Abstract It is widely known that exogenous formaldehyde exposure induces human cognitive impairment and animal memory loss; and recent studies show that formaldehyde at pathological levels induces Aβ deposition and misfolding of tau protein to form globular amyloid-like aggregates. Endogenous formaldehyde may be a marker for progressive senile dementia. The aim of this study was to investigate the correlation of endogenous formaldehyde in urine of senile dementia and mini mental state examination (MMSE) scores. Formaldehyde level was analyzed by high-performance liquid chromatography (with fluorescence detection) in human urine from dementia patients ( n = 141), patients with hypertension ( n = 33) or diabetes ( n = 16) and healthy individuals ( n = 38), autopsy hippocampus samples from Alzheimer's disease (AD) patients and brains of three types of AD animal model: namely, senescence accelerated mice (SAMP8), APP-transgenic mice and APP/PS1-transgenic mice. In a double-blind study, there was marked elevation of urine formaldehyde levels in patients ( n = 91) with dementia, and a slight increase in patients ( n = 50) with mild cognitive impairment. Urine formaldehyde level was inversely correlated with mini mental state examination scores ( Rs = −0.441, p < 0.0001). Furthermore, formaldehyde levels were significantly increased in the autopsy hippocampus from Alzheimer's patients ( n = 4). In SAMP8 brains the formaldehyde level was significantly increased, suggesting that the endogenous formaldehyde is related to aging in mice. The brain formaldehyde level in APP/PS1-transgenic ( n = 8) mice at age of 3 months and APP-transgenic ( n = 8) mice at age of 6 months was increased (0.56 ± 0.02 mM), respectively, as compared with their respective age-matched controls, when these two types of AD-like animals, respectively, started to form Aβ deposits and memory loss obviously. According to the level of formaldehyde in the brain of the transgenic mice, we treated normal mice with formaldehyde (0.5 mM, intraperitoneal administration) and observed the memory loss of the animal in Morris water maze trial. Cognitive impairments for the senile dementia are probably related to endogenous formaldehyde levels; and the mini mental state examination scores referred to the evaluation of urine formaldehyde level in dementia patients may be used as a non-invasive method for the investigation and diagnosis of senile dementia.