An enlargement of the brain ventricle might set off alarm bells in a neurologist's office. And yet, in people on anti-amyloid immunotherapy, it occurs quite commonly. Is this a red flag, or an indication that the therapy is working? A new meta-analysis of AD clinical trial data rekindles this old debate, with expert opinion coming down on both sides.
- Anti-Aβ therapies come with some brain volume reduction.
- For immunotherapies, this correlates with ARIA and plaque removal.
- Scientists disagree on whether this represents neurodegeneration.
- They do want to see further study.
In the March 27 Neurology, scientists led by Scott Ayton, the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia, report that ventricular expansion, a sign of shrinking white and gray matter, tightly correlates with ARIA, aka amyloid-related imaging abnormalities, an MRI marker of brain inflammation. Lacking access to the full trial data, the authors were unable to determine if ARIA caused the volume loss. Still, they think these changes are not to be taken lightly. “We want to raise this as an issue that has been largely neglected in the analysis of these drugs, but is a safety concern, and we think it should be reviewed,” Ayton told Alzforum. The paper was covered in the news section of Science magazine.
The response from other experts in the field? Some think this volume loss is concerning. Others do not. They say the paper fuels anxiety in people who are candidates for anti-amyloid treatment, and could be used as a rationale to refuse reimbursement. The crux of the matter is whether this volume reduction represents neurodegeneration or something more benign, and whether it is progressive or stops after amyloid has been removed. The phenomenon is so little studied that nobody can answer these questions at present.
ARIA and Volume. In clinical trials, anti-Aβ immunotherapies that caused ARIA increased brain ventricular volume by an average of 2.1 mL. [Courtesy of Alves et al., 2023.]
That anti-Aβ therapies cause some shrinkage in the brain is nothing new. Ever since Aβ immunotherapy began 20 years ago, clinicians noted that people treated with the vaccine AN1792 lost parenchymal volume and gained ventricular volume faster than those on placebo (Jul 2004 conference news). Since then, therapeutic antibodies have been shown to increase ventricular volume, as well.
Ayton, first author Francesca Alves, and colleagues meta-analyzed clinical trials that had shown a favorable change in at least one Aβ biomarker, and which had sufficient data to measure volume change in at least one region of the brain. Of 145 trials surveyed, 31, testing 14 drugs, met the criteria. The treatments included passive and active immunotherapy, and secretase inhibitors. All told, the trials had enrolled more than 10,000 patients.
The highest doses of aducanumab, lecanemab, donanemab, and bapineuzumab all associated with increased ventricular volume. These antibodies cause ARIA, and the correlation between ARIA frequency in these trials and ventricular expansion was tight. On average, the therapies increased the ventricles by 2.1 mL, or 39 percent compared to placebo. “We were shocked by the degree of change, believe the acceleration is worthy of concern, and that the association with ARIA is a red flag,” Ayton said.
Lon Schneider, University of Southern California, Los Angeles, considers the volume change important. “Relatively speaking, it is an equal and opposite effect to the clinical CDR-SB effect,” he wrote. Schneider believes the primary outcome differences between treatment and control groups would be more compelling if accompanied by an increase, not decrease, in brain volume. “Without further consideration, we would be celebrating increased MRI volume as neuroprotection. This of course did not happen, and we are left explaining away the unexpected, and unwanted.”
Alves and colleagues emphasized that loss of brain tissue has been deemed the proximate cause of cognitive dysfunction in AD. They view the volume changes as evidence of disease progression. In general, brain atrophy is considered a marker for neurodegeneration, including in the A/T/N biomarker classification system for Alzheimer’s disease. The Alzheimer’s Association/NIA draft “ATN” research criteria recommend MRI volumes be used for the N, aka “neurodegeneration” component (Jack et al., 2016). "A finding of ‘N’ moving opposite to A and T might undermine ATN criteria for use in trials or as a surrogate outcome unless there is better understanding,” wrote Schneider.
To others, the volume changes in a treatment setting imply something else. “The authors are suggesting that MRI volumes are indicators for neurodegeneration, and certainly MRI volumes are useful in tracking disease in untreated individuals. But they are not viewed as being helpful in the context of therapy,” Paul Aisen, University of Southern California, San Diego, told Alzforum. Mike Weiner, University of California, San Francisco, had a similar interpretation. “It is correct that previous studies have shown a correlation of brain volume (especially hippocampal volume) with neuronal cell counts or neuronal volume. But those observations do not necessarily indicate that the volume loss that occurs in response to anti-amyloid treatment (especially plaque-lowering monoclonal antibodies) is caused by neuronal loss or reductions of neuronal volume,” Weiner wrote.
Gael Chételat, Cyceron, Caen, France, thinks volume is too broad a measure. “It is a nonspecific marker that might reflect many different underlying processes, including both ‘negative’ (pathological) and ‘positive’ (less inflammation or edema, fewer pathological molecules, etc.), even if greater volume usually correlates with greater cognitive performance,” she wrote (full comments below).
Aisen believes the more important observation is that amyloid-removing antibodies have shown clinical benefit in multiple trials. “In Clarity, a huge Phase 3 with about 2,000 individuals, every cognitive and clinical measure indicated a treatment benefit,” he said. “How can you call that neurodegeneration when every cognitive measure showed benefit?” Rather, Aisen and others, including Jeff Cummings, University of Nevada, Las Vegas, see the volume loss as a direct response to the treatment. “I would not call it atrophy, since atrophy implies cell loss and we do not know that to be the case,” Cummings wrote (comment below).
