Formaldehyde has been shown to play important roles in contributing to age-related cognitive impairment including Alzheimer’s disease (AD) and vascular dementia (VD). Gut microbiota, also called “the second brain,” can modulate brain function and participate in pathogenesis of neurodegenerative diseases. However, whether there is a link among formaldehyde, gut microbiota and cognitive impairment remains unclear. In this review, we briefly summarized the research progress of formaldehyde and gut microbiota, and discussed their relationships with age-related cognitive impairment. We propose a probable link between gut microbiota and formaldehyde based on the probable functions of 5-HT and NE during these neurodegenerative diseases. We hypothesize that formaldehyde derived from gut microbiota may be involved in cognitive function and its dysmetabolism may be a risk factor of AD or even lead to cognitive decline. It is also intriguing to predict that, within several specific AD-related gut microorganisms reported to date, the shortage of hexulose-6-phosphate synthase (HPS)/6-phospho-3-hexuloisomerase (PHI) in these probiotics may contribute to the onset of AD and cognitive impairment. In order to clarify that dysmetabolism of formaldehyde in intestinal microbiota is involved in AD, we compared the concentration of intestinal formaldehyde in APP/PS1 double-transgenic mice and that of C57BL/6j wild-type mice. There is a significantly elevated level of formaldehyde in the cecum digestion content of the APP/PS1 transgenic mice, and so is the formaldehyde level in the small intestinal wall for the APP/PS1 transgenic mice compared to the control. In human feces, formaldehyde level is tenfold of that in urine. These data suggest intestinal microbiota is a main source of formaldehyde, which may have a link to cognitive impairment. It was observed that the intestinal length also extended from month 4 to month 24 in 129S2/SvPasCrl mice and C57BL/6 J wild-type mice. To prevent or delay the progress of neurodegeneration, it is reasonable to use formaldehyde scavengers, such as probiotics, in addition to previously proposed antioxidative and anti-inflammatory chemicals to prevent, delay, attenuate, and/or block the progress of age-related cognitive impairment, therefore improving the human health and quality of life.