Amyloid burden and white matter hyperintensities mediate age-related cognitive differences

Area of Science:

• Neuroscience
• Gerontology
• Cognitive Science

Background:

• Cognitive decline in aging is multifactorial.
• Understanding the interplay of brain pathologies like beta-amyloid (Aβ) and white matter hyperintensities (WMHs) is crucial.
• The contribution of these pathologies to specific cognitive domains requires further elucidation.

Purpose of the Study:

• To investigate the additive and synergistic effects of Aβ and WMHs on 7 cognitive domains in cognitively normal older adults.
• To determine the extent to which brain pathology mediates age-related cognitive differences.
• To explore the relationship between measurable brain pathology and cognitive function in aging.

Main Methods:

• Neuropsychological assessment of 104 cognitively normal older adults.
• Magnetic resonance imaging (MRI) and Pittsburg Compound B-positron emission tomography (PiB-PET) for Aβ quantification.
• Quantification of WMH severity using the Age-Related White Matter Changes (ARWMC) scale; statistical analyses including stepwise regressions, moderation, and mediation modeling.

Main Results:

• Aβ deposition alone predicted poorer episodic memory.
• Aβ and WMHs showed additive effects on working memory and language.
• Synergistic associations were observed between Aβ, WMHs, and executive functions/attention.
• Mediation analysis revealed that brain pathology fully mediates the effect of age on episodic memory, working memory, executive functions, and language.

Conclusions:

• In healthy older adults, Aβ burden and WMHs exhibit synergistic effects on specific cognitive domains.
• Age-related cognitive differences in most domains are predominantly driven by underlying brain pathology.
• Findings underscore the critical role of neurodegenerative markers in cognitive aging and dementia risk.