Associations Between Sub-Threshold Amyloid-β Deposition, Cortical Volume, and Cognitive Function Modulated by APOE ɛ4 Carrier Status in Cognitively Normal Older Adults

Abstract

Background: There has been renewed interest in the deteriorating effects of sub-threshold amyloid-β (Aβ) accumulation in Alzheimer's disease (AD). Despite evidence suggesting a synergistic interaction between the APOE ɛ4 allele and Aβ deposition in neurodegeneration, few studies have investigated the modulatory role of this allele in sub-threshold Aβ deposition during the preclinical phase.

Objective: We aimed to explore the differential effect of the APOE ɛ4 carrier status on the association between sub-threshold Aβ deposition, cortical volume, and cognitive performance in cognitively normal older adults (CN).

Methods: A total of 112 CN with sub-threshold Aβ deposition was included in the study. Participants underwent structural magnetic resonance imaging, [18F] flutemetamol PET-CT, and a neuropsychological battery. Potential interactions between APOE ɛ4 carrier status, Aβ accumulation, and cognitive function for cortical volume were assessed with whole-brain voxel-wise analysis.

Results: We found that greater cortical volume was observed with higher regional Aβ deposition in the APOE ɛ4 carriers, which could be attributed to an interaction between the APOE ɛ4 carrier status and regional Aβ deposition in the posterior cingulate cortex/precuneus. Finally, the APOE ɛ4 carrier status-neuropsychological test score interaction demonstrated a significant effect on the gray matter volume of the left middle occipital gyrus.

Conclusion: There might be a compensatory response to initiating Aβ in APOE ɛ4 carriers during the earliest AD stage. Despite its exploratory nature, this study offers some insight into recent interests concerning probabilistic AD modeling, focusing on the modulating role of the APOE ɛ4 carrier status during the preclinical period.

Keywords: APOE ɛ4 allele; cognitively normal older adults; cortical volume; function; sub-threshold amyloid-β.

Fig. 1

Flow chart describing the selection process of the participants in our cohort study. ^*Exclusion Criteria: a history of alcoholism, drug abuse, head trauma, or psychiatric disorders and those taking any psychotropic medications; uncontrolled multiple cardiovascular risk factors; evidence of subcortical ischemic changes corresponding to a score ≥2 on the Fazeka’s scale. FMM, [¹⁸F] flutemetamol.

Fig. 2

A) Brain regions showing a significant interaction between Aβ deposition in the posterior cingulate cortex/precuneus and APOE ɛ4 carrier status on gray matter volume in cognitively normal older adults with sub-threshold Aβ deposition. B) Scatter plots visualizing relationships between sub-threshold Aβ deposition in the posterior cingulate cortex/precuneus and gray matter volume in regions of interest according to APOE ɛ4 carrier status. General linear model analysis adjusting for age, sex, years of education, and total intracranial volume, FDR-adjusted p < 0.001, cluster p < 0.05. The cluster size of the regions of interest was greater than 100 voxels. SUVR_PONS, standardized uptake value ratio of [¹⁸F] flutemetamol.

Fig. 3

Impact of the interaction between global cognitive function and APOE ɛ4 carrier status on cortical volume in cognitively normal older adults with sub-threshold Aβ deposition. General linear model analysis adjusting for age, sex, years of education, and total intracranial volume. Thresholds were set using GRFT correction at a p < 0.05, voxel p < 0.001. The statistical threshold of cluster size > 44. Total CERAD-K, composite score summing respective z-scores of the CERAD-K VF, BNT, WLM, CP, WLR, and WLRc domains.