AbstractBackgroundCurrent cerebrospinal fluid (CSF) biomarker data of preclinical AD are based largely on cross‐sectional studies across the disease spectrum and short‐term longitudinal studies, with most studies conducted among older adults. However, neuropathological studies indicate that AD pathology is present in midlife. To better understand within‐person biomarker trajectories, we examined longitudinal changes in CSF biomarkers, potential modifiers (e.g., demographics, APOE4 genotype), and changes with respect to MCI symptom onset among participants who were primarily middle‐aged and cognitively normal at baseline, and have on average 10.7y of follow‐up (max 23y).MethodCSF was collected from 278 BIOCARD Study participants (M baseline age = 57.5y; Table 1); 94 (33.8%) have since progressed to MCI or dementia. These analyses focused on z‐transformed values of AB42/AB40, p‐tau181, and t‐tau, measured using the Fujirebio Lumipulse G1200 assays.ResultIn longitudinal mixed‐effects models, there were accelerated (quadratic) increases in p‐tau181 and t‐tau over time, and a trend for accelerated (quadratic) decreases in AB42/AB40 (p=0.09). APOE4 carriers had lower levels of AB42/AB40 at baseline and greater rates of change in all biomarkers (Table 2; Figure 1). Older participants had more abnormal baseline biomarker levels and greater rates of change in AB42/AB40 and t‐tau. Biomarker levels and trajectories were unrelated to sex and years of education. In a separate set of models, low baseline AB42/AB40 was associated with increases in p‐tau181 and t‐tau over time, whereas baseline t‐tau and p‐tau181 were not associated with change in AB42/AB40. Finally, compared to those who remained normal, those who progressed to MCI/dementia had more abnormal AB42/AB40, p‐tau181, and t‐tau at baseline, and greater rates of change in t‐tau and p‐tau prior to MCI clinical symptom onset.ConclusionThese results indicate that, in preclinical AD, lower levels of amyloid are associated with increases in p‐tau181 and t‐tau, while accelerations in p‐tau181 and t‐tau are more closely linked to MCI symptom onset. They also suggest earlier and greater rates of pathology accumulation among APOE4 carriers, but that sex and education‐related differences in AD dementia risk are not due to differences in AD biomarker accumulation early in the disease course.