November 8, 2023 | It may be possible one day soon to prevent Alzheimer’s disease, a devastating illness currently suffered by more than 30 million people worldwide. The good news comes straight from the mouth of Randall J. Bateman, M.D., professor of neurology at Washington University School of Medicine and director of the Dominantly Inherited Alzheimer Network (DIAN) and DIAN Trials Unit (DIAN-TU).
Bateman was making a keynote address at the recent Clinical Trials on Alzheimer’s Disease conference in Boston where he received a lifetime achievement award for his groundbreaking work in Alzheimer’s research, including the development of plasma biomarkers in Alzheimer’s diagnostics. Sequential events in the 30-year process from disease onset to death provide a quantitative map regarding how to approach the disease in clinical trials, what can be targeted, and how much those abnormal biomarkers can be normalized, he says.
Alzheimer’s disease has long been associated with grim numbers, including its ranking as the sixth leading cause of death and $200 billion in annual spending in the U.S. “But this is now changing, [and] the fact that there was no cure may no longer stand,” Bateman says.
Clinical cases of Alzheimer’s disease have been described in texts from thousands of years ago, he continues, but not until recently has humanity been able to change the course of it by removing one of the pathological changes—amyloid plaques. Medicine now has anti-amyloid treatments approved by the Food and Drug Administration (FDA) and available to patients in the clinic.
Work in the Bateman Lab has been heavily focused on individuals with dominantly inherited Alzheimer’s disease (DIAD), a rare form of the disease that has an early age of onset (typically before the age of 60). Studies within these families have revealed a lot about the course of the disease and potential paths to preventing it, says Bateman.
One of the cross-functional studies conducted by the DIAN demonstrated in a living cohort that the amyloid plaque buildup in the brain of patients is a process that begins 15 to 20 years before the first symptom onset, he reports. The decade-long clinical progression includes brain atrophy and brain hypermetabolism as the years tick forward, culminating in death.
DIAN investigators subsequently learned that tau tangles, the other main pathology of Alzheimer’s disease, could be tracked via PET scans, says Bateman. The tangles appear in the brain at the year of symptom onset and are well correlated with clinical progression. This is what allows mapping of the disease and its progression, not just for amyloid plaques and tau tangles but many other disease biomarkers such as “molecular diagnostic forms” providing clues as to how the disease starts and evolves.
Some of the fist clinical trials served to demonstrate the benefit of plaque-removing drugs in the symptomatic phase of the disease. Ongoing studies include “secondary prevention trials” that hold the promise of preventing disease symptoms from starting, Bateman says.
Primary prevention trials both underway and planned aim to prevent the pathology of the disease from developing, says Bateman. Investigators are optimistic that they might be able to “slow, stop, or minimize the number of people who actually end up getting Alzheimer’s disease, even as we reach older ages in our societies.”
The impact of these trials relates not just to the cognitive benefits but improvement to the quality of life of people enrolled in the studies, he adds. “Even if they are only slowing the clinical progression by 30% or so, this is having a real-world impact for people.”
As shown in a study that published recently in Neurology (DOI: 10.1212/WNL.0000000000207438), “the number of people who become amyloid negative is directly proportional to the kinds and magnitude of effects that we see in these [anti-amyloid treatment] trials,” points out Bateman. “If we don’t get enough people to become amyloid negative in a short enough time there is very little benefit.” But trials where plaque is fully removed in most participants show clear cognitive and clinical benefits.
The unknown is what needs to be done to help prevent the disease, although several trials are underway that explore that question, Bateman says. The DIAN-TU launched its first prevention trial in 2012 and it began as a phase 2 trial that transitioned to a phase 3 trial of a pair of investigational drugs (gantenerumab and solanezumab) in mutation carriers with the goal of reversing plaques and stopping disease biology and onset of dementia.
The drugs succeeded in removing many amyloid plaques in both symptomatic and asymptomatic individuals over the course of the original four-year trial, although people in the former group did not reach normal based on a clinical dementia rating tool, says Bateman. But plaque removal was associated with relatively large improvements in multiple biomarkers, including cerebrospinal fluid (CSF) levels of amyloid beta (Aβ)42/40, total tau, phosphorylated-tau (p-tau)181, and partial mitigation of the neurofilament light chain.
This provided biological evidence that the drug was beneficial, just not as measured clinically or cognitively, he continues. Researchers decided to do an open label extension on the study to see what would happen if a subgroup of participants—all destined to get Alzheimer’s disease in their 30s, 40s, and 50s—continued with treatment.
After an average of eight years on gantenerumab, those in the group receiving the highest doses of the amyloid-removing drug may have cut their risk of progressing to symptomatic Alzheimer’s disease in half. If validated in larger studies, the implication is that Alzheimer’s disease can be prevented, says Bateman.
The next question was how to translate findings from a trial in people with DIAD to those with sporadic Alzheimer’s disease. A comparison of different trials and drugs that have been tested in the two groups reveals matched findings, Bateman says. “We can use these two forms of disease to inform each other and to inform the field about strategies and ways that we may be able to slow down or stop this disease.”
Since tau tangles in the brain of Alzheimer’s patients correlates best with clinical and cognitive progression, “surely it is worth testing to try to ameliorate the disease in symptomatic people,” says Bateman. However, it is not yet known if the pathology can be slowed or stopped.
