Alzheimer Disease Prevention: Part 2

In this highly anticipated sequel to his 2022 blog entitled "Alzheimer Disease Prevention," Marc Agronin, MD, geriatric psychiatry section editor at Psych Congress Network, offers deeper expert clinical insights on Alzheimer disease prevention.

In part 1 of Alzheimer Disease Prevention, I discussed the growing interest in identifying and modifying major risk factors through a brain-healthy lifestyle. In part 2, I will explore a more detailed analysis of several risk factors and preventive strategies involving supplements and medications that clinicians might want to integrate into clinical discussions with patients and overall practice. Many of the items discussed here have found their way into the news, social media, and advertising, either because they are touted as brain-boosting formulas, or they are associated with fears about the excessive risk of getting dementia. As a result of all this media attention, these items are often more well-known than standard practices.

Supplements and Brain Tonics

There are myriad supplements and formulas being sold over-the-counter with supposed benefits for brain function, and roughly one-quarter of adults in the United States take 1 of these, accounting for an astonishing $5.8 billion industry.¹ Producers of these nootropic (i.e., brain healthy) substances generally claim that they improve general brain health, “mental sharpness” or “focus” (among many similarly descriptive terms), or various elements of cognitive function (e.g., working memory, processing speed) based on relatively small studies with limited effect sizes. Some of the main ingredients in many of these supplements, alone or in combination, include ginkgo biloba, ginseng, bacopa monnieri, curcumin, omega-3 fatty acids, phosphatidylserine, acetyl-l-carnitine, huperzine A, B vitamins (e.g., B1, B2, B3, B6, B6, and B12), various amino acids (e.g., l-glutamine, l-tyrosine, l-theanine), alpha lipoic acid, DMAE (dimethylaminoethanol bitartrate), choline formulas (e.g., CDP-choline, alpha-GPC), guarana (which contains caffeine), apoaequorin (originally derived from jellyfish), cocoa extract and multivitamins—to name just a few!

Hands down, the best series of scientific summaries for these and all other potentially brain-saving medications and supplements can be found in the Cognitive Vitality Reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation.² Each report details scientific data (or its absence) for each agent in terms of potential efficacy and safety. Another great source is a report by the AARP-sponsored Global Council on Brain Health.³ Both sources contain sobering reports in contrast to the hype for many of the supposed brain-healthy formulas, indicating that many of them are digested in the gut and never reach the brain.

Although most of the supplements have very limited efficacy data, there are some with promising research pointing to minor benefits for select cognitive skills. For example, the COSMOS-Mind study was a randomized controlled trial of over 2000 cognitively normal older individuals comparing a daily dose of cocoa extract (with 500 mg of flavanols) and a multivitamin with minerals versus placebo.⁴  Cocoa extract had no effect on cognition, while those on the multivitamin with minerals had a modest benefit in terms of global cognition, including memory and executive function.

Another example is bacopa monnieri, an herb-derived substance used in Ayurvedic medicine. It is touted to improve cognition and longevity and have anti-inflammatory and antioxidant properties. One systematic review of 6 studies found that 3 months of taking bacopa was generally safe and was associated with some benefit in memory recall, but in no other cognitive domains.⁵  Some supplements, such as huperzine A and choline, are aimed at improving cholinergic or glutamate function and hence cognition, although this goal can be accomplished more effectively with FDA-approved agents already shown to do that in individuals already diagnosed with Alzheimer disease. Despite the many studies of all these supposed brain-boosting agents, none of them have evidence to support their role in delaying or averting the onset of Alzheimer disease or any other form of dementia. None of them have undergone any rigorous government review, and there are potential side effects that cannot be ignored.

