APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals

Purpose To determine whether the APOE-epsilon 4 allele modulates the relationship between regional beta-amyloid (A beta) 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 [F-18]flutemetamol A beta positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional A beta 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 A beta PET positivity and APOE-epsilon 4 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-epsilon 4 carriers. No significant APOE-epsilon 4*global A beta PET interactions were associated with cognitive change for any cognitive test. However, APOE-epsilon 4 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-epsilon 4 and regional VR+ were found in temporal and parietal regions, and in the striatum. Conclusion CU APOE-epsilon 4 carriers with a positive A beta 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 A beta PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD.

Automated summary

The purpose of this study was to investigate the relationship between regional beta-amyloid (Aβ) accumulation and cognitive decline in middle-aged cognitively unimpaired (CU) individuals and whether it is modulated by the APOE-epsilon 4 allele. The results showed that CU individuals who were APOE-epsilon 4 carriers with positive Aβ PET in regions known to accumulate amyloid at later stages of Alzheimer's disease exhibited a steeper decline in cognitive function. This finding suggests that regional visual reading (VR) of Aβ PET may provide prognostic information about future cognitive decline in individuals at higher risk of developing Alzheimer's disease.