Neurofilament light (NfL) has been proposed as a blood-based biomarker for neurodegeneration. We examined plasma NfL concentrations in over 2,000 members of a Colombian kindred with autosomal-dominant Alzheimer's disease (ADAD) due to the E280A mutation in the presenilin1 (PSEN1) gene at baseline and longitudinally. NfL concentrations were measured with a single molecule array (Simoa) method from 1071 mutation carriers and 1077 age-matched noncarriers (8-75 years old). Longitudinal NfL analyses (mean follow-up 4.4 years) were performed in 281 carriers and 246 noncarriers. Clinical and cognitive measures from 598 unimpaired carriers, 154 impaired, 675 noncarriers were used to examine associations between NfL and cognitive performance. Relationships between plasma NfL concentrations and age were characterized using a cubic spline model with Hamiltonian Markov Chain Monte Carlo. NfL elevation onset in the mutation carrier group was defined by the initial age at which 99% credible intervals in the carrier and non-carrier groups did not overlap. Linear mixed effect (LME) models were used to estimate the fixed slope and intercept of mutation carriers and non-carriers. At baseline, NfL was elevated in impaired carriers (mean, 59.9 pg/mL) and unimpaired carriers (mean, 15.8 pg/mL), compared to noncarriers (mean, 8.1 pg/mL) (P < .001). Carriers showed higher NfL levels at average age 38 (7 years before the kindred's mean age at MCI onset). Longitudinally, LME models estimated that the NfL levels separate the carriers from non-carriers at the age of 28 years (about 17 years before estimated age of clinical onset). Significant associations between plasma NfL levels and age were observed in carriers and noncarriers (carriers: r=.32, P<.001; noncarriers (r=.26, P<.001). Elevated plasma NfL concentrations were associated with lower Mini-Mental-State-Examination (MMSE) and lower episodic memory scores in impaired and unimpaired carriers (e.g. unimpaired: MMSE r= −.37; CERAD Word List Recall, r=−.23, P<. 001), after adjustment for older age. Plasma NfL concentration was significantly elevated in PSEN1 mutation carriers, years before their estimated age of clinical onset. Higher NfL levels were associated with older age, and with lower scores in clinical and cognitive measures. Plasma NfL may be a useful non-invasive biomarker to monitor neurodegeneration in ADAD.