What Happens After Amyloid Plaque Removal? Who Benefits Most?

Series - International Conference on Alzheimer's and Parkinson's Diseases 2023:

Even though there were no big revelations from immunotherapy trials at this year’s International Conference on Alzheimer’s and Parkinson’s Diseases, held March 28 to April 1 in Gothenburg, Sweden, new data from several programs deepened the field’s understanding of what happens when amyloid plaque is cleared from a person's brain. Different sets of trial data painted a remarkably consistent picture, showing that mopping up large amounts of plaque blunts downstream biomarkers of tau pathology, inflammation, and neurodegeneration. Clinical differences only become detectable once Aβ is mostly banished, i.e., below the threshold for brain-wide positivity.

  • Removing plaque normalizes downstream tau and neuroinflammation markers.
  • Complete removal is crucial for cognitive benefit.
  • People with lots of tangles—that's often women—benefitted the least.

Not everyone benefits equally from amyloid immunotherapy. Several presentations reported that people with a high tangle load clear less plaque, and their downstream biomarkers respond less robustly. Women tend to have more tangles than men at a given stage of disease, producing a sex difference in outcome in some studies. Some speakers offered a glimpse at long-term data that hint removing plaque can stabilize biomarkers and flatten disease trajectories, though the number of people remaining in studies after several years is tiny, hence subject to bias (see next story, Part 7 of this AD/PD series).

Throughout the conference, speakers extolled the historic nature of the meeting, the first AD/PD to be held since the field witnessed unambiguous Phase 3 results that removing amyloid slows disease progression (Dec 2022 conference news). Appropriately enough, that molecule, lecanemab, was developed in Sweden, originally by Lars Lannfelt and colleagues at Uppsala University.

“This meeting marks a milestone—117 years after the discovery of β-amyloid, and 39 years after identifying the polypeptide sequence, we have succeeded in removing it from the brain,” Roger Nitsch of Neurimmune, Switzerland, said in the meeting's opening address. He noted that this now allows scientists to investigate whether the aging brain can restore itself toward healthier function in the absence of plaque, and if so, by how much.

“We are witnessing the validation of the first disease-modifying target for Alzheimer’s disease,” Wagner Zago of Prothena said, adding, “The success of anti-amyloid immunotherapy increases the odds that other therapies will work. We now know that Alzheimer’s disease can be slowed.”

Clinicians and researchers have been desperate for a win, after decades of trying and failing. This conference reverberated with a sense of relief about finally having made what feels like a real start toward disease modification. This story will cover how plaque clearance affects the brain, and what factors determine whether a given person responds.

Threshold Effect? Read from right to left, this diagram shows that positive immunotherapy trials pushed plaque load to below 25 centiloids. Trials falling just short of that were negative, implying that something crucial happens in the brain when plaque is substantially eliminated. [Courtesy of Roger Nitsch.]

Plaque Gone? Downstream Markers Edge Toward Normal
No matter the antibody, removing large amounts of plaque seems to be key for nudging other biomarkers back toward healthier values. Consider data from Lilly’s Trailblazer-Alz4 trial, which compared donanemab and aducanumab treatment head-to-head, without a placebo group. The company had earlier reported that during the first six months, donanemab mopped up 62 centiloids of plaque, four times as much as aducanumab, partly due to donanemab’s faster titration to the effective dose. In addition, plasma p-tau217 fell by a quarter on donanemab (Dec 2022 conference news).

In Gothenburg, Hong Wang of Lilly added six-month data showing that other biomarkers of inflammation and neurodegeneration moved, as well. Plasma p-tau181, which reflects the presence of both plaques and tangles, fell 16 percent in the 66 people on donanemab, while rising 5 percent in the 64 on aducanumab. GFAP, a marker of gliosis, fell 8 percent on donanemab, while rising 9 percent on aducanumab. NfL, believed to be a marker for damaged neurons, rose in both groups, by 11 percent on donanemab and 17 percent on aducanumab. All these group differences were statistically significant. Importantly, all indicated normalization of biomarkers with large plaque removal, but continued progression with only modest removal. About 40 percent of people on donanemab became amyloid-negative by six months, versus a single person on aducanumab.

