Formaldehyde is directly toxic to cells and its intermediate metabolite formic acid leads to acidosis in microenvironment in vivo. According to recent literatures, endogenous formaldehyde production is related to several metabolic pathways such as amine oxidation (catalyzed by semicarbazide-sensitive amine oxidase, SSAO), methylation and demethylation. Under oxidation stress and energy metabolic imbalance, formaldehyde markedly increases in human circulation. Here, the authors found that formaldehyde is released from the reaction of malondialdehyde with a protein (BSA) in which protein side chains such as amino groups are chemically modified. Moreover, formaldehyde is also produced from the sphingomyelin solution in the presence of hydrogen peroxide as the myelin peroxidation occurs. Formaldehyde at low concentration induces neuronal Tau aggregation, resulting in formation of globular like aggregates which are toxic to SH-SY5Y cells, HEK-293 cells and hippocampus neurons in the primary culture. According to Chen et al. (2006), endogenous aldehydes are related to beta-amyloid misfolding, oligomerization and fibrillogenesis. Furthermore, formaldehyde is able to react with some neurotransmitters and thus impairs their structures and functions. Under physiological conditions, the human blood formaldehyde is dynamically kept approximately (0.087±0.004) mmol/L. Notably, this concentration is close to the half-lethal dose of formaldehyde (0.10～0.12 mmol/L) to neural cells in the in vitro cell culture such as SH-SY5Y cells. Furthermore, cell growth can be partially affected and inhibited in the presence of formaldehyde at (0.087± 0.004) mmol/L during the in vitro culture. This suggests that human body needs a strong degradation system to remove endogenous formaldehyde. As shown in clinical trials, the formaldehyde level in urine of Alzheimer's patients was markedly higher than the control subjects. The urine formaldehyde level was shown to be related to the cognitive impairment. Therefore, the level of blood (brain) formaldehyde is supposed to be changeable and increased under aging, leading to a higher risk chance to impair human brain, especially under stressing. The formaldehyde chronic damage to neural cells (grey mater) and neural fibers (white mater) may be one of the most important pathological mechanisms for sporadic neurodegeneration for instance Alzheimer's disease, because hypofunction in scavengering endogenous formaldehyde occurs as aging.