Novel genetic risk factors discovered for Alzheimer’s disease

Postdocs Iris Jansen and Jeanne Savage from the teams of Danielle Posthuma (CNCR-CTG) and Wiesje van der Flier (Alzheimer Centrum) find novel genetic risk factors for Alzheimer’s dementia, published in Nature Genetics.

A large-scale international study discovered novel genetic risk loci for Alzheimer’s disease.
Combining genetic data on a large-scale and in a non-conventional manner resulted in the discovery of multiple novel genetic factors and biological mechanisms that contribute to the pathogenesis of the disease. The study was led by Danielle Posthuma from the VU University in Amsterdam, Ole Andreassen from the University of Oslo and Stephan Ripke from the Broad Institute in Boston, and was carried out as part of an initiative of the Psychiatric Genomics Consortium.

Alzheimer’s disease (AD) is the most common neurodegenerative disease.  More than 30 million people are affected worldwide, and this is predicted to double every 20 years, expecting 115.4 million people to be diagnosed with AD by 2050. To improve the current treatment of AD we require an improved understanding of underlying biological mechanisms that are involved in the initiation of pathological processes leading to clinical AD. AD is largely under genetic influence and identifying genetic risk factors will increase our insight into this devastating disease.

Genetic defects within the immune system and lipid components
The current study is the largest genetic study of AD so far, including over 455,000 individuals. The study included clinical diagnoses to define the patient group, but also included a group of people where parental AD status was considered. For all individuals, genetic information was available which allowed to scan the genome for possible genetic risk factors. This combined analysis yielded 29 genome-wide significant loci for AD, including 9 novel genetic loci. Results imply that genetic defects in genes involved in the immune system and components associated to lipids, contribute to the risk for AD.
“Specifically, using single cell gene expression patterns, we show that genetic changes in genes that are expressed in microglia cells, are associated with increased risk for AD. Microglial cells are an important part of the immune system of the brain. This finding suggests that we should widen our focus to also include microglia models when performing functional research in AD, in addition to the conventional approach of neuronal models”, says Danielle Posthuma. Iris Jansen, shared first author of the publication continues:  ”We additionally detect genetic changes in proteins that are involved in lipid components. This link has already been described for the APOE gene, the strongest genetic risk factor for AD, but our results show that other lipid proteins might also be genetically affected. This observation strengthens the hypothesis that AD pathogenesis involves an interplay between inflammation and lipids, as lipid changes might harm immune responses of microglia, thereby affecting the vascular health of the brain.” 

Indirect genetic effects on Alzheimer’s through cognitive reserve
The study also tested the involvement of any indirect genetic effects on AD risk. In accordance with previous clinical research, which showed a protective effect of cognitive reserve on Alzheimer, the study reports a similar positive effect of cognitive skills on AD, yet this time supported by genetics. “This finding implies that a portion of the genetic risk factors affect cognitive reserve, which subsequently decrease the risk for AD”, says Jeanne Savage, shared first author of the study.

This study of unprecedented size was made possible by using data from various clinical cohorts as well as the UK Biobank, and is published online in Nature Genetics on Jan 7, 2019.

Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Fred Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, de Leeuw CA, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Homan T, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene N, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Stephan Ripke S, Andreassen OA, Posthuma D. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature genetics. http://dx.doi.org/10.1038/s41588-018-0311-9