The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 1 • April 2015


Cumulative Use of Strong Anticholinergics May Be Associated with An Increased Risk of DEMENTIA

A new paper1 just published in JAMA INTERN MED reports that, among a cohort population of 3434 men and women aged 65 or older with no signs of dementia at the start of the study, during a mean followup of 7.3 years, higher cumulative use of anticholinergic drugs was associated with an increased risk of DEMENTIA. Anticholinergic drugs are used as, for example, antispasmodics for the gastrointestinal tract, antimuscarinics for the bladder (“overactive bladder”) and antiparkinsonians. The paper notes that the use of anticholinergics in older adults ranges from 8% to 37%.

During the 7.3 years of mean followup, 797 participants (23.2%) developed dementia, with 637 of these reported to develop Alzheimer’s disease. There was a 10 year cumulative dose-response relationship observed for both dementia and Alzheimer’s disease, that is, the higher the cumulative dose used during that period, the greater the likelihood of developing dementia and Alzheimer’s disease.

Though this was an association, not proof of cause and effect, it is important to keep in mind that Alzheimer’s disease and dementia are both positively linked to dysfunction in the cholinergic nervous system in the brain. Hence, this association is likely (but not proven) to be a causative one.

Use It Or Lose It

The relationship between the cholinergic nervous system in the brain and cognitive aging has been a hot research subject for at least the past 40 years.2 In an important 1974 paper,2 for example, the authors say: “The cognitive and memory disturbances occurring with aging may reflect some relatively specific disorder of cholinergic neurotransmitter function — such as impaired synthesis, release or receptor iuptake of acetylcholine — that is largely reproduced by pharmacologic cholinergic blockade.” The paper2 itself was a test of anticholinergic drugs in young subjects and showed memory/cognitive impairment. The authors conclude that their data “raise the interesting association between cholinergic blockade and the mental deterioration of aging, however, and suggest the need for further study of the integrity of the cholinergic pharmacosystem in the elderly.”

Declining Ability of the Older Brain to Transport Choline Across the Blood-Brain Barrier

We have written extensively about the markedly decreasing ability of the human brain, as it ages, to import choline across the blood-brain-barrier into the brain from the general circulation. [See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the March 2004 issue.]

Moreover, in the explanatory material in the paper,1 the authors note that, while “the general view is that anticholinergic-induced cognitive impairment is reversible on discontinuation of medication therapy,” “several investigators have reported that anticholinergics may be associated with an increased risk for sustained cognitive deficits, such as mild cognitive impairment or dementia.” The authors suggest that a plausible biological mechanism for these findings is that “cumulative use of these agents results in pathologic changes in the brain similar to those observed with Alzheimer’s disease (AD).”

All of the first generation and many of the second generation antihistamines have anticholinergic effects, though not the third generation. One way to tell is if the antihistamine you use causes your mouth to become dry, it likely has anticholinergic activity.


  1. Gray, Anderson, Dublin, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 175(3):401 – 7 (2015).
  2. David A. Drachman, Janet Leavitt. Human memory and the cholinergic system. Arch Neurol. 30:113 – 21 (Feb. 1974).

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