Alzheimer's disease and methanol toxicity (part 2): lessons from four rhesus macaques (Macaca mulatta) chronically fed methanol

J Alzheimers Dis. 2014;41(4):1131-47. doi: 10.3233/JAD-131532.


A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology.

Keywords: Alzheimer's disease; amyloid plaque formation; cognitive impairment; disease progression; formaldehyde; methanol toxicity; tau hyperphosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / chemically induced*
  • Alzheimer Disease / complications
  • Alzheimer Disease / pathology
  • Analysis of Variance
  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Cognition Disorders / etiology
  • Disease Models, Animal
  • Macaca mulatta
  • Male
  • Memory Disorders / cerebrospinal fluid
  • Memory Disorders / chemically induced
  • Memory Disorders / diagnosis
  • Methanol / blood
  • Methanol / toxicity*
  • Phosphorylation / drug effects
  • Photic Stimulation
  • Solvents / toxicity*
  • Space Perception / physiology
  • Time Factors
  • tau Proteins / cerebrospinal fluid


  • Solvents
  • tau Proteins
  • Methanol