Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

The genetic regulation of protein expression in cerebrospinal fluid

“…This finding may first be perceived as counterintuitive, since smaller ventricles is generally thought to indicate less neurodegeneration, and increased CSF P‐tau is generally associated with more neurodegeneration. However, the findings in our current study suggest that the association described by Jansen et al ( 2022 ) may have been confounded by the genetic effects on brain anatomy, causing differences in dilution and concentration across a range of CSF biomarkers. We noted that variants in the GMNC‐OSTN region were common among the CSF pQTLs where ventricular volume had large confounding effects (Fig EV5 ).…”

“…The results point to ventricle volume as a possible confounder for many CSF pQTL studies, although we demonstrate that most findings remain significant (but sometimes attenuated) after adjustment for ventricle volume. Recently, it was reported that genetic variants in the GMNC‐OSTN region on chromosome 3 (described in detail in this study) were associated both with smaller ventricles and with increased CSF levels of the AD biomarker P‐tau (Jansen et al , 2022 ). This finding may first be perceived as counterintuitive, since smaller ventricles is generally thought to indicate less neurodegeneration, and increased CSF P‐tau is generally associated with more neurodegeneration.…”

Concordance of Alzheimer’s Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus

“…However, a study conducted with healthy volunteers found no correlation between AD core biomarkers and ventricular volume nor the intracranial pressure and CSF production rate [ 39 ]. In a recent genome wide meta-analysis, a link between CSF P-tau 181 , lateral ventricle volume and the genes of GMNC and C16orf95 was established, implying causative relationship for these phenomena [ 40 ].…”

A year in review: brain barriers and brain fluids research in 2022

“…There continue to be many studies examining CSF for biomarkers of disease. This has been a particular focus in Alzheimer’s disease where studies have examined the correlation between CSF biomarkers and disease pathology [ 66 – 68 ], examining potential biomarkers that are upregulated before the onset of cognitive impairment [ 69 ] and distinguishing between different types of dementia [ 70 , 71 ]. Apart from β-amyloid (Aβ) and tau proteins, there has been particular interest in microglia-derived sTREM2 (soluble triggering receptor expressed on myeloid cells 2) [ 72 – 74 ].…”