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Aging (Albany NY). 2019 Jul 7;11(13):4579-4586. doi: 10.18632/aging.102070.

Ketones improves Apolipoprotein E4-related memory deficiency via sirtuin 3.

Yin J1, Nielsen M1,2, Li S1,3, Shi J1,4,5.

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Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ 85013, USA.
School of Life Sciences, Arizona State University, Tempe, AZ 85257, USA.
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100160, China.
China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100160, China.



Apolipoprotein E4 (ApoE4) is the major genetic risk factor of Alzheimer's disease (AD). ApoE4 carriers have cerebral hypometabolism which is thought as a harbinger of AD. Our previous studies indicated ketones improved mitochondria energy metabolism via sirtuin 3 (Sirt3). However, it is unclear whether ketones upregulate Sirt3 and improve ApoE4-related learning and memory deficits.


Ketones improved learning and memory abilities of ApoE4 mice but not ApoE3 mice. Sirt3, synaptic proteins, the NAD+/ NADH ratio, and ATP production were significantly increased in the hippocampus and the cortex from ketone treatment.


Human ApoE3 and ApoE4 transgenic mice (9-month-old) were treated with either ketones or normal saline by daily subcutaneous injections for 3 months (ketones, beta-hydroxybutyrate (BHB): 600 mg/kg/day; acetoacetate (ACA): 150 mg/kg/day). Learning and memory ability of these mice were assessed. Sirt3 protein, synaptic proteins (PSD95, Synaptophysin), the NAD+/ NADH ratio, and ATP levels were measured in the hippocampus and the cortex.


Our current studies suggest that ketones improve learning and memory abilities of ApoE4 transgenic mice. Sirt3 may mediate the neuroprotection of ketones by increasing neuronal energy metabolism in ApoE4 transgenic mice. This provides the foundation for Sirt3's potential role in the prevention and treatment of AD.


Alzheimer’s disease; apolipoprotein E4; sirtuin

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