APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals
Authors: Brugulat-Serrat Anna , Sánchez-Benavides Gonzalo , Cacciaglia Raffaele , Salvadó Gemma , Shekari Mahnaz , Collij Lyduine E. , Buckley Christopher , van Berckel Bart N. M. , Perissinotti Andrés , Niñerola-Baizán Aida , Milà-Alomà Marta , Vilor-Tejedor Natàlia , Operto Grégory , Falcon Carles , Grau-Rivera Oriol , Arenaza-Urquijo Eider M. , Minguillón Carolina , Fauria Karine , Molinuevo José Luis , Suárez-Calvet Marc , Gispert Juan Domingo ,   the ALFA Study, Cañas Alba , Canals Lidia , Iglesias Laura , Marne Paula , Beteta Annabella , Deulofeu Carme , Emilio Maria , Cumplido Irene , Domínguez Ruth , Fuentes Sherezade , Hernández Laura , Vilanova Marc , Solsona Lluís , Huesa Gema , Huguet Jordi , Menchón Tania , Polo Albina , Pradas Sandra , Sala-Vila Aleix , Soteras Anna , Stankeviciute Laura , Akinci Müge , Palpatzis Eleni , Genius Patricia , Rodríguez Blanca , García Marina , Ortiz-Romero Paula 
Published: March 2023

Abstract
Purpose
To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants.

Methods
The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer’s Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume.

Results
In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum.

Conclusion
CU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer’s disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD.
ClinicalTrials.gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969.