Like others, Cummings suspects amyloid dynamics are behind the volume loss. Early on, scientists had wondered if plaque removal alone accounted for it. Later, once they had calculated the total amount of amyloid plaque in the AD brain, they considered this explanation unlikely. Researchers led by Colin Masters, University of Melbourne, calculated that the AD brain only holds about 6.5 mg Aβ (Aug 2016 conference news; Roberts et al., 2017). Alves and colleagues, too, calculated that plaque removal itself would only explain one-thousandth of the volume change.
Then what explains the rest? The leading idea these days is that a kind of swelling goes down following plaque removal. “There is an inflammatory reaction around the neuropathology in AD, and if you reduce that reaction, you might see a resultant shift that would play out as a loss of volume,” Aisen said. “That is a conjecture, but it is more plausible than the idea—which nobody adheres to—that it is simply the removal of amyloid," Aisen added. Weiner was of the same mind. “Possibly, changes in volumes of astrocytes or glia could account for some of this,” he wrote. Oskar Hansson, Lund University, Sweden, recently reported that changes in diffusion MRI in cortical regions affected by plaque pathology are mediated by changes in reactive astrocytes (Spotorno et al., 2022; comment below).
Previously, Chételat had reported slightly higher brain volumes in asymptomatic amyloid-positive than amyloid-negative people (Chételat et al., 2010). Could this reflect inflammation, with a mild edema? Nick Fox, University College London, noted other examples in neurology where a treatment-related volume change does not mean neurodegeneration. “When steroids or mannitol are given to reduce brain edema, they also reduce brain volumes. In MS trials, ‘pseudo-atrophy’ did not imply a worse outcome for patients,” he wrote (full comment below).
Ayton does not buy it. “Volume loss is how we measure neurodegeneration,” he said. "If we are going to have a new interpretation, then it is up to others to prove it. We should not have optimistic interpretations without proof. It is better to be conservative.” Alves calculated that monoclonal antibodies that cause ARIA would shorten, by seven months, the time for brain ventricles in someone with MCI to reach the size typically seen in someone with AD.
Others took exception to that calculation. “Where I think more caution is needed is in equating ‘excess’ volume loss to ‘excess’ cognitive loss—which the evidence just does not support,” wrote Fox. “Nor should volume change be extrapolated to imply ‘increased rates of atrophy,’ or indeed, increased neurodegeneration,” Fox added. Indeed, in trials of the γ-secretase inhibitor verubecestat, volume changes were rapid but not progressive. In other words, they stopped. “It certainly does not seem justified to take a volume change, translate that into a rate of atrophy, and then project it forward to imply … that progression from MCI to AD would be more rapid,” wrote Fox.
Research clinicians urge investigation of the phenomenon now. “The imminent introduction of lecanemab into clinical practice forces us to confront evidence of apparent accelerated neurodegeneration with this therapy,” wrote Frederik Barkhof, Amsterdam University Medical Center, and David Knopman, Mayo Clinic, Rochester, Minnesota, in a Neurology editorial.
Barkhof and Knopman offered a positive note, too. In the lecanemab Phase 2 trial, there was a long gap between the end of the trial and an open-label extension, during which people regressed, but those who had been on lecanemab in the blinded phase did better in the extension. “With caveats about selective attrition and interruption in treatment, the persistence of a lecanemab benefit might be taken as provisional evidence that there was no looming neurodegenerative acceleration that would abolish lecanemab’s clinical benefit,” they wrote. Barkhof and Knopman conclude that this is uncharted territory. “The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain.”
Greater access to clinical trial data could help resolve the question. “The companies should report brain volume changes associated with treatment, the relationship to loss of amyloid plaques, ARIA, and cognition,” Weiner wrote.
Hansson calls for analysis of patient-level data. “It would be great if the companies with access to the individual-level data from anti-Aβ immunotherapies trials would study this phenomenon in greater depth and share their experience with the AD community,” he wrote.—Tom Fagan
- Philadelphia: Can a Shrinking Brain Be Good for You?
- Refining Models of Amyloid Accumulation in Alzheimer’s Disease
- Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. Epub 2016 Jul 1 PubMed.
- Roberts BR, Lind M, Wagen AZ, Rembach A, Frugier T, Li QX, Ryan TM, McLean CA, Doecke JD, Rowe CC, Villemagne VL, Masters CL. Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET. Brain. 2017 May 1;140(5):1486-1498. PubMed.
- Spotorno N, Strandberg O, Vis G, Stomrud E, Nilsson M, Hansson O. Measures of cortical microstructure are linked to amyloid pathology in Alzheimer's disease. Brain. 2022 Sep 21; PubMed.
- Chételat G, Villemagne VL, Pike KE, Baron JC, Bourgeat P, Jones G, Faux NG, Ellis KA, Salvado O, Szoeke C, Martins RN, Ames D, Masters CL, Rowe CC. Larger temporal volume in elderly with high versus low beta-amyloid deposition. Brain. 2010 Nov;133(11):3349-58. PubMed.
No Available Further Reading
- Alves F, Kalinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis. Neurology. 2023 May 16;100(20):e2114-e2124. Epub 2023 Mar 27 PubMed.
- Barkhof F, Knopman DS. Brain Shrinkage in Anti-β-Amyloid Alzheimer Trials: Neurodegeneration or Pseudoatrophy?. Neurology. 2023 May 16;100(20):941-942. Epub 2023 Mar 27 PubMed.