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.
Mori-Fegan et al. (2026) studied this question.