Novel Genetic Risk Factors Detected for Alzheimer’s disease

22 September 2021

Douglas Wightman (PhD student CNCR-CTG) publishes his first results in Nature Genetics. The large scale genetic study resulted in the discovery of novel genes and biological mechanisms that contribute to the pathogenesis of the disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is expected to cause large medical and economic problems with the aging of the worldwide population. To improve the current treatment of AD we require an advanced understanding of the underlying biological mechanisms that are involved in the initiation of pathological processes leading to clinical AD. Genetics might shed important light on this subject, as it allows for objectively (without assumptions about underlying functional mechanisms involved in the disease) obtaining novel knowledge on the biological origin of the disease.

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 the well-known journal 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. 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.

This study is part of the international Psychiatric Genomics Consortium – Alzheimer’s Workgroup and was led by professor Posthuma from the VU University in Amsterdam, and professor Andreassen from the University of Oslo.