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A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status
Published on: October 20, 2016
CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex,
Barry D Greenberg1, Corinne Pettigrew2, Anja Soldan2
1From the Department of Neurology (B.D.G., C.P., A.S., J.A.D., M.S.A., A.M.), Johns Hopkins University School of Medicine; and Department of Biostatistics (J.W., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. bgreen45@jhmi.edu.
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.
Insights
Alzheimer disease (AD) biomarkers in cerebrospinal fluid (CSF) predict mild cognitive impairment (MCI) onset differently over time. These associations vary by age and sex, impacting clinical trial strategies.
Area of Science:
- Neuroscience
- Biomarkers
- Gerontology
Background:
- Alzheimer disease (AD) pathology can be measured in cerebrospinal fluid (CSF).
- Understanding the temporal relationship between CSF biomarkers and mild cognitive impairment (MCI) onset is crucial.
- Factors like age, sex, and Apolipoprotein E (ApoE4) status may modify these associations.
Purpose of the Study:
- To investigate if baseline CSF AD biomarkers are associated with the time to MCI onset.
- To determine if these associations differ based on age, sex, ApoE4 status, and time to symptom onset (proximal vs. distal).
Main Methods:
- Utilized CSF samples from the Biomarkers for Older Controls at Risk for Alzheimer Disease (BIOCARD) study.
- Measured amyloid-beta (Aβ1-42, Aβ1-40), phospho-tau (ptau181), and total tau (t-tau) using Lumipulse G immunoassay.
- Employed Cox regression models to analyze the relationship between baseline biomarkers and time to MCI, including interactions with demographic factors.
Main Results:
- Elevated ptau181 and t-tau were linked to MCI onset within 7 years (HR 1.386, 1.329).
- A lower Aβ42/Aβ40 ratio predicted MCI onset >7 years later (HR 0.596).
- Significant three-way interactions (CSF × age × sex) were observed for ptau181 and Aβ42/Aβ40, with stronger associations in men that diminished with age.
Conclusions:
- CSF biomarker associations with MCI onset are time-dependent.
- Age and sex significantly modify the predictive value of CSF biomarkers for MCI.
- Findings can inform clinical trial design, enrollment, and the use of biomarkers as surrogate endpoints.
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