TREM2 and Alzheimer disease: Examples include heterozygous LOF mutations in the progranulin gene (PGRN) causing FTD but homozygous mutations causing a lysosomal storage disorder [4, 29]; mutations in GBA causing Parkinson’s disease in heterozygosity and Gaucher’s disease in homozygosity [1]; and mutations in TREM2 causing Alzheimer’s disease and Nasu–Hakola disease [11, 14]; however, homozygous mutations in gain-of-function neurodegenerative diseases such as inherited prion disease (PRNP), ALS (SOD1) and Huntington disease (HTT), manifest with severe phenotypes, that fall within the range of disease [13, 15, 28, 30].