Counseling Points for Pharmacists on Brain Health Treatments

Clinical trials of a new experimental drug for Alzheimer disease have raised safety concerns making it more important for health care providers to set proper expectations for experimental drugs and OTC supplements for brain health.

Lecanemab

An experimental medication called lecanemab is the most recent development in the Alzheimer drug discovery process. Lecanemab created a lot of buzz and excitement in the Alzheimer disease community, as the drug met its primary and all of its secondary endpoints in clinical trials.¹

The primary endpoint was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes rating scale.¹ The secondary endpoints were the score on the 14 item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14), the Alzheimer’s Disease Composite Score (ADCOMS), the score on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and, most significantly, a change in amyloid burden on PET.¹

The secondary endpoint of a change in amyloid burden on PET was a significant finding of the study. Amyloid beta is a hallmark finding in the brains of persons with Alzheimer’s disease and may initiate or potentiate the disease.¹

At the same time, the reduction in brain amyloid burden produced significant toxicities.¹ One key toxicity of lecanemab was the Amyloid Related Imaging Abnormalities (ARIA).¹

These are brain imaging abnormalities that appear on MRI and are linked to the use of monoclonal antibodies targeting amyloid beta.² These imaging abnormalities can manifest as edema in the brain (ARIA-E) or hemorrhages in the brain (ARIA-H).² Both ARIA-E and ARIA-H were present with lecanemab treatment.¹ These adverse events are suspected to have caused 3 post-trial deaths to date.³

Neuriva

Neuriva is a common OTC supplement pharmacists recommend to support brain health. Neuriva Original is composed of 100 mg of coffee fruit extract (Coffea arabica) and 100 mg of phosphatidylserine.⁴

Neuriva Plus is composed of 200 mg of coffee fruit extract (Coffea arabica), 100 mg of phosphatidylserine, 1.7 mg of vitamin B6 (as pyridoxine hydrochloride), 680 mcg of dietary folate equivalents (400 mcg of folic acid), and 2.4 mcg of vitamin B12 (as cyanocobalamin).⁵ Neuriva may increase the levels of brain-derived neurotrophic factor (BDNF), enhance neuronal membrane function, and restore diminished acetylcholine neurotransmitter activity.⁷

There is some evidence to support the 2 main ingredients of Neuriva: coffee fruit extract and phosphatidylserine. In a trial of adults with mild cognitive decline, giving coffee fruit extract resulted in improved reaction time in the post-hoc analysis of the study.⁶

In a separate trial of adults with mild cognitive decline, phosphatidylserine may have produced an improvement in verbal recall delays in the post-hoc analysis of the study.⁸ As both of these findings occurred in the post-hoc analysis of each study, they were just observations of the studies outside of the pre-specified major outcomes.

In each study there were no statistically detectable differences in the pre-specified major outcomes that the authors had planned to find at the outset of the studies, therefore, the evidence is limited.

Prevagen

Prevagen is another commonly recommended product by pharmacists to support brain health. Prevagen is composed of vitamin D (as D3 cholecalciferol 50 mcg) and apoaequorin 10 mg (regular strength)⁹, 20 mg¹⁰, or 40 mg.¹¹ Prevagen works mainly through the active ingredient apoaequorin.

Apoaequorin is a calcium binding protein found in luminescent jellyfish (Aequorea victoria).¹² Calcium binding proteins have a role in the regulation of intracellular calcium homeostasis, which is a part of neuronal cell function.

A decline in intracellular calcium binding proteins and their dysregulated distribution in the central nervous system may contribute to cognitive decline, neuronal cell damage, and death associated with aging.¹³ The Madison Memory study was a randomized, double blinded, placebo-controlled trial that investigated the effects of Prevagen on cognitive performance in adults with self-reported cognitive concerns.¹⁴

The results showed that those with no cognitive impairment and those with very mild cognitive impairment showed statistically significant improvement in cognitive function compared with the placebo treatment group.¹⁴ However, the use of Prevagen in patients with anywhere from mild to severe levels of cognitive impairment remains inconclusive.¹⁴

One of the exclusion criteria of the trial was the history of significant neurological disease, dementia, or related memory impairment disorders, therefore the benefit of Prevagen in this patient population remains uncertain.¹⁴ Furthermore, those who reported some cognitive impairment in the study were tested, but were not found to show statistically significant improvement in cognitive function compared with the placebo treatment group.

In those with mild to moderate self-reported cognitive dysfunction, the benefit of Prevagen remains uncertain.¹⁴ There is also strong evidence to suggest that Prevagen does not survive digestion in the gut and there is evidence to suggest that Prevagen does not cross the blood brain barrier.^15,16

Which product should a pharmacist recommend?

Much of the difference in the recommendation between Neuriva and Prevagen will come to patient preference, which may be based on the formulation. Neuriva comes in capsules, gummies, and energy shots. Prevagen comes in capsules, chewables, and a protein shake formulation.

