Brains Shrink With Anti-Amyloid Alzheimer’s Drugs

Anti-amyloid therapies for Alzheimer’s disease accelerated brain atrophy, a systematic review and meta-analysis of MRI data showed.

Across 31 clinical trials, brain volume changes were seen for different classes of anti-amyloid agents, reported Scott Ayton, PhD, of the University of Melbourne in Australia, and co-authors in Neurology.

The analysis focused mainly on two types of anti-amyloid drugs: secretase inhibitors (which have failed in clinical trials and worsened cognition) and monoclonal antibodies, including two drugs with accelerated FDA approvals, aducanumab (Aduhelm) and lecanemab (Leqembi).

Compared with monoclonal antibodies, secretase inhibitors had a prominent effect on volume changes in the hippocampus and whole brain.

Monoclonal antibodies led to accelerated ventricle enlargement, especially monoclonal antibodies that caused amyloid-related imaging abnormalities (ARIA). The frequency of ARIA was strongly correlated with the degree of ventricular enlargement (r=0.86, P=6.22 × 10^-7).

Brain shrinkage — a reduction in brain volume or an increase in the volume of the brain’s ventricles — typically is associated with Alzheimer’s progression. Why it occurs after treatment with anti-amyloid drugs isn’t known.

“Monoclonal antibodies caused about a 40% acceleration to enlargement of the lateral ventricle, which is a classic marker of neurodegeneration,” Ayton told MedPage Today. “This was only observed in drugs that induced ARIA, and we found a striking correlation between the frequency of ARIA and the extent of ventricular volume enlargement.”

“These findings call for an urgent re-evaluation of clinical trial data on brain volume and ARIA,” Ayton said.

“We don’t have access to patient-level data to investigate, for instance, whether people who developed ARIA had greater volume changes,” he noted. “We also don’t know which brain regions are most affected, the clinical characteristics of those people at risk, and whether these changes are related to cognitive and non-cognitive clinical outcomes.”

The analysis raises important questions, said Madhav Thambisetty, MD, PhD, of the National Institute on Aging in Bethesda, Maryland. “Is the emergence of ARIA in some patients an early warning sign that they are at greater risk of worsening neurodegeneration and potentially worse long-term clinical outcomes? Are APOE4 carriers, who are at greater risk of ARIA, also at greater risk of brain volume loss or increase in ventricular volume?”

“These questions can only be answered by the trial sponsors by fully reporting the results of such analyses or by making individual-level patient data from the randomized controlled trials available to qualified researchers,” Thambisetty told MedPage Today.

“It is equally important for regulatory authorities like the FDA and the European Medicines Agency to ensure that these analyses are fully reported and their implications clearly communicated to patients and physicians,” he added.

What these results mean for drugs like lecanemab, which is being considered for traditional FDA approval later this year, is unclear.

“The fact that consistent clinical and biomarker findings otherwise point towards a beneficial effect of lecanemab is reassuring and suggests that the brain volume declines may be irrelevant to the therapeutic pathway,” observed Frederik Barkhof, MD, PhD, of Amsterdam University Medical Center in the Netherlands, and David Knopman, MD, of the Mayo Clinic in Rochester, Minnesota, in an editorial accompanying the meta-analysis.

“Prior to the phase II trial of donanemab and then the phase III trial of lecanemab, brain volume declines did not attract much attention in the context of the repeated failures that anti-amyloid therapies experienced from 2001 up until 2021,” Barkhof and Knopman noted.

Bulk plaque amyloid removal seems like a plausible but unlikely explanation, the editorialists observed. “It is also possible that other mechanisms such as off-target reductions in inflammatory responses or alterations in cerebrospinal fluid dynamics could account for brain volume changes that are not due to neurodegeneration,” they suggested. Paradoxical changes in brain volume due to anti-inflammatory effects — known as pseudo-atrophy — have been observed in multiple sclerosis therapeutics, they pointed out.

“We cannot ignore the alternative, however,” they added. “Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate, or if they attenuate or disappear.”

Ayton and colleagues evaluated changes from baseline in 31 clinical trials of 14 anti-amyloid drugs in their meta-analysis, looking at the highest dose in each trial on commonly reported brain regions including the hippocampus, lateral ventricle, and whole brain. Drugs that favorably changed at least one biomarker of pathological amyloid-beta were included in the study.

Secretase inhibitors accelerated atrophy of the hippocampus (mean difference -37.1 μL, 95% CI -47.0 to -27.1; +19.6% relative to change in placebo) and whole brain (mean difference -3.3 mL, 95% CI -4.1 to -2.5; +21.8% relative to change in placebo) from baseline.

Monoclonal antibodies led to accelerated ventricular enlargement (mean difference +1.3 mL, 95% CI 0.6-2.1; +23.8% relative to change in placebo), which was driven by monoclonal antibodies that cause increased ARIA (mean difference +2.1 mL, 95% CI 1.5-2.8; +38.7% relative to change in placebo).

ARIA-inducing monoclonal antibodies had variable effects on whole brain volume. Donanemab (mean difference -4.6 mL, 95% CI -7.6 to -1.6; +23% relative to change in placebo) and lecanemab (mean difference -5.2 mL, 95% CI -8.1 to -2.4; +36.4% relative to change in placebo) showed accelerated whole brain volume loss, but aducanumab and bapineuzumab did not.

The lack of individual patient data limited interpretation of the findings, Ayton and colleagues acknowledged. Unmeasured confounders also may have influenced results.