Increasing evidence indicates that sirtuins have neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of AD. However, it is unclear whether Sirt6 is associated with cognitive performance and pathological changes in AD.

We conducted a case-control study of the postmortem brains of AD (n= 16), mild cognitive impairment (n= 11) and age- and education-matched cognitively normal (CN, n= 11) subjects. We measured the protein levels of Sirtuins (Sirt1, Sirt 2, Sirt4, Sirt5,Sirt6, and Sirt7), and assessed its association with cognitive performance and AD pathology, its association with synaptic proteins (postsynaptic density 95 (PSD95) and Synapsin 1) and nucleus signal molecules (phosphor AMP activated protein kinase (pAMPK) and nuclear respiratory factor 1 (NRF1)).

Sirt6 level was reduced in the middle temporal gyrus of AD subjects compared to that of CN. This reduction was associated with severity of tau pathology (Tangle score), and poorer cognitive performance (MMSE, Mattis DRS score, and Stroop word). Furthermore, Sirt6 was associated with synaptic proteins and nucleus signal molecules.

These data suggest that Sirt6 is downregulated in the postmortem brains of AD. Sirt6 decline was associated with cognition dysfunction and synapse loss. Sirt6 may play a critical role in pathogenesis of AD.