Exposure to Metals

There has long been concern that certain toxic metal exposure could cause Alzheimer disease, including aluminum (from cooking utensils, soda cans, antiperspirants, or antacids), lead (from old lead-based paint residue), mercury (from dental amalgams or the vaccine preservative thimerosal), cadmium (from smoking) and other heavy metals.^{6, 7} Exposure to toxic levels of these metals is known to cause acute and chronic neurologic symptoms, including neurocognitive changes. However, such exposures are generally rare and often specific to certain jobs (e.g., being a bauxite miner) and have not been shown to be associated with Alzheimer disease in the average person. Part of the concern about aluminum, in particular, comes from studies showing that it may be involved in the pathophysiology of cerebral beta-amyloid and phosphorylated tau deposits in Alzheimer disease.⁸ This concern is coupled with the fact that aluminum is one of the most abundant metals on earth—found in the air, water, and food supply. The only potential association found in large studies has been slightly increased risks for dementia with higher levels of aluminum in drinking water.⁹ There is no evidence, however, indicating an increased risk of Alzheimer disease from eating or drinking from aluminum cans or cooking utensils, using antiperspirants, or ingesting antacids containing aluminum salts. ^{10, 11}

Exposure to Medications

Recent studies have raised concerns about an increased risk of Alzheimer disease from 3 commonly used medication groups: proton pump inhibitors (PPIs), benzodiazepines (BZs), and antihistamines. It is particularly important for clinicians to be aware of patient concerns and know the actual data since many doctors and patients may restrict the use of necessary medications due to unfounded concerns. Initial concern about PPIs stemmed from a retrospective analysis of medical diagnoses in a large number of individuals in an insurance claims database that found 1.5 times increase in dementia diagnoses in those taking PPIs.¹² The limitation of that and similar studies is the lack of any causality attached to PPIs as well as the large number of potentially confounding factors, especially concomitant medication use. In one large prospective clinical trial called the ASPirin in Reducing Events in the Elderly or ASPREE trial, initially designed to assess the effects of low-dose aspirin versus placebo in nearly 20,000 Australian and American subjects 65 years and older, researchers conducted a post-hoc observational study looking at any potential association between PPI or histamine-2 receptor antagonist (H2RA) use and annual cognitive assessment results over 5 years.¹³ They found no association between PPI or H2RA use and cognitive decline, cognitive impairment without dementia, or incident dementia.¹² A separate large systematic review and meta-analysis also found no association between PPIs and dementia across 11 studies.¹⁴

Benzodiazepines are widely used by older individuals for anxiety and insomnia, and although they are generally safe and effective when used in low doses for short periods of time, they do carry with them risks for acute oversedation, cognitive impairment, and increased falls. For these and other potential risks, benzodiazepines are listed in the Beer’s Criteria put out by the American Geriatrics Society as medications to minimize or avoid in aging individuals.¹⁵ Long-term use is more problematic given the additive risk of side effects, potential for addiction, and a reported concern for more enduring cognitive impairment including a higher risk for Alzheimer disease. There are 2 studies of particular concern. One meta-analysis of 6 studies found a 1.5 times elevated risk of Alzheimer disease in individuals using benzodiazepines, which increased with higher doses.¹⁶ Another systematic review of 10 studies found a 1.24 to 2.3 times increased risk of dementia with benzodiazepine use longer than 3 months, with the higher rates associated with longer-term use, greater cumulative dosing, and longer-acting benzodiazepines.¹⁷ More extensive research has continued to highlight the risks of benzodiazepine use for those with and without Alzheimer disease, although the verdict is not perfectly settled. Benzodiazepine use, in general, should be done judiciously and only when truly clinically indicated for as short duration as possible in those without cognitive impairment and avoided as much as possible in those already diagnosed.

Antihistamines are another commonly used class of medications in older individuals, with diphenhydramine being the most popular. Diphenhydramine is a histamine 1 receptor antagonist used for allergic reactions and is a main component in many over-the-counter sleeping pills due to its sedating properties. It also has anticholinergic effects, which help to amplify its acute side effects of sedation, fogginess, and memory loss. Short-term use is clearly associated with cognitive toxicity in certain individuals and is problematic in those with pre-existing cognitive impairment.¹⁸ The concern with longer-term use of diphenhydramine stems from general research showing an association between anticholinergic medications and increased dementia risk. One prospective population-based cohort study looked at cumulative anticholinergic exposure over ten years, which included diphenhydramine as one agent of several, and found an increased risk of dementia associated with increased total daily dosing. ¹⁹ Diphenhydramine thus has a double whammy, given the concerns about cognitive toxicity from short-term use and increased dementia risk from long-term use. In contrast, second generation antihistamines (e.g., loratadine, cetirizine and fexofenadine) have not been associated with any of the short- and long-term problems seen with diphenhydramine. ²⁰

The above risk factors and prevention methods are summarized in Table 1.

