Furthermore, a caveat with the interpretation of functional endpoints from AD models crossed with Trem2 KO mice is that loss of TREM2 function (or its binding partner DAP12) in humans results in Nasu-Hakola disease, a white matter-targeting age-dependent neurodegenerative disease [63], suggesting that absence of TREM2 has detrimental effects on the brain in the absence of plaques. This evidence concerns the gene TYROBP and neurodegenerative disease.