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Abstract
BackgroundAlzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers.MethodsWe used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer’s Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ42 ratio, Aβ42, tau, and ptau181.ResultsWe found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau181 (r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006).ConclusionsCSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0742-9) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative
cerebrospinal fluid (CSF) levels of tau correlate with the amount of neurodegeneration, phosphorylated tau levels correlate with tangle pathology, and Amyloid beta (Aβ42) levels inversely correlate with the amount of plaques, which makes these ideal biomarkers for AD pathology [3, 7]
Studies have shown that CSF levels of YKL-40 can be used to distinguish AD from non-AD dementia, Parkinson’s disease, dementia with Lewy bodies, and to distinguish between mild cognitive impairment (MCI) that progresses to AD vs MCI not due to AD indicating that CSF YKL-40 is not a marker for inflammation due to neurodegeneration but may be specific enough for AD [16, 17]
Summary
Alzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers. Studies have found that the ratio of cerebrospinal fluid (CSF) tau to Aβ42 is a better predictor of AD status and cognitive decline than either of these proteins individually and improves discrimination of AD from other dementias such as vascular dementia and frontotemporal lobar degeneration [4,5,6]. Due to individual variability and group overlap in these CSF protein levels, further studies are necessary to find ways to improve sensitivity and specificity for AD. We hypothesized that adding genetic information may provide a means to improve specificity and sensitivity of CSF YKL-40 as a biomarker for AD
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