Table 1 — Guide to Mitigating Risk and Boosting Alzheimer Prevention with Respect to Supplements and Medications

Marc Agronin, MD, is a geriatric psychiatrist and the Chief Medical Officer of the Frank C. and Lynn Scaduto MIND Institute at Miami Jewish Health, Miami FL.  

References

1. Roe AL, Venkataraman A. The safety and efficacy of botanicals with nootropic effects. Curr Neuropharmacol. 2021;19(9):1442-1467.

2. Cognitive Vitality. Reports: For Researchers. Accessed: June 20, 2024.
3. Global Council on Brain Health: The Real Deal on Brain Health Supplements: GCBH Recommendations on Vitamins, Minerals, and Other Dietary Supplements. 2019. Accessed June 20, 2024.

4. Baker LD, Manson JE, Rapp SR, et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimers Dement. 2023 Apr;19(4):1308-1319.

5. Pase MP, Kean J, Sarris J, et al.: The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials. J Altern Complement Med. 2012 Jul;18(7):647-52.

6. Babić LM, Langer HL, Španić PE, et al. Metals in Alzheimer disease. Biomedicines. 2023 Apr 12;11(4):1161. 

7. Xu L, Zhang W, Liu X, et al. Circulatory levels of toxic metals (aluminum, cadmium, mercury, lead) in patients with Alzheimer disease: a quantitative meta-analysis and systematic review. J Alzheimers Dis. 2018;62(1):361-372.

8. Mold MJ, O’Farrell A, Morris B, Exley C. Aluminum and neurofibrillary tangle co-localization in familial Alzheimer disease and related neurological disorders. J Alzheimers Dis. 2020, 78, 139.

9. Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic review. BMC Geriatr. 2016 Oct 12;16(1):175.

10. Virk SA, Eslick GD. Brief report: meta-analysis of antacid use and Alzheimer disease: implications for the aluminum hypothesis. Epidemiology. 2015; 26, 769-773.

11. Hara Y. Is there a link between aluminum and Alzheimer?. Cognitive Vitality blogs, 2018 March 12. Accessed June 20, 2024.

12. Gomm W, von Holt K, Thomé F, et al: Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73:410–416.

13. Mehta RS, Kochar B, Zhou Z, et al. Association of proton pump inhibitor use with incident dementia and cognitive decline in older adults: a prospective cohort study. Gastroenterology. 2023 Sep;165(3):564-572.e1. 

14. Khan MA, Yuan Y, Iqbal U, et al. No association linking short-term proton pump inhibitor use to dementia: systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2020;115:671–678.

15. By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023 Jul;71(7):2052-2081. 

16. Zhong G, Wang Y, Zhang Y, Zhao Y. Association between benzodiazepine use and dementia: a meta-analysis. PLoS One. 2015 May 27;10(5):e0127836. 

17. Billioti de Gage S, Pariente A, Bégaud B: Is there really a link between benzodiazepine use and the risk of dementia? Expert Opin Drug Saf. 2015 May;14(5):733-47.

18. Basu R, Dodge H, Stoehr GP, Ganguli M: Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition. Am J Geriatr Psychiatry. 2003 Mar-Apr;11(2):205-13.

19. Gray SL, Anderson ML, Dublin S, et al.: Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015 Mar;175(3):401-7.

20. Banerji A, Long AA, Camargo CA Jr: Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review. Allergy Asthma Proc. 2007 Jul-Aug;28(4):418-26.