Biomarkers

Area of Science:

• Neuroscience
• Cognitive Science
• Medical Imaging

Background:

• The medial temporal lobe (MTL) and posteromedial cortex (PMC) are crucial for episodic memory and are early sites of Alzheimer's disease (AD) pathology.
• APOE4 genotype is a significant risk factor for AD, influencing pathology accumulation and cognitive decline.
• Functional connectivity (FC) alterations within and between MTL and PMC may reflect compensatory or detrimental neural network changes in AD pathogenesis.

Purpose of the Study:

• To investigate the relationship between longitudinal changes in functional connectivity (FC) within and between the MTL and PMC and Alzheimer's pathology burden.
• To examine how these FC changes relate to cognitive performance, specifically delayed memory recall and object recognition.
• To explore the moderating role of the APOE genotype in these associations.

Main Methods:

• Longitudinal 3-Tesla fMRI data and cross-sectional amyloid-beta and tau PET imaging were analyzed from the PREVENT-AD cohort.
• Changes in resting-state FC (RSFC) and task-based FC during object-location encoding were assessed within (ΔFC_PMC, ΔFC_MTL) and between (ΔFC_MTL-PMC) these regions.
• Multiple regression and linear mixed models were used to investigate associations between ΔFC, pathology, memory changes, and APOE genotype in 152 cognitively unimpaired older adults.

Main Results:

• APOE genotype modulated the association between FC changes and pathology: declining RSFC_PMC correlated with higher amyloid in APOE4 carriers, while increasing encoding-FC_MTL correlated with higher tau in APOE4 carriers.
• Increased encoding-FC_PMC was associated with poorer memory performance (RBANS and object recognition) irrespective of APOE status.
• Increased RSFC_MTL-PMC was linked to improved RBANS performance, whereas increased encoding-FC_MTL-PMC was linked to decreased object recognition.

Conclusions:

• Longitudinal FC changes within and between MTL and PMC show APOE-dependent associations with AD pathology and memory performance.
• Network alterations manifest differently during rest versus task conditions, highlighting the importance of dynamic FC assessments.
• In APOE4 carriers, increased MTL connectivity during encoding relates to tau pathology, while decreased PMC connectivity during rest relates to amyloid, suggesting distinct pathological mechanisms in these regions.