The evidence build is underway to answer that question and to know if and how tau drugs should be coupled with the amyloid removal tactic, he says. The Bateman lab is comparing the possibilities by treating participants in different orders—the symptomatic group first with the anti-amyloid therapy and then randomizing them to a tau drug (E2814) and, for the asymptomatic group, starting with the tau drug and then pivoting to amyloid-removing agents.
The “ultimate impact” of plaque removal remains a mystery, Bateman adds. What is known is that plaques at the microscopic scale are “dystrophic,” destroying the normal architecture of the brain. “It’s possible that the best benefit, the strongest benefit, may come from preventing people from getting plaques in the first place.”
Primary prevention efforts at Washington University are being led by Eric McDade, DO, including one about to launch by DIAN-TU, reports Bateman. Previous trials of DIAN-TU have looked at three anti-amyloid drugs, including a beta secretase inhibitor, and a trial is now underway combining lecanemab with the E2815 tau antibody. Two additional tau drug arms will also be enrolling participants.
Prevention of aggressive forms of disease is not only possible but has been done before, Bateman notes. He specifically references statin drugs used to treat hypercholesterolemia, thereby giving individuals decades of good quality life otherwise lost to heart attacks and strokes. In a similar way, people with DIAD might one day soon be given many years free of dementia.
In the general population, delivering on that promise requires knowing who is going to have Alzheimer’s and, ideally, roughly when they’ll get it and the stage of their disease.
Blood tests for Alzheimer’s disease, considered the holy grail as recently as seven years ago, are now well accepted in the field, says Bateman. But they must deliver “the right kinds of properties for the intended use,” which might variably be for diagnosing individuals, screening for clinical trials, or tracking drug effects in studies.
Multiple blood tests now exist, including those that rival the performance of CFS tests and PET scans, allowing biomarker tracking in the blood and the running of large, well-represented trials in Alzheimer’s disease, he says. They represent a “transformational opportunity” in how medicine gets delivered, at-risk individuals are diagnosed or identified as being at risk, and clinical trials are conducted.
First-generation blood tests look at Aβ42/40 and require “incredibly precise” measurement because differences between the two peptides are relatively small, says Bateman. “But in multiple cohorts across multiple studies, it has been demonstrated to be a fairly good test.” When combined with other types of tests, accuracies are far better than gold standard tests currently used in the clinic and the disease can be detected five years earlier than it would be on a PET scan.
The phosphorylated soluble form of tau that is discoverable in the blood and specific to Alzheimer’s is different than the part that aggregates into tau tangles, he points out. The Bateman lab ran the five-year Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (aka SEABIRD) that enrolled 1,120 people at a single center in St. Louis where participants gave blood and had cognitive assessment tests and some also had a PET scan and APOE genotyping.
The purpose was to understand the relationship between Aβ in the blood and Aβ deposits in the brain. Study participants represented a real-world population with diversity in terms of medical comorbidities, race, and socioeconomic status, says Bateman.
Performance of the ratio test pT217/T217 had a negative predictive value of 0.96 while the Aβ42/40 test had an AUC (a global measure of diagnostic accuracy) of 0.88, mirroring prior studies in DIAD populations. “Recent developments and discoveries have shown that we can now track the process in the brain that leads to the tau tangles,” he adds, referencing work being led by his colleague Kanta Horie, Ph.D., finding that the microtubule-binding region (MTBR) of tau243 is tied to tau tangle pathology (Nature Medicine, DOI: 10.1038/s41591-023-02443-z).
In two independent cohorts, investigators looked at the relative relationship of multiple different markers—MTBR-tau243, p-tau181, p-tau205, p-tau217, and p-tau231—to demonstrate that each of them is independently a sensitive and specific biomarker of both amyloid plaque and tau tangles. “We can now use this information in our trials, including our combination trials [of the two pathologies] ... to track clinical progression of the disease, even of individuals,” says Bateman.
“Instead of screening 10 people to enroll one... who has amyloid plaques, or has a certain amount of tau tangles, you can use these blood-based biomarkers at the beginning of the screening process and save substantial amounts of resources but importantly time,” he continues. “And as soon as we can bring an effective treatment forward, the more benefit it has for patients.”
New data currently under review suggests that p-tau217 ratios, as measured in the Bateman lab using mass spectrometry, “rival or surpass” the precision of FDA-approved CSF tests. “Blood tests are not just for screening; we can use [them] as a single confirmatory test as to whether someone has amyloid plaques or not, and I predict in the future we’ll be able to use these to track an individual disease process.”
Bateman and his team hope to receive funding so they can launch a study taking the research opportunity to patients rather than asking them to go to a research site. The so-called SUNBIRD study, now under consideration by the National Institutes of Health, will be much like SEABIRD except for the setting, he says. Eighty percent of the proposed 1,000-person cohort will be followed over the years to determine the impact of a blood test done in real-world primary care clinics.
Among Bateman’s predictions is “continued development and approval of disease-modifying treatments for symptomatic patients.” He also says it’s “only a matter of time before we implement in the clinic rapid and accurate diagnosis... not for people who have access to PET scans and spinal taps, not for people who have insurance coverage of some test and not others, but for everyone.
“I do think we will deliver on the promise of changing the course of the disease and I think that demonstration may not come in research studies; it may come from our clinics where we will demonstrate we can keep more patients with their thinking, their memory, their cognition, and their function intact, and we will delay the onset of their dependency, of their admission to nursing homes,” he continues. Additionally, current and future prevention trials are likely to see some degree of success, enabling widespread screening of the general population to “herald a new era where we can prevent Alzheimer’s disease for millions of people.”