The fact that [1] the expression of the APPSW/Ind is under a predominantly neuronal promoter in brain [2], the Nlrp1-Casp1-Casp6 pathway was validated by genetic ablation of either of these three genes in J20 mice [3], the activation of Nlrp1-Casp1-Casp6 in neurons leads to neurodegeneration, and [4] VX-765 normalize or improve cognition in J20 mice without a significant effect on Iba1+-microglia, Il-1β, and TNF-α, GFAP+-astrocytes, and Aβ levels support the hypothesis that neuronal degeneration drives cognitive deficits rather than Aβ and inflammation. This evidence concerns the gene NLRP1 and Cognitive impairment.