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

Abstract

Background and objectives: This 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.

Methods: Measures 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.

Results: Analyses 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.

Discussion: The 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.

Figure 1. Kaplan-Meier Plots Showing the Relationship Between Baseline Levels of CSF t-tau, ptau181, and the Ratio Aβ42/Aβ40 and Time to Onset of Clinical Symptoms of MCI

Higher levels of CSF t-tau (A) and ptau181 (B) and lower levels of Aβ42/Aβ40 (C) are significantly associated with a shorter time to onset of clinical symptoms of MCI among individuals who were cognitively normal at baseline. MCI = mild cognitive impairment; t-tau = total tau.

Figure 2. Kaplan-Meier Plots Showing the Relationship Between Baseline CSF Ratios of t-tau/Aβ42 and ptau181/Aβ42 and Time to Onset of Clinical Symptoms of MCI

Higher levels of ratios of t-tau/Aβ42 (A) and ptau181/Aβ42 (B) are significantly associated with a shorter time to onset of clinical symptoms of MCI among individuals who were cognitively normal at baseline. MCI = mild cognitive impairment; t-tau = total tau.

Figure 3. Hazard Ratios for the Baseline CSF Measures at Specific Baseline Ages, Stratified by Sex

In male participants (blue line), compared with female participants (red line), higher CSF ptau (ptau181) levels (A) and lower ratios of CSF Aβ42/Aβ40 (B) are associated with a shorter time to symptom onset, with the difference between the sexes diminishing as baseline age increases. For illustration purposes, hazard ratios were calculated from the Cox regression models at specific age points (age 50, 60, and 70 years) stratified by sex, using the Cox regression models with the 3-way interactions (CSF measures × age × sex, years of education, and ApoE4 carrier status). ApoE = Apolipoprotein E.