Study identifies autoimmunity as a key component in dementia causing pathologies

In the study, Professors Archana Singh-Manoux, Gill Livingston and Mika Kivimäki, along with researchers from the US and Finland, show that dementia-causing conditions such as Alzheimer´s disease may have an autoimmune component that is modifiable with currently available drugs.

Earlier studies have linked diseases related to inflammation, such as diabetes and severe infections, to increased risk of dementia but the underlying mechanisms between the immune system and dementia have remained unclear.  

Using data from genome-wide association studies, the authors analysed thousands of gene variants to identify potential biomarkers linking immune system dysfunction to dementia related pathologies.

The findings suggest that autoimmunity may drive cognitive decline and dementia. This means that targeting the brain-damaging autoimmunity by anti-inflammatory drugs might provide an avenue to prevent dementia.

To confirm their findings, the authors conducted four additional analyses; these examined circulating proteins related to immune dysfunction in the UK Whitehall II cohort of 6,500 adults, and contribution of several genes, human leucocyte antigens and drug prescriptions in the Finnish FinnGen cohort of 340,000 individuals.

All the different strands of analyses were consistent with the autoimmune hypothesis. In addition, analysis of drug prescriptions suggested that anti-inflammatory drugs, such as methotrexate, may lower the risk for Alzheimer´s disease, especially in 10-20% of people who carry a specific gene known as APOE e4 allele.

Professor Mika Kivimäki, Director of the Whitehall II study, said:

“Accumulation of amyloid beta and tau are hallmarks of Alzheimer’s disease but drugs preventing this accumulation have not reversed dementia. Our findings highlight an additional feature of dementia pathogenesis, the death of brain neurons caused by autoimmune response against body’s own healthy cells and tissues. Our observational data suggest that targeting the brain-damaging autoimmunity by anti-inflammatory drugs might provide an avenue to prevent dementia. Obviously clinical trials are still needed to determine their effectiveness in practice.”

Lead author Joni Lindbohm MD, PhD from the Broad Institute of MIT and Harvard, University College London and University of Helsinki, said:

“By using genome-wide data, circulating biomarker analyses and long-term follow-ups of electronic health and prescription records, this is the largest multiapproach study on this issue to date. Our findings are very promising, but before repurposing methotrexate for dementia prevention, validation in randomized control trials is needed.”

Related

• Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing disease
• Professor Mika Kivimäki's academic profile
• Professor Gill Livingston's academic profile
• Dr Archana Singh-Manoux's academic profile
• UCL Psychiatry