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KosAbility: High usage of acetaminophen associated with more than doubled Alzheimer's risk [1]

['This Content Is Not Subject To Review Daily Kos Staff Prior To Publication.']

Date: 2025-08-31

Last month we looked at how observational studies can mislead. With those lessons in mind, we now look at an observational study worth paying attention to:

The study made use of the records of the French national healthcare system. They stratified the results according to the cumulative daily dosage of individual patients:

[O]nly the use of non-opioid analgesics [in this study that refers primarily to acetaminophen and not to NSAIDS such as ibuprofen]... was correlated with a more frequent occurrence of ADRD [Alzheimer's], depending on the duration of exposure [non-opioid analgesics: mild exposure = OR 1.76, 95%CI (1.39–2.23); moderate exposure = OR 2.54, 95%CI (2.00–3.24); and strong exposure = OR 2.83, 95%CI (2.23–3.60)]

From the supplementary data we have:

Non-opioids = PARACETAMOL and NEFOPAM (Paracetamol accounts for +90% of cases).

Note that these are big odds ratios - more than a doubling of risk, at moderate or high exposure. Recall that in last month's discussion of a poorly done study we had a confidence interval with a low end of 1.01 - barely a valid result because it did not cross under 1.0. Here we see that for moderate exposure and above, the low end of the confidence interval is about 2.0, still a robust result - double the risk of Alzheimer's or more. These numbers included the effect of both acetaminophen and a small proportion of nefopam. Table 5 shows the increased odds ratio due solely to the effect of acetaminophen and gives similar numbers, with a p value of <.0001:

Odds ratio of Alzheimer's diagnosis subsequent to acetaminophen use

Click to embiggen.

Observational studies can be misleading due to confounding factors, as we have discovered. So perhaps there's something about chronic pain that is causative of Alzheimer's? If so, we would expect NSAIDs other than acetaminophen to have a similar association. But in the same study NSAID usage other than acetaminophen was found to have an inverse association with Alzheimer's:

the use of NSAIDs [other than acetaminophen] was correlated with a lower presence of ADRD and depended on the duration of exposure [mild exposure = OR 0.93, 95% CI (0.82–1.05); moderate exposure = OR 0.67, 95% CI (0.54–0.85); and strong exposure = OR 0.72, 95% CI (0.58–0.89)]

From the supplementary data we have:

NSAIDs = ... ASPIRIN... CELECOXIB, DICLOFENAC... IBUPROFEN, KETOPROFEN ... NAPROXEN...

Their usage reduced the likelihood of a subsequent diagnosis of Alzheimer's. So in this study acetaminophen stands out as uniquely neurotoxic. Note that for moderate and strong NSAID exposures the confidence interval now stayed well below 1.0.

This was a big study:

During the inclusion period (2006–2010), 15,136 individuals over 50 years old and with chronic pain were identified. After matching, 13,596 chronic pain and 40,788 control individuals were analyzed. As expected from the matching procedure, cases and controls were comparable in terms of age (66 years), sex (62% female), and Charlson score* (0.4). Chronic pain and control individuals had a median follow-up time of 10.2 years.

*The Charlson Comorbidity Index

the most widely used comorbidity index used to determine survival rate (1yr and 10yr) in patient with multiple comorbidities.

How much exposure qualifies as moderate or strong exposure to acetaminophen?

The cumulative dose was computed during the study time window and converted it into a number of defined daily doses (DDDs) by dividing it by the average recommended daily dose for this product, as previously published by Billioti de Gage et al. (2014). Therefore, one DDD corresponded to an average one-day exposure.

The indicated reference was not forthcoming as to the dosage of acetaminophen they designated as a defined daily dose. However, we do have this study of Usage patterns of paracetamol in France, done around the period covered by the study of hand, which tells us:

paracet amol … defined daily doses (DDD, 3 g)

Moderate ex posure is defined as a cumulative dose equivalent to 3 to 18 months of exposure at the defined daily dose; strong exposure is defined as more than 18 months such exposure.

Moral of the story: if you need to take 3 grams daily of acetaminophen for 3 months or longer, or a cumulative exposure exceeding 270 grams, consider some other treatment instead. Other possibilities include ibuprofen and aspirin, which can cause GI problems. Some additional ideas are suggested below. Consult with your doctor before making any changes.

NAC may mitigate acetaminophen toxicity

Liver toxicity is a result of a toxic metabolite of acetaminophen depleting stores of glutathione. The essential building block of glutathione is N-acetylcysteine (NAC). The medical treatment for acetaminophen overdose is high dose NAC via IV.

Oral NAC is safe up to 3000 mg/day according to Safety of N‑Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review:

N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the efficacy of NAC at higher doses. The aim of this review was to evaluate the adverse effects profile of NAC at higher than the standard dose in chronic respiratory diseases to establish a risk–benefit ratio in increasing the daily dose; therefore, studies using NAC at a dose of at least 600 mg/day were selected. Forty-one articles where NAC

has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. Most of the studies used oral NAC and were conducted on patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, chronic bronchitis and cystic fibrosis. In general, the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group

More on NAC safety:

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance.

Oral NAC supplementation for the purpose of preventing acetaminophen induced liver toxicity has yet to be the subject of a human study, but in an animal study it worked:

formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases [liver enzymes] increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP.

So this may serve to reduce the likelihood of Alzheimer's if you have to take acetaminophen.

NAC also improves the effectiveness of acetaminophen. So if a person must undertake ongoing treatment with acetaminophen, one should also consider taking NAC, which is available over the counter. In addition —

NAC itself is anti-inflammatory

For respiratory conditions:

NAC’s anti-inflammatory activity is noteworthy, ... In ex vivo models of COPD exacerbation, the anti-inflammatory effects have been observed even at very low doses, especially with prolonged treatment.... The unique combination of mucolytic, antioxidant, anti-infective, and anti-inflammatory properties positions NAC as a safe, cost-effective, and efficacious therapy for a plethora of respiratory conditions.

For prostatitis:

over the 12-week treatment, NAC+tamsulosin was statistically superior to placebo+tamsulosin in reducing the total NIH-CPSI score, pain subscore, and quality-of-life subscore (P value <.001). Further, after 12 weeks, more patients in the NAC+tamsulosin group than in the placebo+tamsulosin group met the responder criterion, defined as a decrease of at least 6 points in the NIH-CPSI total score (65.6% vs 29.0%). A more favorable outcome was also noted in the NAC+tamsulosin group regarding the number of patients reporting moderate or marked improvement in symptoms (62.5% vs 25.80%)

So, NAC alone may serve the purpose of pain relief instead of acetaminophen.

In addition, several compounds that have been found to be effective in relieving osteoarthritis pain are identified here.

This material cross posted, in part, here.

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