Introduction: Establishing valid diagnostic strategies is a precondition for successful therapeutic intervention in Alzheimer's disease (AD).

Methods: One hundred forty-four healthy 75-year-old participants from the Vienna-Transdanube-Aging longitudinal cohort study were tested for neuroaxonal damage by single molecular array (Simoa) plasma neurofilament light chain (NfL) levels at baseline, 30, 60, and 90 months, and onset of AD dementia. Individual risk for sporadic AD was estimated by continuous shrinkage polygenic risk score (PRS-CS, genome-wide association study).

Results: Nineteen participants developed AD after a median of 60 months (interquartile range 30). In participants with AD, baseline NfL plasma levels correlated with PRS-CS (r = 0.75,p < 0.001; difference to controls: Fisher'sr-to-z:z = 3.89,p < 0.001). PRS-CS combined with baseline plasma NfL predicted onset of AD (p < 0.01).

Discussion: Our data suggest that polygenic risk for AD and plasma NfL closely interact years before onset of clinical symptoms. Peripheral NfL may serve as a diagnostic measure supporting early therapeutic intervention and secondary prevention in AD.