miR-214-3p and NCKAP1: A microglial functional dimension of Alzheimer's progression

Biological Alzheimer's disease (AD) pathology does not fully explain the marked heterogeneity in clinical severity or progression. We investigated whether patient-derived induced microglia-like cell (iMG) profiles capture a functional dimension of AD progression beyond conventional plasma biomarkers.

We studied 114 participants comprising amyloid-negative healthy controls (n = 18) and amyloid-positive AD-continuum groups (cognitively unimpaired, n = 2; mild cognitive impairment, n = 18; AD dementia, n = 76). Plasma biomarkers, patient-derived iMG phagocytic function, and molecular markers were measured from the same blood draw. Longitudinal clinical follow-up was available in 102 participants, and paired baseline/follow-up blood samples were analyzed in a longitudinal biomarker cohort (n = 38).

iMG phagocytic capacity progressively declined across the AD continuum, accompanied by reduced NCK-associated protein 1 (NCKAP1) expression and the strongest association with plasma glial fibrillary acidic protein (GFAP). Baseline NCKAP1 primarily reflected current cognitive impairment, whereas plasma miR-214-3p independently predicted faster cognitive decline beyond plasma tau phosphorylated at threonine 217 (p-tau217), GFAP, neurofilament light chain (NfL), age, and baseline cognition. Within amyloid-positive AD dementia, plasma miR-214-3p identified rapidly progressive disease and substantially improved prognostic discrimination beyond conventional plasma biomarkers. Longitudinally, declining NCKAP1 and increasing plasma miR-214-3p tracked the rate of cognitive deterioration, whereas plasma p-tau217, GFAP, and NfL changed over time but did not track disease tempo.

Patient-derived iMG profiling identifies microglial phagocytic dysfunction as a complementary functional dimension of AD progression beyond conventional plasma biomarkers. Longitudinal microglial dynamics tracked disease tempo more closely than conventional plasma pathology markers and may help interpret biological-clinical discordance, supporting biologically informed staging, prognosis, and patient stratification in AD.