The Role of Short Tandem Repeats in Alzheimer's Disease

• Applicants: Professor Dr. Lars Bertram; Dr. Valerija Dobricic
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Genetics ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433110779

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by progressive loss of memory and cognition eventually leading to dementia. While the pathogenic mechanisms underlying AD susceptibility are not yet completely understood it is well established that genetic factors play a crucial role. These genetic effects can unfold via either the action of rare disease-causing mutations (leading to “monogenic AD”; typically with an early-onset age [<65 years]), or via the combined action of common genetic risk factors modifying disease susceptibility (leading to “polygenic AD” with late-onset [>65 years]). Despite significant progress in AD genetics, much of the disease-liability portion estimated to be contributed by genetic factors remains elusive, a situation often referred to as the “missing heritability” problem. There exists a growing body of evidence suggesting that research into the contribution of tandem repeats represents a new and promising frontier to resolve the missing heritability problem. Tandem repeats are types of repetitive elements in the human genome that are arranged in a tandem (i.e. head-to-tail) pattern of variable motif size, typically categorized either as “short tandem repeats” (STRs; motif sizes from 1-9bp) or “minisatellites” (10-100bp). Although a disease-causing role of longer-than-normal (“expanded”) STRs has been established for nearly three dozen disorders, systematic research into the role of STRs in human disease was hindered until recently by limitations of both sequencing technology and downstream computational analyses. Fortunately, these problems have now been overcome on the experimental and computational levels. In this project, “STaR-AD”, we will systematically investigate the potential role of STR expansions in contributing to AD liability. This will be achieved by assessing DNA samples from index AD patients and their unaffected siblings from early-onset, multiplex AD families collected as part of the NIMH AD Genetics Initiative. Specifically, we will whole-genome sequence 130 individuals from 65 of these AD families using experimental and computational protocols optimized for STR detection and genotyping with the aim to pinpoint novel AD-causing repeat expansions (WP1). The discovery effort will be buttressed by in-depth technical verification (WP2) and biological validation (WP2, 3) experiments to establish causality. In addition, all identified STR expansions emerging to show compelling signals in the multiplex families will be assessed in an independent sample of 500 early-onset familial and sporadic AD cases from the French National Reference Centre for Early-Onset Alzheimer’s disease (CNR-MAJ). Taken together, our project will represent the first bona-fide genome-wide STR analysis in the field, and – in addition to furthering our understanding of AD pathogenesis – will help to establish new experimental and computational protocols for STR mapping in other diseases.

• DFG Programme: Research Grants