Formaldehyde and alzheimer's disease: A brief history

Abstract

Formaldehyde has recently been placed at the forefront of Alzheimer's disease research. The reasons for this impetus is multi-fold and because the properties of formaldehyde, a planar polar single carbon aldehyde, have strong relevance to the disease. Alzheimer's disease is an age-related neurodegenerative dementia that presents with cognitive decline and memory impairments and is diagnosed with neuritic plaques, neurofibrillary tangles and neuronal atrophy. First, formaldehyde has been found to be an age-related factor whose concentrations in blood and cerebral spinal fluid increase with age and has been found to be higher in Alzheimer's patients post-mortem. Formaldehyde and methanol, a one-carbon precursor of formaldehyde, have been found to cause memory impairments in laboratory animals. Moreover, formaldehyde is a known protein cross-linker that has been shown to cause the aggregation of both amyloid peptides and tau protein as well as tau protein phosphorylation in vitro. These properties are central to the two main pathological hallmarks of Alzheimer's disease: the amyloid plaque and neurofibrillary tangle. As such, chronic methanol exposure has been found to induce all of these hallmarks, including memory impairments, in rhesus monkeys. While these findings have implications related to exogenous exposure to both methanol and formaldehyde, there are a number of indications that endogenous metabolic processes may also contribute formaldehyde to the pathological state. Most notably is the condition of hyperhomocysteremia in Alzheimer's disease. Hyperhomocysteremia represents an imbalance of the one-carbon metabolic cycle that favors the metabolite homocysteine, while potentially contributing free one-carbon moieties like formaldehyde to the blood or cerebral spinal fluid. However, no correlation studies between these two related metabolites and Alzheimer's disease have been investigated to date. Nonetheless, formaldehyde offers a unique chemical toxicity that has the potential to explain a large gambit of the pathological progression of the disease; from age-related progression, memory impairments and genetic risk factors. Although there is considerable implications of formaldehyde, such as in the development of novel therapies for the treatment of Alzheimer's disease, very little research and focus have been given to one-carbon toxicity in the past. This brief review serves to focus related research and raise awareness of formaldehyde in Alzheimer's disease pathology so that it may receive better consideration in the future.