Living Among Us: People Whose Alzheimer’s Is Already Being Prevented
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At early symptomatic stages of Alzheimer’s disease, amyloid immunotherapy taps the brakes on cognitive decline, but does not halt the disease. Many researchers think the full promise of plaque removal lies in prevention. If plaques were abolished before they could kick off downstream pathologies such as tangles, would the disease be stopped in its tracks?
- In the DIAN secondary prevention trial, gantenerumab halved the risk of developing memory problems.
- The drug only moderately cleared plaque, but still prevented tangles in some people.
- A few individuals remain cognitively healthy years after their expected age of symptom onset.
First glimmers of this were on display at the Alzheimer’s Association International Conference, held July 28 to Aug 1 in Philadelphia. Randall Bateman of Washington University in St. Louis presented data from the Dominantly Inherited Alzheimer Network that showed knocking down plaque halved the odds that cognitively healthy people who carry an autosomal-dominant AD mutation would develop memory problems over a 10-year period. In some individuals, the effects were dramatic, with their brains free of plaques and tangles and their memories normal as many as 12 years past their expected age of disease onset.
The numbers are small. Still, Bateman believes the data prove the principle that preventing Alzheimer’s is possible. This group of people has taken plaque-removing drugs for longer than anyone else in the world. Therefore, their data are leading the way in showing what is possible with amyloid immunotherapy.
At the Dominantly Inherited Alzheimer Disease Family Conference, held before AAIC, Teresa Buracchio of the U.S. Food and Drug Administration agreed with this view. “DIAN efforts have been groundbreaking in advancing the science,” she said. Buracchio told participating families that their data inform trial design in sporadic AD, determining parameters such as what biomarkers to use and how long trials should be. They will also aid the FDA in interpreting trial results. “This improves our ability to approve drugs,” Buracchio said.
Delayed Symptom Onset
The first trial in the DIAN cohort, dubbed DIAN-TU-001, enrolled 144 mutation carriers, as well as 50 noncarrying relatives, who received either gantenerumab, solanezumab, or placebo for as long as seven years. After a one-year gap, about half the mutation carriers entered an open-label extension of high-dose gantenerumab for up to three years. That ended last year when Roche stopped development of gantenerumab due to insufficient Phase 3 efficacy in late-onset AD.
Preliminary analysis of the OLE data, presented at the 2023 Clinical Trials on Alzheimer Disease conference, suggested a lower risk of clinical progression in people who had been on gantenerumab throughout. A few developed symptoms six years later than their expected year of onset (EYO) (Nov 2023 conference news).
Further analysis has now firmed up the numbers. In Philadelphia, Bateman said 22 initially asymptomatic mutation carriers received gantenerumab throughout the double-blind and OLE periods. These periods added up to an average of eight years of exposure. These 22 were compared with 74 untreated people; they comprised participants who received placebo in the double-blind period as well as matched controls from the DIAN observational study.
By the end of the OLE, the gantenerumab group had half the odds of developing symptoms as did controls. The finding missed statistical significance at p=0.07. Fleshing out the control group by adding the 12 participants who switched from placebo to gantenerumab strengthened the finding, making it nominally significant at p=0.03. Meanwhile, separate analyses of people who took gantenerumab only during the OLE showed no difference from controls.
The lesson? In order to make a difference, robust amyloid removal needs to start early and continue for a long time, Bateman concluded.
He noted caveats. Not only was the study small, but using external controls from the DIAN observational trial also weakens the conclusions. OLE data are subject to selection bias, as healthier participants tend to stay in. The blinded portion of the trial initially contained 53 people on gantenerumab, meaning more than half discontinued before the end of the OLE. Indeed, the family meeting welcomed care partners who had been accompanying their affected spouses for many years, but were no longer able to bring them as the spouse’s dementia had advanced beyond the point where they could continue in the trial, or travel. These care partners are now coming with their young adult children, who are hoping for primary prevention.
In addition, the study population was not uniform in terms of disease stage. This first DIAN trial had a range of presymptomatic and symptomatic carriers at baseline. This was done to learn, and also to offer a treatment trial to loved ones of family members who were giving time and effort to the DIAN project.
Even Incomplete Plaque Removal Arrested Tangles
From another point of view, however, the findings are remarkable, given the limited plaque-busting power of the low-dose gantenerumab used for much of this trial. Dosing started at 225 mg monthly, was quintupled to 1,200 mg halfway through the placebo-controlled period, and then nearly tripled again, to 1,500 mg biweekly, for the OLE’s last two years as scientists learned more about gantenerumab’s safety and required dosing. As a result, most plaque clearance happened late, according to data presented by Tammie Benzinger at WashU. During the placebo-controlled period, people taking the drug cleared only 10 centiloids of their plaque on PiB PET, while those on placebo or solanezumab accumulated 20 more centiloids. Familial AD mutations produce rapid, massive plaque deposition, unlike the slower accumulation seen in late-onset AD.
During the gap year, plaque rose similarly in all groups, by 5 to 10 centiloids. At the start of the OLE, participants had an average of 62 centiloids of plaque in their brains. For context, this is not far below the 76 centiloids that symptomatic late-onset AD patients started with in the lecanemab Phase 3 trial. It also tops a 60-centiloid threshold used to predict who in that cohort had higher tangle loads (Nov 2023 conference news).
During the first year of the extension, participants cleared only five centiloids. After the dosage was upped, they cleared about 12 centiloids per year, for a total removal of 29 centiloids in the OLE. This meant participants ended the trial with an average amyloid load of 33 centiloids, still above the positivity threshold of 24. Overall, only a third of participants became amyloid-negative by the end of the OLE, Benzinger said. In sporadic AD trials, cognitive benefits only emerge when plaque is completely removed (Nov 2023 conference news).
In essence, plaque removal was “underdosed” relative to what scientists have since learned from lecanemab and donanemab Phase 3 LOAD trials. Even so, the treatment helped check tangles. During the placebo-controlled period, the flortaucipir tau PET signal rose about 0.5 SUVR in people taking solanezumab or placebo, but stayed relatively flat over three years in those on gantenerumab. Looking a bit closer, tau PET actually rose slightly during the first two years on very-low-dose gantenerumab, but fell back to baseline levels once the dose went up. During the gap year without treatment, tau PET rose by 0.2 SUVR in people previously on gantenerumab or solanezumab, and shot up 0.6 SUVR in those previously on placebo. In the OLE, tau PET flattened again for the previous gantenerumab and solanezumab groups, but continued to rise in the former placebo group.
Why did people previously on solanezumab respond more robustly to gantenerumab, compared with those who started on placebo? DIAN researchers did not speculate. They did say the data were consistent, in that the same pattern showed up with cerebrospinal fluid biomarkers Aβ42/40 and p-tau217, according to Laura Ibáñez at WashU.
Underlying these averaged group results lay great variation in tau PET outcomes at the individual level. Some people remained tau-negative throughout the study. Others started the OLE tangle-positive and in some the signal went down with treatment, whereas in others it rose. It is not yet known what factors influenced this. For case reports of this trial, and more, continue on to the next story.—Madolyn Bowman Rogers
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