Approximately 5.8 million Americans are currently living with Alzheimer’s disease. According to the Alzheimer’s Association, this figure is projected to reach 14 million by 2050. The financial costs associated with this condition are estimated to be $290 billion in 2019 with a projected increase over the $1 trillion mark by 2050. Considering there is currently no known cure for Alzheimer’s disease (AD) and available treatments are highly ineffective, shifting focus to potential prevention or at the very least risk reduction may bear more fruit. Researchers are zeroing in on commonly used pharmaceutical drugs that may increase risk for AD with an eye toward deprescribing these in an effort to stem the tide on the coming AD tsunami.

Drugs developed to treat AD have been lackluster at best, with some of them actually making the disease progress faster. Each and every one of the much-touted and initially promising anti-amyloid drugs has been a disappointment. But those were drugs for patients who already have AD. What about drugs that might contribute to increased risk for AD in someone who does not yet have it?

A case-control study published recently in JAMA Internal Medicine identified associations between long-term use of powerful anticholinergic drugs and increased risk for dementia. The drugs noted in the study were anticholinergic antidepressants, drugs for Parkinson’s disease, antipsychotics, bladder antimuscarinics and anticonvulsant drugs. (A press release regarding a grant to study the deprescribing of these drugs noted that as many as half of older adults may be using an anticholinergic drug and many of them are using two or more.)

It’s not certain whether the association between anticholinergic use and increased risk for dementia implies a causal relationship. In order to get a better understanding of whether this is causal or only associative, researchers have proposed conducting a well-designed prospective randomized clinical trial for deprescribing these drugs. The trial design is summarized in a commentary on the case-control paper and calls for a follow-up period of 24 months to understand the long-term effects of deprescribing. (The authors note that short-term improvements in cognitive measures would be expected, so assessing longer anticholinergic-free periods would be needed to better understand the association between anticholinergic medications, AD and related dementias.)

Moving on from anticholinergic drugs, what about statins? Considering approximately 25% of the body’s cholesterol is in the brain, it would be surprising if the statin drugs that cross the blood-brain barrier didn’t have an impact on the structure and function of brain tissue and an ultimate influence on cognitive function. Randomized clinical trials concerning statins and cognition generally don’t find an association between statin use and impaired cognitive function but the US FDA considers the risk for statin-induced “cognitive side-effects” such as memory loss and confusion to be significant enough that a warning about these is now included on statin labels. In a safety communication, the FDA informs healthcare professionals of “rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use.” It’s noted that these cognitive symptoms “are generally not serious and reversible upon statin discontinuation,” but what happens when statins are not discontinued but instead are used for years and in some cases decades?

Antacids are another very commonly used class of drugs that may influence risk for dementia. Healthy cognitive function doesn’t happen in a vacuum. The brain requires B12, magnesium, iodine, zinc and other nutrients for proper function. Chronic, long-term use of acid-blocking or neutralizing drugs may impair the body’s ability to liberate and absorb these critical nutrients. Beyond this, lesser-known mechanisms exist—including effects of PPIs in the brain itself—to suggest long-term PPI use may increase risk for AD.

Research is mixed but evidence suggests an increased risk for dementia (including AD) among users of proton pump inhibitors compared to non-users. However, a 2019 systematic review and meta-analysis found no such association, a conclusion that was echoed in a different 2019 meta-analysis. Nevertheless, the authors of the latter noted an association between PPI use and “cognitive harm” and wrote, “…asserting that PPI avoidance may prevent dementia with a long follow-up period is appropriate.” Their conclusion, despite saying that “PPI use does not increase dementia and AD risk,” was to “recommend that physicians should regularly reconsider the appropriateness of treatment [with PPIs] if long-term treatment is required.” (For those with acid reflux or GERD who wish to avoid antacid drugs, low-carb diets may be an effective alternative.)

The crippling Alzheimer’s epidemic, which is on track to get even worse, demands that we gain a better understanding of how long-term use of commonly prescribed medications may be affecting cognitive function and risk for dementia. In many cases there may be alternative drugs available that come with less potential risk for adverse effects on the brain.