Do Anti-Amyloid Beta Drugs Accelerate Brain Atrophy in Alzheimer Disease?

Anti-amyloid beta (Ab) drugs may potentially compromise brain health in the long-term by accelerating brain atrophy, according to the findings of a systematic review and meta-analysis published in Neurology.

In recent years, secretase inhibitor and monoclonal antibody anti-amyloid beta therapies have been under development for the treatment of Alzheimer disease (AD). Some evidence suggests that these therapies reduce plaque and have promising effects to cognition, however, they have also been associated with magnetic resonance imaging (MRI)-detectable amyloid related imaging abnormalities (ARIA).

As potential volumetric changes caused by anti-amyloid beta drugs have not been sufficiently interrogated, researchers from the University of Melbourne in Australia searched publication databases through December 2022 for data about brain volumetric changes associated with anti-amyloid beta drugs.

A total of 31 trials met the inclusion criteria. The anti-amyloid beta drugs included in this analysis were aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, semagacestat, solanezumab, tramiprosate, AAC-001, IV immunoglobulin, and verubecestat.

In the pooled analysis, the highest drug dose used in the trials associated with accelerated volumetric changes in the hippocampus (mean difference [MD], -14.5 mL; I², 64.01%), whole brain (MD, -1.4 mL; I², 76.88%), and ventricles (MD, +0.9 mL; I², 87.64%).

Stratified by drug mechanism, secretase inhibitors associated with accelerated atrophy of the hippocampus (MD, -37.1 mL) and whole brain (MD, -3.3 mL), whereas monoclonal antibodies associated with accelerated ventricular enlargement (MD, +1.3 mL), driven by increased ARIA (MD, +2.1 mL).

Among monoclonal antibodies, donanemab (MD, -4.6 mL) and lecanemab (MD, -5.2 mL) associated with accelerated whole brain volume loss.

In studies reporting ARIA with monoclonal antibody use, ventricular enlargement correlated with the percentage of ARIA (r, 0.86; P =6.22×10^-7) and hippocampal volume changes with ARIA frequency (r, 0.51; P =.002).

To assess whether these brain volume losses may be attributable to plaque volume loss caused by treatment, the change in anti-amyloid beta plaque volumes as measured by positron emission tomography (PET) indicated that standardized uptake value ratio (SUVR) negatively correlated with ventricular enlargement (r, -0.76; P =7.5×10^-5) and the frequency of ARIA with the extent of SUVR reduction (r, -0.682; P =1.70×10^-5).

Researchers modeled changes in brain volumes over time among patients treated with anti-amyloid beta drugs. They predicted that patients with mild cognitive impairment who were taking secretase inhibitors would have a whole brain volume typical of someone with AD in 3.0 years if treated or 3.6 years if not treated, hippocampal volumes in 3.7 or 4.4 years, and lateral ventricular enlargement in 1.5 or 2.1 years, respectively.

Researchers noted that “These findings reveal the potential for anti-Aβ [amyloid beta] therapies to compromise long-term brain health by accelerating brain atrophy, and provide new insight into the adverse impact of ARIA.”

“Our analysis calls for urgent revaluation of prior trials and renewed procedures to monitor patients in current trials and in the community,” they concluded.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.