Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease

TLDR

Alzheimer disease is marked by progressive cerebral atrophy measurable by MRI, yet the mechanisms underlying observed volume changes in immunotherapy trials remain unclear and may involve amyloid removal and fluid shifts. The study sought to compare cerebral volume changes between high‑titer antibody responders to AN1792 and placebo patients with probable AD. In a randomized, multicenter, double‑blind, placebo‑controlled trial of 372 AD patients, participants received 1–3 injections of AN1792/QS‑21 or saline, and volumetric MRI scans were performed pre‑dose and at 12 months or early termination to measure brain, ventricular, and hippocampal volume changes. Among 288 patients with paired scans, antibody responders experienced significantly greater brain volume loss (3.12 % vs 2.04 %, p = 0.007) and ventricular enlargement (1.10 % vs 0.48 %, p < 0.001) than placebo, but cognitive composite scores favored responders (0.03 vs –0.24, p = 0.008), revealing a dissociation between brain atrophy and cognition.

Abstract

<b>Background: </b> Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients. <b>Objective: </b> To assess cerebral volume changes in patients immunized with AN1792 (β-amyloid [Aβ] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of ≥1:2,200) compared with placebo patients. <b>Methods: </b> This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 μg plus QS-21 50 μg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs. <b>Results: </b> Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; <i>p</i> = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; <i>p</i> &lt; 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 ± 2.63 vs 2.86 ± 3.19%; <i>p</i> = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite <i>z</i> score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs −0.24 ± 0.45; <i>p</i> = 0.008). <b>Conclusions: </b> A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.