The findings revealed several new biomarkers, or biological factors, associated with Alzheimer’s and other dementia-causing diseases. In particular, autoimmunity, or the process in which the immune system attacks the body’s own tissues, was an important risk mechanism for dementia.
For years, research on dementia has focused on disease processes related to amyloid and tau proteins, but drugs targeting them have failed to cure or prevent dementia. This has encouraged researchers to look for other underlying disease mechanisms.
Previous studies have pointed to the significance of the immune system, for example, by demonstrating a link between dementia and chronic inflammatory diseases such as diabetes.
In the new study, the researchers examined the connection between the immune system and dementia more extensively than before, using several datasets and different approaches. They utilised genetic data, blood-sample biomarkers and registries of diseases, causes of death and drug prescriptions.
“Our results provide much-needed new information on the onset of dementia. Our multidisciplinary approach enabled us to find the connection between autoimmune diseases and dementia,” says lead author Joni Lindbohm, MD, PhD from the Broad Institute of MIT and Harvard, and the University of Helsinki.
Potential new drug target for Alzheimer’s disease
The significance of autoimmunity was supported by the Finnish FinnGen dataset, with the analyses of medication data proving particularly interesting. The data showed that methotrexate, used in the treatment of rheumatic arthritis, may protect against Alzheimer’s disease. This was seen especially in individuals with an APOE ε4 allele that predisposes them to the disease. This risk factor can be found in approximately one in four Finns.
“Our findings suggest that autoimmune mechanisms in which the body’s own cells attack neurons in the brain may be a promising drug target for the prevention of Alzheimer’s disease. Autoimmune mechanisms can be treated with existing drugs, but their practical benefit in the treatment of dementia-causing diseases must still be validated with randomised studies,” notes Professor Mika Kivimäki of the University of Helsinki, who was one of the principal investigators responsible for the study. He is also the Director of the Whitehall II study at University College London.
As Alzheimer’s disease develops slowly, investigation of its mechanisms requires long-term follow-up studies.
“The results linking autoimmune mechanisms and Alzheimer’s disease were possible because the extensive genetic findings associated with plasma protein levels in Whitehall II could be linked to FinnGen data on prevalence. Collaboration was the key to success,” says Professor Samuli Ripatti of the University of Helsinki, the other principal investigator behind the study.
The researchers’ findings were recently published in the Nature Aging journal and recognised at a world-leading conference in genetics held in Los Angeles.
Original publication: Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases. Joni V. Lindbohm, Nina Mars, Pyry N. Sipilä, Archana Singh-Manoux, Heiko Runz, FinnGen, Gill Livingston, Sudha Seshadri, Ramnik Xavier, Aroon D. Hingorani, Samuli Ripatti, Mika Kivimäki. Nat Aging 2, 956–972 (2022). DOI: 10.1038/s43587-022-00293-x
Joni Lindbohm, MD, PhD, University of Helsinki, Broad Institute of MIT and Harvard, University College London, +1 617 251 5642, email@example.com
Professor Mika Kivimäki, University College London, University of Helsinki, firstname.lastname@example.org
Professor Samuli Ripatti, Institute for Molecular Medicine Finland FIMM, University of Helsinki, email@example.com