Exome‐wide rare variant analysis of Alzheimer’s disease biomarkers: The EMIF‐AD multimodal biomarker discovery study

Background Alzheimer’s disease (AD) biomarkers show promise in aiding diagnosis and prediction by representing several neurodegenerative processes, such as synaptic dysfunction, neuronal injury, inflammation or neuronal loss. Biomarkers could also aid in the discovery of AD‐related genes and inform which biological mechanisms underlie a genetic risk effect. We performed an exome‐wide rare variant analysis of six biomarkers measured in cerebrospinal fluid (β‐amyloid, total tau/phosphorylated tau, NFL, YKL‐40, and Neurogranin) and hippocampal volume as measured by MRI. The aim was to discover genes associated with these indicators and test whether they mediate genetic effects on AD. Method We performed the exome‐wide analysis in two studies: the EMIF‐AD study and ADNI. Whole exome sequencing and biomarker information data was available for 505 (CSF biomarkers) and 508 (hippocampal volume) participants with AD, mild cognitive impairment and controls. We applied a principal component (PC) analysis to derive combinations of CSF biomarkers, which represent statistically independent biological processes. We then tested whether rare (MAF < 1%) variants in 13,799 protein‐coding genes associate with the PCs or hippocampal volume using a Meta‐SKAT test. We also tested whether the PCs are intermediary to gene effects on dementia symptoms with a SMUT test. Result One PC loaded on NFL and YKL40, indicators of neuronal injury and inflammation. Three genes were associated with this PC: IFFO1, NLRC3, and DTNB. Mediation tests suggested, that these genes also affect dementia symptoms by increasing susceptibility to neuronal injury and inflammation. We also observed an association between a PC loading on Neurogranin and GABBR2 and CASZ1, but no mediation effects. Furthermore, BUB1B was associated with left hippocampal volume. Conclusion The results suggest that rare variants in IFFO1, DTNB and NLRC3 impact neuronal injury and inflammation, by potentially altering cytoskeleton structure, impairing repair abilities and disinhibition of immune pathways, which then could lead to dementia symptoms. Furthermore, the findings support a role of BUB1B in hippocampal atrophy. Curiously, this gene has previously been linked to longevity and memory in animal models. This study suggests a similar influence in humans and proposes a pathway through hippocampal neurodegeneration.