What can SNP-based heritability tell us about the etiology of AD today?

Here's a nice article from Baker et al 2022, "What does heritability of Alzheimer's disease represent?"

Here is a summary of some of their findings:

- The heritability of Alzheimer's disease is complex and variable, depending on factors like age and population. Regarding age, in samples with older participants, there is a greater likelihood that AD genetic factors will play a role in disease risk.

- SNP-based heritability estimates decrease by 12% when APOE is excluded. When all other genome-wide significant hits were removed, SNP-based heritability only decreased by 1%.

- In APOE e44 carriers, the average age of onset is about 68 years, whereas for APOE e4 non-carriers, it is about 84 years. The authors suggest that for the APOE e4 non-carriers, disease burden is mostly due to the aggregate effect of a large number of common SNPs as well as comorbid disorders.

- When they restricted SNPs to a microglia gene set that was only 3% of SNPs, it still explained between 50% and 93% of the SNP-based heritability. This strongly suggests that microglia are critical for the mechanism of AD. It would have been nice to see this compared to gene sets for other cell types, such as neurons or oligodendrocytes, which could have given a better sense of how variability in the function of these different cell types may contribute to AD risk and also helped to assess the robustness of their methods.

- The authors suggest that for neurodegenerative disorders, heritability estimates should be adjusted for the age-related prevalence of cases. This would help to account for the genetic liability for the disease of individuals who do not yet show symptoms.

- The article provides helpful insights into the complex nature of Alzheimer's disease heritability. It highlights the need for further research to identify biologically relevant AD gene-sets/pathways that could increase the signal-to-noise ratio by highlighting the most influential SNPs/genes in AD.