BACKGROUND: Subjective memory complaints (SMCs) refer to memory concerns reported by an individual, regardless of objective test impairment. We conducted a study to evaluate the association of SMCs with serum biomarkers of neurodegeneration, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau). In addition, we evaluated the association of SMCs with the rate of cognitive decline. METHODS: This study included 1096 individuals participating in the Chicago Health and Aging Project, with data on SMCs, neurodegenerative biomarkers (NfL, GFAP, and t-tau), and global cognitive scores. The SMC score ranges from 0 to 8 and higher scores reflect more memory complaints. Linear regression models were developed to investigate the association of SMCs with serum biomarkers, adjusted by age, sex, race, education, and APOE e4. Linear mixed-effects models were used to examine the independent association of SMCs with cognitive decline in a multivariable model that was additionally adjusted by biomarkers of neurodegeneration. RESULTS: Of the 1096 individuals, 665 (60.7%) were female, 643 (58.7%) were African Americans, and the mean (SD) age at the baseline was 78.0 (5.8) years. Compared to individuals with fewer memory complaints (i.e., people in the first tertile of SMCs), those reporting more memory complaints (i.e., people in the third tertile of SMCs) had a 12.0% increase in serum concentrations of NfL and an 9.4% increase in GFAP. In addition, individuals reporting more memory complaints (i.e., those in the 3rd versus the 1st tertile of SMCs) had a faster rate of cognitive decline by 0.029 ( CONCLUSIONS: Individuals who reported more memory complaints had higher levels of biomarkers of neurodegeneration and a faster rate of cognitive decline, suggesting that SMCs may be valuable for identifying people at high risk of cognitive impairment.