The Alzheimer Pandemic: Is Paracetamol to Blame?

Abstract

Historical Background: The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD).Disease development: PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.Conclusion: F-AD is primarily a man-made condition with PA as its principal risk factor.

Bioassay Directed Isolation, Biological Evaluation and in Silico Studies of New Isolates from Pteris cretica L.

“…Oxidative stress has been linked to the neuronal cell death since long. The induction of nitric oxide (NO) produced by nitric oxide synthase (NOS) has been found to play a role in oxidative damage linked to neurodegeneration [86]. Pro-inflammatory cytokines have been found responsible for neuroinflammation leading to neurodegeneration of which TNF-α tops the list [87].…”

Chronic pain is a risk factor for incident Alzheimer’s disease: a nationwide propensity-matched cohort using administrative data

“…These results are consistent with those previously published, showing a protective effect of NSAIDs against dementia (Szekely et al, 2008). Likewise for paracetamol (Jones, 2014) and opioids (Dublin et al, 2015), which were shown to be risk factors for the development of dementia. Unfortunately, our results are only exploratory, the low prescription rate of several drugs did not allow us to assess precisely and reliably the correlation with the presence of ADRD for each pain medication.…”

“…Regarding paracetamol, our results should be taken with caution. To date, there is no reliable study showing a link between paracetamol consumption and the development of cognitive disorders (Jones, 2014). Moreover, the difficulty in separating the effect of pain from the effect of its treatment makes the interpretation of such exploratory results even more complicated.…”

Acetaminophen/paracetamol: A history of errors, failures and false decisions

“…This again shows that ‘historical’ drugs may yield surprising and dangerous effects and we should not trust that old means safe. Nevertheless, relating the ubiquitous paracetamol (Modick et al., ) to the worldwide increase of Alzheimer's disease (Jones, ) appears somewhat far‐fetched.…”