Wang linked these biomarker changes directly to clearance, showing that across the cohort, people who cleared more plaque lowered their plasma p-tau217, p-tau181, and GFAP by more. Plasma NfL was an exception. It did not correlate with amyloid removal; however, it did weakly correlate with the other plasma markers.

Data from the negative Phase 3 Graduate 1 and 2 studies of gantenerumab paint a similar picture. Roche had previously reported insufficient amyloid clearance in this trial, with participants on drug losing about 53 centiloids over more than two years, short of the expected clearance of 70. Only a quarter of participants became amyloid-negative. Cognitive decline on the CDR-SB and ADAS-Cog 13 nudged down an average of 11 percent, below statistical significance (Dec 2022 conference news). In Gothenburg, Roche’s Janice Smith added MMSE data to this, reporting a similar non-significant slowing of 9 percent on drug.

Treatment Effect. On gantenerumab (blue), CSF biomarkers of amyloid, tau, and neurodegeneration consistently normalized compared to untreated controls (gray). [Courtesy of Tobias Bittner, Roche.]

As with donanemab, plaque removal tracked with downstream markers. Tobias Bittner presented data from Roche’s NeuroToolkit suite of fluid biomarkers. In the two Graduate studies, a total of 293 people on gantenerumab and 269 on placebo donated cerebrospinal fluid. In this pooled CSF subgroup, Aβ42 rose 26 percent with treatment, while p-tau181 and total tau fell 23 and 16 percent, respectively. These changes normalized biomarkers, were statistically significant, and seemed to be a response to plaque removal. Surprisingly, CSF Aβ40, which fell 7 percent on placebo, fell further, by 17 percent, in those on gantenerumab. The difference was nominally significant, though it is unclear why it happened, Bittner noted.

Likewise, the inflammatory markers GFAP and S100B nudged downward by 5 and 14 percent on drug, while the synaptic markers neurogranin and α-synuclein fell 21 and 15 percent. Both inflammatory and synaptic markers rise in AD, the latter perhaps due to damaged synapses leaking these proteins into interstitial fluid. Meanwhile, the synaptic marker NPTX2 gave puzzling results, falling 19 percent on placebo and 26 percent on gantenerumab, a nominally significant difference. Bitter noted that NPTX2 is a newer marker in the toolkit and is not yet fully understood (see also Mar 2023 news). Finally, the neurodegeneration marker NfL, which rose 20 percent in the placebo group, rose 11 percent on drug.

The scientists also found effects in plasma, which was collected from all participants. As expected, Aβ42, Aβ40, and the Aβ42/40 ratio all rose on gantenerumab. This was likely not an effect of plaque removal, but rather due to antibody binding Aβ in the blood and prolonging its half-life, Bittner said. More telling was plasma p-tau, which does reflect brain pathology. P-tau181 and p-tau217 rose 9 and 13 percent, respectively, on placebo, but fell 16 and 32 percent on drug. Likewise, plasma GFAP rose 13 percent on placebo, and fell 10 percent on drug. There was no treatment effect on plasma NfL, perhaps due to the confounding effects of peripheral production, Bittner noted.

Notably, plasma markers were sensitive to the degree of plaque removal. Participants in Graduate 2 cleared about 10 centiloids less plaque on average than those in Graduate 1. This small difference showed up in blood, with the Graduate 2 cohort displaying a slightly smaller therapeutic effect on all biomarkers, even Aβ. The difference between studies did not show up in CSF because those data were pooled, due to the smaller number of participants. In plasma, the amount of plaque clearance correlated with the change in Aβ42 at r=-0.43, p-tau181 at 0.34, and GFAP at 0.16, again linking cleanup to widespread effects on pathology.

