Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk

Abstract

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.

The Early‐Onset Alzheimer's Disease Whole‐Genome Sequencing Project: Study design and methodology

“…As these biomarkers have been generated in different centers using different platforms it is not possible to simply combine the data across studies. We have developed robust approaches to harmonize AD biomarkers across datasets 69,70 . Briefly, normalized z‐scores are calculated by using the mean and standard deviation units across each cohort and applied to the entire endophenotype in order to account for within cohort variation.…”

“…Based on the assumption of two univariate normal distributions within each study we will obtain two estimated means (μ1 and μ2), two estimated standard deviations (σ1 and σ2), and two estimated mixing proportions. From these models we can determine biomarker status for each of the specific analytes, and perform further analyses 69,70 …”

“…We have developed robust approaches to harmonize AD biomarkers across datasets. 69,70 Briefly, normalized z-scores are calculated by using the mean and standard deviation units across each cohort and applied to the entire endophenotype in order to account for within cohort variation. Then, we used a mixture modeling, which is a statistical method for estimating subpopulations within an overall group, to determine the biomarker-positive and negative individuals.…”

Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer’s Disease

“…In contrast to KL -VS het+ , the ε4 allele has been associated with a more aggressive course of NFT pathology, evidenced in neuroimaging studies in AD patients [ 47 , 48 , 49 ] and transgenic animal model experiments [ 25 , 50 ]. Interestingly, two independent studies have found that KL -VS het+ protective effects in Aβ-induced NFT pathology benefits ε4 carriers relatively more than non-carriers, despite the fact that the former have greater NFT loads [ 19 , 51 ]. The mechanisms responsible for the protective effect of KL -VS het+ against NFT pathology have not yet been fully analyzed in AD transgenic mouse models and remain speculative.…”

Systematic proteomics in Autosomal dominant Alzheimer’s disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways

“…Thus, we utilized Gaussian mixture models to dichotomize quantitative Aβ42 and pTau measures into positive and negative groups and applied separately for each sAD cohort. 34,35 Individuals with low CSF Aβ42 and high pTau levels were classified as amyloid/tau positive (A + T + ). Individuals with high Aβ42 and low pTau levels were defined as controls (A − T − ).…”