Cognitive and Neuroanatomical Effects of Fatty Acid Amide Hydrolase Polymorphism rs324420 in Aging and Alzheimer Disease.

INTRODUCTION

Therapeutic options for Alzheimer disease (AD) are limited. Modulating the endocannabinoid system through fatty acid amide hydrolase (FAAH) is a promising target. We investigated how the FAAH functional polymorphism rs324420 influences cognition and brain structure across the AD continuum, particularly in interaction with amyloid (Aβ) pathology.

METHODS

One thousand, five hundred seven Alzheimer Disease Neuroimaging Initiative participants were analyzed [631 cognitively normal (CN); 876 AD/Mild Cognitive Impairment (ADMCI)]. Cross-sectional and 48-month longitudinal models assessed interactions between rs324420 minor-allele carrier status and Aβ-positivity [(18F)-Florbetapir PET SUVR>1.11] on cognitive tests and regional brain volumes as judged by MRI.

RESULTS

Cross-sectionally, CN and Aβ-positive CN carriers demonstrated better executive function than noncarriers. Aβ-positive ADMCI carriers showed greater baseline episodic memory, while Aβ-negative carriers had larger inferior temporal and nucleus accumbens volumes compared with noncarriers. Longitudinally, Aβ-positive CN carriers showed slower whole-brain atrophy. Whole-ADMCI carriers exhibited significantly slower declines in global cognition and language. Aβ-positive ADMCI carriers showed preserved anterior cingulate, fusiform gyrus, and nucleus accumbens volumes. Aβ-negative ADMCI carriers had greater atrophy in the inferior temporal and nucleus accumbens regions.

DISCUSSION: Neuroprotective effects of rs324420 (lowered FAAH activity) appear contingent on cerebral Aβ-positivity, specifically preserving brain volume and slowing cognitive decline longitudinally. Findings support biomarker-informed precision approaches for endocannabinoid-targeted interventions in AD and aging.