It should be noted that the indication plays a major role in which product can be recommended for which group of individuals. Prevagen can only be used in adults with no history of cognitive impairment. Neuriva can be used in individuals with or without cognitive impairment.

Pharmacists should also be aware to recommend the appropriate non pharmacological recommendations to support individuals with cognitive impairment, which include establishing a predictable routine and maintaining a consistent environment. It includes keeping requests and demands simple and avoiding complex tasks. In general, it helps to modify the patient’s environment so it's easy to understand. Large clocks, calendars, and signs on doors can help.

Finally, the Alzheimer disease patient’s denial should not be confronted.18 The pharmacist should remember that patient, family, and caregiver disease education is the most important with Alzheimer disease, and that the pharmacist plays a key role in this education. Even in individuals without cognitive impairment, the pharmacist can recommend interventions to support individuals’ cognitive health, namely regular physical and social activity.^19,20

References

1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. November 2022:1-13. doi:10.1056/nejmoa2212948

2. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurology. 2021;79(1):13-21. doi:10.1001/jamaneurol.2021.4161

3. Piller C. Scientists tie third clinical trial death to experimental Alzheimer’s drug. Science. https://www.science.org/content/article/scientists-tie-third-clinical-trial-death-experimental-alzheimer-s-drug. Published December 21, 2022. Accessed December 29, 2022.

4. Neuriva Original, Brain Health Supplement With Coffee Cherry Extract & Phosphatidylserine. Schiff Vitamins. https://www.schiffvitamins.com/collections/capsules/products/neuriva-original-brain-performance-clinically-proven-brain-supporting-supplement-with-natural-ingredients. Accessed December 28, 2022.

5. Neuriva Plus, Brain Health Supplement With Coffee Cherry Extract & Phosphatidylserine. Schiff Vitamins. https://www.schiffvitamins.com/collections/capsules/products/neuriva-plus-brain-performance-clinically-proven-brain-supporting-supplement-with-natural-ingredients. Accessed December 28, 2022.

6. Robinson JL, Hunter JM, Reyes-Izquierdo T, et al. Cognitive short- and long-term effects of coffee cherry extract in older adults with mild cognitive decline. Aging, Neuropsychology, and Cognition. 2020;27(6):918-934. doi:10.1080/13825585.2019.1702622

7. Jorissen BL, Brouns F, Van Boxtel MP, Riedel WJ. Safety of soy-derived phosphatidylserine in elderly people. Nutr Neurosci. 2002;5(5):337-343. doi:10.1080/1028415021000033802

8. Kato-Kataoka A, Sakai M, Ebina R, Nonaka C, Asano T, Miyamori T. Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints. J Clin Biochem Nutr. 2010;47(3):246-255. doi:10.3164/jcbn.10-62

9. Prevagen Regular Strength Capsules 10mg, 30count. Prevagen. https://prevagen.com/products/prevagen-regular-strength-brain-health-memory-supplements. Accessed December 28, 2022.

10. Prevagen Extra Strength Capsules 20mg, 30count. Prevagen. https://prevagen.com/products/prevagen-extra-strength-brain-health-memory-improvement-supplements. Accessed December 28, 2022.

11. Prevagen Professional Formula Capsules 40mg, 30count. Prevagen. https://prevagen.com/products/prevagen-professional-healthy-brain-function-supplements. Accessed December 28, 2022.

12. Apoaequorin. Alzheimer's Drug Discovery Foundation. https://www.alzdiscovery.org/cognitive-vitality/ratings/apoaequorin. Published June 13, 2016. Accessed December 28, 2022.

13. Brini M, Calì T, Ottolini D, Carafoli E. Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci. 2014;71(15):2787-2814. doi:10.1007/s00018-013-1550-7

14. Moran DL, Underwood MY, Gabourie TA, Lerner KC. Effects of a Supplement Containing Apoaequorin on Verbal Learning in Older Adults in the Community. Adv Mind Body Med. 2016;30(1):4-11.

15. Moran DL, Tetteh AO, Goodman RE, Underwood MY. Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli. Regul Toxicol Pharmacol. 2014;69(2):243-249. doi:10.1016/j.yrtph.2014.04.004

16. Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD, eds. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Philadelphia, PA: Lippincott-Raven; 1999.

17. Galvin JE, Roe CM, Powlishta KK, et al. The AD8: a brief informant interview to detect dementia. Neurology. 2005;65(4):559-564. doi:10.1212/01.wnl.0000172958.95282.2a

18. Spencer B, White L. Coping with Behavior Change in Dementia: A Family Caregiver's Guide. Ann Arbor, MI: Whisppub LLC; 2015.

19. Buchman AS, Yu L, Wilson RS, et al. Physical activity, common brain pathologies, and cognition in community-dwelling older adults. Neurology. 2019;92(8):e811-e822. doi:10.1212/WNL.0000000000006954

20. Cacioppo S, Grippo AJ, London S, Goossens L, Cacioppo JT. Loneliness: clinical import and interventions. Perspect Psychol Sci. 2015;10(2):238-249. doi:10.1177/1745691615570616