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Identification and characterization of rare coding variants modulating the rate of disease progression in pre-dementia stages of Alzheimer's disease.

Subject Area Molecular and Cellular Neurology and Neuropathology
Human Genetics
Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 418087061
 
Final Report Year 2023

Final Report Abstract

Alzheimer’s disease (AD) starts years before dementia diagnosis. Predicting, however, which person at-risk will progress to dementia is a major challenge, and biological determinants of disease progression are poorly understood. Genetic research on the disease progression is currently in its infancy. Herein, our preliminary work raised the possibility that only a subset of the identified AD loci are related to symptom progression in at-risk-stages of AD (mild cognitive Impairment patients (MCI)) and there are still novel variants to discover. To this end, we applied for funding to generate whole exome sequencing (WES) data on 1500 MCI samples with extensive neuropsychological and biomarker data, including several follow-up assessments up to 15 years. After extensive quality control analysis (QC), sequencing data was called using a pipeline developed by the European Alzheimer’s Disease Sequencing (ADES) initiative, of which Dr. Ramirez is an active member of the steering board. This step was important to harmonize sequencing QC and allele calling with large international initiatives. The WES data was combined with the existing longitudinal data using state-of-the-art methods to analyze cognitive decline (led by Prof. Michael Wagner). We initially focused the analysis on candidate genes while we, in parallel, optimized an approach to expand the analysis of rare variants to the genome-wide level. Thus, during the funding period, we published several peer-reviewed publications in wellknown high-impact scientific journals. By combining cognitive and genetic data, we could show that MCI carriers of the rare variants p.P522R in the gene coding for the phospholipase D gamma 2 enzyme (PLCG2) had a slower rate of cognitive decline compared to non-carriers. We also found that a genetic risk score containing all known susceptibility variants for AD, including rare variants, was significantly associated with the progression to dementia in patients with MCI. In addition, the evident overlap in etiology between cerebrospinal fluid (CSF) biomarkers for AD and clinical AD dementia led us to explore the association of these known AD loci with CSF biomarkers, i.e., amyloid beta and phosphorylated Tau. Finally, our MCI dataset was also used to contribute to international collaborative efforts to identify and confirm novel genetic associations with the susceptibility to AD dementia. Finally, we have several ongoing projects dedicated to identifying and characterizing rare variants and biological pathways modulating different endophenotypes in MCI, including cognitive decline and fluid biomarkers. Importantly, we are in the process of acquiring additional funding to generate additional “omics” in these samples that can be combined with genetics. Hence, the sequencing dataset generated in the present project will be a lasting resource that will further contribute to our knowledge of the genetic architecture of AD and cognitive performance.

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