“These are quite robust treatment effects,” Bittner said, adding that this was surprising, given the clinically negative findings in these studies. Future analyses should compare participants’ final biomarker levels with values in healthy age-matched controls, to determine how close to normal they came, Bittner suggested.

Scientists at AD/PD said that even small differences in plaque removal around the clearance threshold appear to matter. Nitsch noted that all positive immunotherapy trials have brought plaque burden below 25 centiloids, whereas negative trials, such as Engage, Graduate 1, and Graduate 2, ended only slightly higher, with average amyloid loads of 35 centiloids or more (see image above). This implies that something important might happen around this threshold, and that near-complete plaque clearance is crucial.

To Christian Haass of Ludwig Maximilians University in Munich, the data validate the connection between amyloid, neuroinflammation, and tau. “The amyloid cascade is no longer a hypothesis,” he said in Gothenburg.

How to Find Likely Responders? Tangles Might Help
Some people clear amyloid faster than others—and have better outcomes. Are there characteristics, such as disease stage or APOE, that might help determine how well a person will respond to amyloid immunotherapy? In Trailblazer-Alz4, APOE genotype made no difference, Wang reported. However, a person’s tangle load at baseline did. People who started out with a lot of tau pathology, defined as a baseline tau PET SUVR of above 1.46, cleared less plaque over six months on donanemab, about 50 centiloids, compared to nearly 70 in the lower-tau subgroups.

This relatively small difference led to a stark effect on plasma biomarkers, with the high-tau subgroup gaining no benefit from donanemab. Their plasma p-tau181 stayed flat, while p-tau217, GFAP, and NfL rose at the same rate as in the aducanumab treatment group. These findings add to the evidence that amyloid removal may help people the most early in disease, before tau pathology takes off.

Wang noted different demographics in the high-tau group than the rest of the cohort. As might be expected, they had more clinically advanced disease and higher baseline biomarkers but, perhaps surprisingly, they also tended to be younger. Curiously high tau PET loads relative to other markers in younger patients have been cropping up in various studies ever since tau tracers came onto the scene (see Apr 2018 conference news) . These high-tangle trial participants also included more women. This could be due to women’s greater propensity to accumulate tangles (Aug 2018 conference news; Feb 2019 news; Nov 2019 news).

A similar effect popped up in subgroup analyses from the Graduate gantenerumab trials. Neither age nor APOE genotype affected the primary outcome, Smith reported in Gothenburg. Clinical stage did, with the mild cognitive impairment subgroup reaping slightly more benefit than the mild dementia group. However, that effect was weak, as slicing disease stage a different way, by baseline CDR score, did not show this difference.

A Girl Can’t Catch a Break. In the Phase 3 gantenerumab trials, women gained no clinical benefit from treatment (left), while men did (right). Findings were similar across all four clinical measures. [Courtesy of Janice Smith, Roche.]

Sexist Antibodies?
In contrast, the one characteristic that robustly affected outcomes was sex. Women gained no benefit from gantenerumab removal on any cognitive or functional measure, with their progression lines nearly identical to the placebo group’s. But men taking gantenerumab declined more slowly than did men on placebo—by 16 percent on the CDR-SB, 22 percent on the ADAS-Cog 13, 19 percent on the ADCS-ADL, and 16 percent on the FAQ. All four measures were statistically significant.

What is going on? Smith found no demographic differences between the male and female groups at baseline. They had the same clinical status, with around 55 percent MCI and the rest mild AD. They received the same number of gantenerumab doses and cleared about the same amount of amyloid. However, women in the study started with about 10 centiloids more plaque than men, 100 versus 90. This means they also ended the study further above the amyloid-negative threshold than did men.

