Large-scale genetic analysis sheds light on the biology of Alzheimer's disease

A large international study of 2.8 million people identified new Alzheimer's disease risk regions – furthering our understanding of the genetic and biological mechanisms underlying the disease.

Alzheimer's disease is the most common cause of dementia worldwide, with both environmental and genetic factors associated with the risk of developing the condition. Earlier twin studies estimated Alzheimer's heritability at 60–80 percent, with recent genome-wide association studies (GWAS) identifying approximately 80 risk locations across our DNA. Thus, previous single-nucleotide polymorphism (SNP) heritability estimates of approximately five percent had led to suggestions that few further common genetic risk factors remained to be identified.

'This is the largest genetic association study on Alzheimer's to date, bringing together data from individuals with diverse genetic backgrounds,' said Dr Douglas Wightman, co-first author of the study published in Nature.

Research led by Vrije Universiteit Amsterdam, Netherlands, with contributions from the University of Exeter's PROTECT study, identified 127 regions in human DNA associated with the risk of developing Alzheimer's disease – with 48 not previously mapped in this context. The research also estimated SNP heritability at 16 percent – nearly three-fold greater than the previous estimate. 

The study comprises a GWAS of 109,479 Alzheimer's cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls, whereby proxy cases were defined as people who reported that one of their parents had Alzheimer's disease. This included meta-analysis of 30 cohorts across five ancestry groups, including UK Biobank, the Million Veteran Program, 23andMe and several US and European biobanks. Although the study included five ancestry groups, 91 percent of the effective sample size was from individuals of European ancestry.

Using gene expression data in healthy controls, scientists discovered a positive correlation between gene overexpression in microglia – immune cells of the brain, associated with clearing away damaged cellular material – and the GWAS gene association. This suggests that these genes are preferentially active in microglia compared with other brain cell types. Thus, the findings implicate the role of microglia in Alzheimer's disease.

Next, scientists also used cell-type-specific differential gene expression data comparing Alzheimer's disease cases with controls, to test whether there was a link between the GWAS gene association and differential expression in a certain cell type. The researchers identified genes overexpressed in microglia and genes underexpressed in neurons compared with controls, including three neuronal subtypes. Two of these had previously been associated with vulnerability during the early stages of Alzheimer's disease.

These findings suggest that genetic variants associated with Alzheimer's disease risk may influence gene expression in vulnerable neuronal subtypes. Moreover, five new genes identified from the study were shown to interact with known Alzheimer's disease genes across two pathways – amyloid processing and the microglial response to amyloid-beta, a protein known to accumulate in the brain in Alzheimer's disease.

'We already knew that immune processes play an important role in Alzheimer's disease,' said senior author Professor Danielle Posthuma. 'What makes this study particularly valuable is that we can now connect new genetic risk factors to more specific biological processes, while also uncovering evidence pointing to the involvement of other brain cell types. This gives us a more detailed picture of the biology underlying Alzheimer's and provides new directions for investigating potential treatments.'