Although numerous studies have demonstrated that poor sleep increases the development of AD, direct evidence elucidating the benefits of good sleep on the AD pathogenesis is lacking. Familial Natural Short Sleepers (FNSS) are genetically wired to have lifelong reduction in nightly sleep duration without evident consequence on cognitive demise, implying that they may have better sleep quality. Here we investigated two FNSS mutations, DEC2-P384R and Npsr1-Y206H, on the development of tau and amyloid pathology in AD-like mouse models. We found that the development of tau pathology is attenuated in the hippocampus of tau mice carrying FNSS mutations. We also found that DEC2-P384R;5XFAD and female Npsr1-Y206H;5XFAD mice exhibit significantly less amyloid plaques than control mice at 6 months of age. Together, these results reveal that these two FNSS alleles are strong genetic modifiers of AD pathology and may confer resilience to the progression of tau pathology and amyloid plaque formation in neurodegeneration. Display omitted •Two FNSS mutations are strong genetic modifiers of AD-like pathology in mice•Mutant DEC2 and Npsr1 reduced tau pathology in PS19 mouse model of tauopathy•Mutant DEC2 and Npsr1 slowed down amyloid plaques in 5XFAD APP transgenic mouse model•Efficient sleep may be an exciting therapeutic target for ameliorating AD development Behavioral neuroscience; Biological sciences; Molecular neuroscience