Novel statistical and bioinformatic methods to identify genetic factors involved in cognitive decline and rate of disease progression in pre-dementia stages of Alzheimer's disease

• Applicants: Professor Michael Nothnagel, Ph.D.; Professor Alfredo Ramirez, Ph.D.
• Subject Area: Biological Psychiatry ; Human Cognitive and Systems Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429106243

• Final Report Year: 2024

Final Report Abstract

Alzheimer's disease (AD) is the primary cause of dementia, which imposes significant societal costs, accounting for about 1% of the global GDP. Delaying the onset of dementia in AD patients by five years could substantially reduce the financial burden of treatment by 2050. Given that AD has a strong genetic basis, many of the disease's pathological pathways are likely influenced by genetic determinants, affecting protein function and expression. To better understand these pathways, we have developed a novel pathway score-based regression approach. This method, which also incorporates longitudinal data and allows for time-dependent effects, has been used to explore genetic data from patients at prodromal stages of AD, i.e., mild cognitive impairment. Preliminary analysis using 22 selected pathways identified four potentially significant pathways, though further validation is needed. We are in the process of preparing a software package that will be made freely available. In addition to genetic analysis, the project also explored epigenetic changes through the largest AD case-control meta-analysis conducted by the EADB consortium. The study found methylation changes at specific CpGs within AD risk loci, which mediate the genetic effects observed in a genome-wide association study (GWAS). The pathway-based analysis approach was also successfully applied in collaborative works, leading to several publications. The pipeline is designed to be adaptable, allowing for the incorporation of new methods for evaluating the functional consequences of genetic variants and for analyzing different phenotypes. This adaptability suggests that the pathway analysis pipeline will be a valuable tool for future genetic research in AD and other phenotypes beyond neurodegeneration.

Publications

• Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurology, 79(7), 652.
  Le Guen, Yann; Belloy, Michael E.; Grenier-Boley, Benjamin; de Rojas, Itziar; Castillo-Morales, Atahualpa; Jansen, Iris; Nicolas, Aude; Bellenguez, Céline; Dalmasso, Carolina; Küçükali, Fahri; Eger, Sarah J.; Rasmussen, Katrine Laura; Thomassen, Jesper Qvist; Deleuze, Jean-François; He, Zihuai; Napolioni, Valerio; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick G. ... & Rujescu, Dan
  
• Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathologica, 144(5), 821-842.
  Jansen, Iris E.; van der Lee, Sven J.; Gomez-Fonseca, Duber; de Rojas, Itziar; Dalmasso, Maria Carolina; Grenier-Boley, Benjamin; Zettergren, Anna; Mishra, Aniket; Ali, Muhammad; Andrade, Victor; Bellenguez, Céline; Kleineidam, Luca; Küçükali, Fahri; Sung, Yun Ju; Tesí, Niccolo; Vromen, Ellen M.; Wightman, Douglas P.; Alcolea, Daniel; Alegret, Montserrat ... & van der Flier, Wiesje
  
• New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics, 54(4), 412-436.
  Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C.; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A.; Boland, Anne; Damotte, Vincent; van der Lee, Sven J.; Costa, Marcos R.; Kuulasmaa, Teemu; Yang, Qiong; de Rojas, Itziar; Bis, Joshua C. ... & Lambert, Jean-Charles
  
• Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences, 120(36).
  Le, Guen Yann; Luo, Guo; Ambati, Aditya; Damotte, Vincent; Jansen, Iris; Yu, Eric; Nicolas, Aude; de Rojas, Itziar; Peixoto, Leal Thiago; Miyashita, Akinori; Bellenguez, Céline; Lian, Michelle Mulan; Parveen, Kayenat; Morizono, Takashi; Park, Hyeonseul; Grenier-Boley, Benjamin; Naito, Tatsuhiko; Küçükali, Fahri; Talyansky, Seth D. ... & Tan, Eng-King
  
• “Pathway Analysis in Cognitive Decline using Longitudinal Data with Respect to Common Variants”, European Alzheimer's Disease DNA BioBank (EADB)/ADES Meeting 2023, Málaga, Spain. Conference abstract (oral presentation)
  Vojgani, E. et al.
  
• "Pathway Analysis in Cognitive Decline using Longitudinal Data with Respect to Common Variants", European Mathematical Genetics Meeting (EMGM) 2024, Vienna, Austria. Conference abstract (poster presentation)
  Vojgani, E. et al.
  
• “Pathway Analysis in Cognitive Decline using Longitudinal Data with Respect to Common Variants”, European Society of Human Genetics (ESHG) 2024, Berlin, Germany. Conference abstract (poster presentation)
  Vojgani, E. et al.