Alfredo Ramirez

Neurogenetics and Molecular Psychiatry

Neuro(epi)genomics in Age-Related Cognitive Disorders

Age-related cognitive disorders, like Alzheimer’s disease, are phenotypes resulting from complex interactions between risk factors like genetics, epigenetics, and environment. Delineation of these factors will translate into personalized treatment and better prevention strategies.

Research Focus

The division of Neurogenetics is interested in understanding the complex (epi)genetic architecture modulating the disease processes underlying neurodegenerative dementias and age-related cognitive disorders. To this end, our main focus is on the development and implementation of innovative and robust methods to identify and characterize genetic and epigenetic factors influencing the risk of these disorders. Reaching this goal is only possible because the division has access to genetic and epigenetic data from several thousands of individuals.

Besides, our group is also interested in mechanisms operating in neurodegeneration that relate to aging. In this context, we explore whether the levels of specific proteins in cerebrospinal fluid (CSF) belonging to the so-called senescence-associated secretory phenotype are associated with accelerated biological aging and whether this acceleration influences the progression to dementia of the Alzheimer's type.

Our Goals

1) Identification of novel genes and pathways related to cognitive disorders. For this, the division has access to genetic data from more than 90,000 European samples of AD cases and healthy controls. This unique setup provides a statistical power that allowed us already to double the number of known genetic risk factors for AD. Currently, we are in the process of expanding this list.

2) Development of novel approaches to explore the genetic architecture modulating the rate of disease progression of AD. To achieve this goal, the division leads the largest European initiative dedicated exclusively to genetic research on disease progression in early stages of AD, i.e., mild cognitive impairments (MCI, ~9,000 cases). In this context, the division is establishing state-of-the-art analytical methods to model and analyze longitudinal phenotypes combined with genetic data.

Predicting individual risk of progressing to dementia will require the combination of static biomarkers, like genetics, with dynamic biomarkers, like epigenetics or proteomics, that report on translation of genetic burden into pathology.

3) Understanding the role of aging in AD progression. Presently, the division has biobanked several thousands of biomaterials from patients affected by cognitive diseases in whom clinical and cognitive assessments are available longitudinally. Using additional “omics” layers, our division is now disentangling the contribution of biological aging to the progression of neurodegeneration. To this end, available DNA methylation data has been used to generate known biological clocks to study the role of biological aging on disease progression. In addition, we have also produced extensive proteomic data in CSF and blood that has been combined with the DNA methylation data and the genetic data to understand the contribution of biological aging to the disease processes occurring in AD.

Combining existing datasets, our group has been crucially involved in several international efforts leading to the identification of several new genetic loci modulating the risk of Alzheimer’s disease. Importantly, we have also defined that a genetic risk variant for Alzheimer’s disease is also modulating the speed with which the disease progress over time. Beyond genetics, our group has also participated in the identification of novel blood and cerebrospinal fluid proteins and metabolites that might serve as biomarkers for Alzheimer’s disease. All these findings have clear translational potential for early detection and prevention strategies for Alzheimer’s disease.

Key Publications

  1. Dalmasso, M.C., de Rojas, I., Olivar, N., Muchnik, C., Angel, B., Gloger, S., Sanchez Abalos, M.S., Chacón, M.V., Aránguiz, R., Orellana, P., Cuesta, C., Galeano, P., Campanelli, L., Novack, G.V., Martinez, L.E., Medel, N., Lisso, J., Sevillano, Z., Irureta, N., Castaño, E.M., Montrreal, L., Thoenes, M., Hanses, C., Heilmann-Heimbach, S., Kairiyama, C., Mintz, I., Villella, I., Rueda, F., Romero, A., Wukitsevits, N., Quiroga, I., Gona, C., Lambert, J.C., Solis, P., Politis, D.G., Mangone, C.A., Gonzalez-Billault, C., Boada, M., Tàrraga, L., Slachevsky, A., Albala, C., Fuentes, P., Kochen, S., Brusco, L.I., Ruiz, A., Morelli, L., Ramírez, A§. (2023). The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease. Alzheimers Dement. Online first. 10.1002/alz.13522. (IF:14)
  2. Jansen IE, van der Lee SJ, Gomez-Fonseca D, de Rojas I, Dalmasso MC, Grenier-Boley B, Zettergren A, Mishra A, Ali M, Andrade V, Bellenguez C, Kleineidam L, [...], Hiltunen M, Ingelsson M, Andreassen OA, Clarimón J, Sleegers K, Ruiz A, Ramirez A*, Cruchaga C, Lambert JC, van der Flier WM. Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers. Acta Neuropathol. 2022 Nov;144(5):821-842. doi: 10.1007/s00401-022-02454-z. (IF:12.7)
  3. Martino Adami PV, Orellana A, García P, Kleineidam L, Alarcón-Martín E, Montrreal L, Aguilera N, Espinosa A, Abdelnour C, Rosende-Roca M, Pablo Tartari J, Vargas L, Mauleón A, Esteban-De Antonio E, López-Cuevas R, Dalmasso MC, Campos Martin R, Parveen K, Andrade Fuentes VM, Amin N, Ahmad S, Ikram MA, Lewczuk P, Kornhuber J, Peters O, Frölich L, Rüther E, Wiltfang J, Tarraga L, Boada M, Maier W, de Rojas I, Cano A, Sanabria A, Alegret M, Hernández I, Marquié M, Valero S, van Duijn CM, Wagner M, Jessen F, Schneider A, Sáez Goñi ME, González Pérez A, Ruiz A, Ramírez A§. Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type. Brain. 2022 Jul 29;145(7):2507-2517. doi: 10.1093/brain/awac024. (IF:14.5)
  4. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, Naj AC, Campos-Martin R, [...], van der Flier WM, Ruiz A, Ramirez A*, Lambert JC. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412-436. doi: 10.1038/s41588-022-01024-z. (IF:41.3)
  5. Kleineidam L, Chouraki V, Próchnicki T, van der Lee S, [...], Sáez ME, Latz E, Ruiz A, Ramirez A§. PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment. Acta Neuropathol. 2020 Mar 12. doi: 10.1007/s00401-020-02138-6.2020. (IF: 18.2)