Alzheimer’s disease (AD), which involved in many molecular pathways in the human central nervous systemCentral nervous system, is a multifactorial complex neurodegenerative diseaseNeurodegenerative disease. The failure of the recent development of AD therapeutic agents in clinical trials is mainly due to their single-target or single-pathogenic pathway effect or late time window for treatments. The metabolism of formaldehyde involves multiple pathways and gene regulation. According to recent studies, endogenous formaldehydeEndogenous formaldehyde levels are positively related to the severity of age-related cognitive impairmentCognitive impairment, with approximately 40% of AD patients suffering from dysmetabolism of formaldehyde. Furthermore, administration of a low concentration of methanol in monkeys, a precursor compound for formaldehyde, induces cognitive impairmentCognitive impairment accompanied by Aβ deposition and the formation of senile plaqueSenile plaque, tau hyperphosphorylation, and aggregation. This evidence suggests that formaldehyde plays a role in the progression of AD. As shown in clinical investigations, urine formaldehyde, including formic acid, is related to age-related cognitive impairmentCognitive impairment. Endogenous formaldehydeEndogenous formaldehyde and formic acid are expected be biomarkers in clinical determination. Development of useful biomarkers will be beneficial to enlighten the understanding of the role of formaldehyde in the neurodegenerative diseaseNeurodegenerative disease, especially age-related cognitive impairmentCognitive impairment. In this chapter, we review some relevent protocols, experimental models (including molecular, cellular and animal models) and clinical investigations pertaining to formaldehyde research, drawing from our own work and contributions by colleags in the field.