New genetic causes for Alzheimer’s discovered

An international research team, led by Brainscapes member Danielle Posthuma from Vrije Universiteit Amsterdam and colleague Ole Andreassen from the University of Oslo, has conducted large-scale genetic research into the different backgrounds of the risk of Alzheimer’s disease. The researchers discovered new genes and biological mechanisms that contribute to Alzheimer’s disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is expected to cause major medical and economic problems as the world’s population ages. To improve current Alzheimer’s treatment, in-depth knowledge is needed on the underlying biological mechanisms involved in initiating pathological processes that ultimately lead to clinical Alzheimer’s. Genetic research can be important to learn more about this, because it makes it possible to gain objectively new knowledge about the biological origin of the disease.

A Manhattan plot of the meta-analysis results highlighting 38 loci, including seven previously unidentified regions.

Genetic evidence for microglia contributing to AD
The current research includes over a million individuals and is the largest genetic study for AD so far. The results, which have been published in Nature Genetics, pointed towards the involvement of genes specifically expressed in microglia, indicating that these types of cells, which are known to be involved in immune system, are important in the pathogenesis of AD. Further results highlighted a role for  biological pathways concerning amyloid protein, neurofibrillary tangles, immune cells, and glial cells in AD. “As a whole, the results highlighting amyloid protein, a biomarker for AD aggregation in the brain, and microglia, the constituent immune cell within the brain, support the current hypothesis that AD pathogenesis is caused in part by protein aggregation and dysregulation of the immune response within the brain.” says prof Posthuma.

How much risk do these results explain?
The study identified 7 regions of the genome not previously associated with AD and implicated 9 specific genes across 38 regions based on gene expression. However, AD is a complex disease with many environmental and genetic contributors, with many associated regions of the genome yet to be discovered. The current results explain a moderate amount of the genetic risk for AD and highlight interesting new genomic regions but there is further work to be done. “The results from a subset of the data can explain approximately 7% of variation in AD diagnosis in an independent dataset. Further studies with larger sample sizes, in non-European populations, and focusing on non-common variation are important to discover further genetic contributors and ensure equity in who benefits from research outcomes”, says Douglas Wightman, first author of the publication and PhD candidate in the team of Prof Posthuma.

Further genetic studies to understand a greater proportion of the genetic risk for AD will expand the number of targets for treatment of AD. The results from this study are expected to be included in larger collaborative efforts to further unravel the genetics of AD. Further work focusing on model organisms is also necessary to further tease apart the genomic regions to identify specific targetable regions for novel treatments.