Tellingly, perhaps, women also had more tau pathology at baseline in all four brain regions examined. In the two regions with the highest tau PET signal, the medial and lateral temporal lobes, women had SUVRs of 1.54 and 1.46, respectively, to men’s 1.35 and 1.28. Both these values would fall into the “high tau” category in the donanemab Trailblazer-Alz4 study. In their parietal and frontal lobes, women averaged 1.23 and 1.15, below this threshold but still higher than men, who had 1.11 and 1.05, respectively.

An audience member wondered if matching men and women by tangle load would eliminate the sex difference. Smith said the numbers in this substudy were too low to parse the data that way, but agreed it would be worth looking at. She also suggested exploring whether co-morbidities in women might contribute to their lack of response to immunotherapy. If the sex difference is solely due to tangle load, it would imply that anti-amyloid treatment might have to start sooner in women than men, placing even more importance on early detection of AD pathology in the clinic.

Frederik Barkhof of University College London reported the overall tau PET findings from the Graduate studies, not broken down by sex. Only 180 participants entered this substudy, and more than half dropped out, with 48 people on gantenerumab and 29 on placebo reaching the two-year mark. In the whole tau PET cohort, tangle load at baseline was 1.47 in the medial temporal lobe and 1.46 in the lateral temporal load, both above the “high-tau” threshold identified in the donanemab program, and there was no treatment effect. Barkhof did not discuss if this high baseline tangle load contributed to gantenerumab’s weak clinical effect in Phase 3.

A larger analysis from Mark Mintun of Eli Lilly jibed with his findings, though. Mintun examined data from positive trials of aducanumab, lecanemab, and donanemab to learn which participant characteristics predicted who would respond best. He found no consistent difference by APOE genotype or disease stage. However, the degree of amyloid clearance mattered; it determined the strength of the brake on tau pathology. In the donanemab Phase 2 trial, people who became amyloid-negative had less tangle accumulation during the trial than did those with only partial plaque clearance. In addition, amyloid removal in general correlated roughly linearly with a drop in p-tau.

Baseline tangle pathology also seemed to matter, Mintun added, referencing Wang’s data on downstream biomarkers stalling in the high-tau subgroup. This effect of baseline tangle load was independent of the amount of plaque clearance. In other words, even if plaques were cleared to below threshold in a person who started with a high tangle load, their downstream biomarkers barely budged. Mintun did not break down data by sex. The field urgently needs more data on how baseline tangles affect outcomes, he concluded.

Others have speculated that after tau pathology takes off in the cortex, Alzheimer’s disease will progress independently of amyloid. Thus, plaque clearance at that stage would do little good. The idea of a tangle threshold was proposed by Eric Karran, Marc Mercken, and Bart De Strooper as one possible model for Alzheimer’s disease, with the other being that accumulating tangles had a continuous, incremental effect (Karran et al., 2011; Alzforum webinar). Data now favor the threshold hypothesis.

More recently, the inflection point where tangles take over has been dubbed the “ca-tau-strophe” by Keith Johnson at Massachusetts General Hospital, Boston.

For more on the long-term effects of amyloid immunotherapy in early AD, see next story.—Madolyn Bowman Rogers

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References

News Citations

  1. Dare We Say Consensus Achieved: Lecanemab Slows the Disease
  2. Donanemab Mops Up Plaque Faster Than Aduhelm
  3. Gantenerumab Mystery: How Did It Lose Potency in Phase 3?
  4. Neuronal Pentraxin 2 Binds Complement Protein, Protects Synapses
  5. News From the PET Front: Early Amyloid Networks and Tau Mystery
  6. Do Brain Changes at Menopause Make Women More Prone to Alzheimer’s?
  7. Is a Woman’s Brain More Susceptible to Tau Pathology?
  8. ApoE4 and Tau in Alzheimer’s: Worse Than We Thought? Especially in Women

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Aduhelm
  4. Gantenerumab

Webinar Citations

  1. Resolving Controversies on the Path to AD Therapeutics

Paper Citations

  1. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011 Sep;10(9):698-712. PubMed.

Other Citations

  1. Part 7

Further Reading

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