CSF Alzheimer Disease Biomarkers: Time-Varying Relationships with MCI Symptom Onset and Associations with Age, Sex, and ApoE4

Background and ObjectivesThis study aimed to examine whether baseline CSF measures of Alzheimer disease (AD)-related pathology are associated with the time to onset of mild cognitive impairment (MCI) and whether these associations differ by age, sex, Apolipoprotein E (ApoE4) status, and proximal (≤7 years) vs distal (>7 years) time to symptom onset.MethodsMeasures of amyloid (Aβ1-42 and Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) were determined from CSF samples obtained at baseline from participants in an ongoing longitudinal project, known as the Biomarkers for Older Controls at Risk for Alzheimer Disease study (BIOCARD) study. The fully automated, Lumipulse G immunoassay was used to analyze the specimens. Cox regression models were used to examine the relationship of baseline biomarker levels with time to symptom onset of MCI and interactions with age, sex, and ApoE allelic status in subjects who progressed from normal cognition to MCI.ResultsAnalyses included 273 participants from the BIOCARD cohort, who were cognitively normal and predominantly middle-aged at baseline, and have been followed for an average of 16 years (max = 23.6). During follow-up, 94 progressed to MCI (median time to symptom onset = 6.9 years). In Cox regression models, elevated ptau181 and t-tau levels were associated with time to MCI symptom onset if it occurred within 7 years of baseline (HR 1.386 and 1.329; p = 0.009 and 0.017, respectively), while a lower Aβ42/Aβ40 ratio was associated with symptom onset if it occurred >7 years from baseline (HR 0.596, p = 0.003). There were also significant 3-way CSF × age × sex interactions for ptau181 and Aβ42/Aβ40, with follow-up analyses indicating that associations between these biomarkers and progression to MCI were stronger among men than among women, but this difference between sexes diminished with increasing age.DiscussionThe lengthy follow-up of BIOCARD participants permitted an examination of time-varying associations between CSF AD biomarkers with MCI symptom onset and the influence of sex, baseline age, and ApoE4 genotype on these associations. These factors may inform clinical trial enrollment strategies, or trial duration and outcomes, which may use these measures as surrogate markers of treatment response.