Amyloid PET predicts atrophy in non-demented individuals: Results from the AMYPAD-PNHS

The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in the preclinical stages of Alzheimer’s disease (AD) is not well understood. Consequently, it is not clear whether brain volume could be used as a secondary outcome in prevention trials. We aimed to determine the effect of cortical Aβ pathology on regional brain atrophy in a non-sdemented population and assess the interaction effect of sex and APOE -ε4 carriership.

We included 1329 participants from the prospective multi-center AMYPAD Prognostic and Natural History Study who underwent [ ¹⁸ F]Flutemetamol or [ ¹⁸ F]Florbetaben amyloid-PET and T1-weighted MRI, with longitudinal data for 684 participants (median follow-up=3.4 years). Linear mixed models assessed the effect of baseline Aβ burden through the Centiloid approach on longitudinal changes in regional gray matter volume and thickness. A second model investigated the effects of sex or APOE- ε4 carriership. We performed power analyses to estimate the number of required subjects in an early 48-month randomized-controlled secondary prevention trial to detect 20% to 30% efficacy of anti-Aβ interventions on regional atrophy measures.

A total of 1329 subjects (56% female) with an age of 68.2 (±8.78 years) were included, 117 (8.8%) and 260 (19.6%) of whom were considered to have intermediate and elevated Aβ respectively. Baseline global Aβ was predictive of widespread atrophy in several brain regions, most strongly in the medial-temporal lobe, cingulate cortex, and precuneus. These associations were largely independent of sex and APOE- ε4 genotype. Aβ burden had a larger impact on changes in thickness than volume. Using hippocampal or lateral ventricular volume as an outcome measure resulted in the smallest sample size to detect Aβ-related treatment effects.

In a non-demented population, baseline amyloid is predictive of atrophy in several brain regions. Regionalized measures of cortical thickness, in addition to hippocampal volume, showed to be more sensitive to early Aβ deposition and could be candidate biomarkers in early primary or secondary AD prevention trials.