 years.
Before and during the test, participants completed a series of cognitive tests that measured memory, attention, and thinking skills. Scores from these standardized assessments were used to track the rate of cognitive decline.
The researchers also collected blood samples to measure a specific type of abnormal tau protein called p-tau217. In addition to blood tests, they used advanced brain imaging tests to determine exact amyloid levels throughout the brain. They also used magnetic resonance imaging scans to measure the precise volume of the hippocampus. The hippocampus is responsible for forming new memories and is one of the first brain regions affected by the disease.
A small subset of exactly 427 participants also underwent a specific type of positron emission tomography scan (PET scan) to directly measure tau tangles. The authors applied complex statistical models to all of this collected data to identify subgroups of unobserved cognitive decline.
The mathematical model was able to determine how many different paths exist based on the data, rather than assuming an average rate of decline for everyone. Data analysis revealed three distinct trajectories of cognitive decline. These include a stable group that showed no change or slight improvement, a slow decline group that showed a gradual decline in test scores, and a rapid decline group that showed a faster and more pronounced decline in scores.
Approximately 70% of all participants remained stable over the approximately 6-year study period. Looking specifically at participants who had elevated brain amyloid, the scientists noticed a similar pattern. Almost 70% of these individuals remained completely cognitively stable during the observation period.
The scientists then investigated whether the biological markers at the beginning of the study could predict which group a person would fall into. They found that participants who showed a gradual or rapid decline had higher p-tau217 levels at the start of the study. These declining people had higher levels of tau in their brain scans than stable people.
“P-tau 217 was one of the strongest indicators of which participants would drop out, but we still cannot predict exactly how an individual’s disease will progress,” Donahue says.
Those in the study with smaller hippocampi were also much more likely to experience cognitive decline sooner. Interestingly, amyloid levels played a role in predicting decline, but blood tests for tau and measurements of brain shrinkage tended to be stronger predictors.
A genetic risk factor known as the APOE e4 allele also increased the likelihood that a person would fall into the decline group. This particular genetic mutation is widely recognized as a major genetic predictor of Alzheimer’s disease. By using all of this biomarker data, the researchers were able to accurately predict whether participants were likely to remain stable or have an approximately 70% chance of worsening.
The authors found an interesting contrast regarding biological changes in the stable group. Although stable participants with elevated amyloid levels showed no signs of memory loss, their biological tests worsened over time. Their brain scans showed increased amyloid and tau accumulation, and their hippocampus continued to shrink. This suggests that these stable individuals are at a much earlier stage of the disease process.
The researchers also performed mathematical simulations to understand how these different groups affect clinical trials. They modeled a hypothetical trial in which 500 participants were given the drug and 500 were given a placebo. They found that trials filled with stable people had little statistical power to detect a drug’s benefit after two or four years.
Stable participants do not spontaneously decline, so drug treatment cannot demonstrate the protective effect of their memory. The statistical power of a trial will ultimately depend almost entirely on a small number of participants, which is actually attrition. This finding indicates that enrolling too many stable individuals diminishes the measurable effects of new treatments.
“These results suggest that we may need to rethink how we design preclinical Alzheimer’s disease clinical trials,” said Lumpeng Li, a postdoctoral fellow at the Keck School of Medicine and lead author of the study. “Many people with Alzheimer’s disease remain stable throughout the study, which can make it difficult to determine whether treatment is effective. Identifying those who are more likely to decline could make clinical trials more efficient and beneficial.”
Although this study provides robust data, there are some potential misconceptions that should be avoided. For example, the results of this study do not mean that stable people do not experience memory loss. The preclinical stage of the disease can last more than 10 years before obvious symptoms surface. The 6 years of observation in this study may be too short to capture the eventual decline of a stable group.
This study also has certain limitations that affect how the findings are applied. The statistical models used to group participants rely on probabilities rather than absolute categories. Furthermore, the specific brain scans used to measure tau tangles were only available for some participants, limiting the broader application of these specific tau findings.
The participant sample also included volunteers who met the clinical trial’s rigorous criteria. This particular group may not be fully representative of the general population of older adults living in the community. Unmeasured factors such as diet, exercise, and other medical conditions can also influence how quickly a person’s memory declines.
A key next step is to refine the model to better predict which patients will quickly decline. Adding more blood tests, brain scans, or other biomarkers is one possible way to achieve that goal. This type of predictive tool could one day provide a more accurate prognosis when a patient is diagnosed with Alzheimer’s disease. Better predictive models could also support more effective clinical trials of potential treatments.
Scientists say future trials should focus on different patterns of decline rather than average results. Next, Donahue and his colleagues plan to study participants who did not meet the model’s expectations. These include patients whose symptoms remain the same but are predicted to worsen, and those whose symptoms remain asymptomatic but are predicted to decline.
“What is different about certain patients that makes them more resilient? And can we use these insights to slow the progression of Alzheimer’s disease in other patients?” Donahue said.
The study, “Diverse patterns of cognitive decline in preclinical Alzheimer’s disease: Implications for secondary prevention trials,” was authored by Runpeng Li, Oliver Langford, Philip S. Insel, Reisa A. Sperling, Rema Raman, Paul S. Aisen, and Michael C. Donohue.
