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Largest ever GWAS of Alzheimer’s disease

The results from the largest GWAS of Alzheimer’s disease have been released as preprint in medRxiv. These findings have implicated microglia and immune cells in disease pathology. 

Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50-70% of cases. It is pathologically characterised by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain. Most patients are diagnosed with AD after the age of 65 – late onset AD (LOAD). Whereas only 1% of cases have early onset. From early twin studies, the heritability of LOAD is estimated to be ~60-80%. A recent study, suggested that LOAD is more of an oligogenic disorder than polygenic. This is because of the large effects of APOE variants. Researchers have also predicted that there are ~100-1000 causal variants contributing to LOAD, only a fraction of which have been found. Therefore, increasing the sample size of GWAS studies can improve the statistical power to identify the missing causal variants and potentially highlight novel disease mechanisms.


In this study, researchers expanded on a previous GWAS of LOAD to include 90,338 (46,613 proxy) cases and 1,036,225 (318,246 proxy) controls. The recruitment of LOAD cases is difficult due to the late age of onset. As a result, proxy cases can allow for the inclusion of younger individuals by estimating their risk of LOAD using parental status.

The team identified 38 loci, seven of which had not previously been reported. These seven novel loci were functionally annotated and fine-mapped to narrow down candidate causal genes. The researchers highlighted eight potential causal genes where gene expression changes were likely to explain the association. Specifically, they found that human microglia were the only cell type where the gene expression pattern was significantly associated with the AD association signal. Gene set analysis identified four independent pathways for associated variants that influenced disease pathology. These functional analyses all implicated immune cells and microglia as cells of interest.

The authors noted that this study was limited in its applicability to non-European populations. They emphasised that further study in non-European populations will improve the equity of genomic information and also help with fine-mapping of associated regions. Nonetheless, these findings provide further understanding of the mechanisms that mediate the effects of genetic variants on disease progression. Additionally, the team anticipate that these results could be included in a larger meta-analyses of AD. This in turn could help further identify genetic variants which contribute to AD pathology.

Image credit: By kjpargeter –

More on these topics

Alzheimer's Disease / Genetic Variants / GWAS