New Perspectives
A Brief Review of Three Common
Supplements Used in Alzheimer’s
Disease
Justin Spence, Monica Chintapenta, Hyanggi Irene Kwon,
Amie Taggart Blaszczyk
Individuals with Alzheimer’s disease (AD) and their caregivers
are using supplements in an effort to halt the progression of
the disease. Individuals at risk for or fearing Alzheimer’s may
use these supplements to try to prevent the disease. Senior care
pharmacists are accessible and uniquely qualified to answer
questions, make recommendations, and attempt to make
drug therapy safe and effective for these individuals. With this
in mind, it is important to know the data supporting (or not
supporting) common supplements marketed toward those with
AD. A review of efficacy and safety data, drug interactions,
as well as the mechanism of action believed to benefit those
with AD of three common supplements (Prevagen, Cerefolin
NAC, and the omega-3 polyunsaturated fatty acid DHA), are
highlighted.
KEY WORDS: Alzheimer’s disease, Supplement.
ABBREVIATIONS: AD = Alzheimer’s disease, DHA =
Docosahexaenoic acid, DR = Delayed recall, ISL = CogState
International Shopping List, ISL-DR = CogState ISL-Delayed
Recall, NAC = N-acetylcysteine, PUFA = Polyunsaturated
omega-3 fatty acid.
Consult Pharm 2017;32:412-4.
412 THE CONSULTANT PHARMACIST   JULY 2017   VOL. 32, NO. 7
Introduction
The financial and psychological burden of Alzheimer’s
disease (AD) is immense.1 It is not surprising that patients
and caregivers of those affected seek out alternative
therapies. The number of older adults using supplements
continues to increase.2 Senior care pharmacists must
remain up to date on the science supporting common
supplements used for enhancing cognitive and functional
outcomes in AD. We sought to review the evidence of a
few common supplements used for AD.
Prevagen
The main ingredient in Prevagen, apoaequorin, is
claimed to give the supplement its cognition-enhancing
action.3 Apoaequorin is a photoprotein naturally found
in bioluminescent jellyfish and a variety of other marine
organisms. Its perceived benefit is believed to be in its
calcium-binding ability. Dysregulation of calcium has
been implicated in the initiation and progression of AD.4
A study in rats reported neuroprotective properties of
apoaequorin from ischemic insults when directly infused
into hippocampal regions of the brain prior to oxygen and
glucose deprivation.5
All studies of the Prevagen commercial product have
been funded by the manufacturer and not published in a
peer-reviewed journal. A 90-day, randomized, placebo-
controlled, double-blind trial looked at 10 mg of daily
apoaequorin. The study was designed to assess the
effects of apoaequorin on verbal learning and working
memory using the computerized CogState International
Shopping List (ISL) and the CogState ISL-Delayed Recall
(ISL-DR) to study Prevagen’s effects on cognition.3 The
results indicated a statistically significant improvement
in verbal learning and recall on the ISL and the ISL-DR,
respectively, in the intervention group. It should be noted
that individuals with significant neurological disease,
dementia, or related memory-impairment disorders, or
an untreated psychotic or major depressive disorder, were
excluded. The study was small, of short duration, and
ultimately didn’t include people with AD, so its utility in
this population is not yet known.
The manufacturer of Prevagen states the product has
undergone extensive safety testing typical for any dietary
 Review of Supplements Used in Alzheimer’s Disease
supplement, noting the most common postmarketing
adverse effects reported were: headaches, dizziness,
nausea, hypertension, diarrhea, memory impairment,
insomnia, anxiety, and stomach pain.6 No known drug-
drug or drug-food interactions are noted at this time.7
Cerefolin NAC
Cerefolin NAC is a medical food containing a
multivitamin formulation (methylcobalamine [Vitamin
B12], L-methylfolate) and N-acetylcysteine (NAC). It
has received Food and Drug Administration approval
for the treatment or prevention of vitamin deficiencies
associated with memory loss. Cerefolin NAC targets the
pathophysiology of increased homocysteine levels and
oxidative stress in AD. Some literature suggests elevated
homocysteine levels are associated with amyloid and
glutamate neurotoxicity, and hippocampal neuronal loss
in mice.8 It is also designed to assist in prevention and/
or treatment of B12 and/or folate deficiency, which can
contribute to memory issues.
Most literature available doesn’t focus on the
commercial combination product, but rather the
component parts separately. Literature studying the use
of folate and B vitamins in cognitive impairment suggests
the impact of supplementation depends on baseline
homocysteine levels. In the Folic acid and Carotid Intima-
Media Thickness trial, a secondary outcome focused on
improvement in cognitive performance.9 Patients with
a homocysteine level of 13 mcmol/L or greater (normal
range: 6-15 mcmol/L) received 800 mcg of folic acid daily
for three years. The secondary outcome analysis observed
that supplementation led to minor improvement in
cognition compared with placebo. Another randomized,
double-blind, controlled, two-group parallel-design
study compared high-dose B-vitamin supplements and
folate versus placebo in patients with mild-to-moderate
AD. 8 This 18-month study observed a reduction in
homocysteine levels in the treatment group versus
the placebo. However, the reduction did not translate
to a beneficial effect in cognition.8 In addition, other
systematic reviews of supplementation with both folic
acid and B vitamins have shown slightly worse cognitive
performance or no effect.9 It is thought within AD, NAC
THE CONSULTANT PHARMACIST   JULY 2017   VOL. 32, NO. 7
can down-regulate the transcription of the amyloid
precursor protein gene, reducing the levels of the protein
and the resultant oxidative stress.10 Unlike folic acid and
B vitamins, there are few data supporting NAC in AD.
However, one six-month trial of NAC in late-stage AD
demonstrated significant improvements in performance
measured by the Letter Fluency Task and the Wechsler
Memory Scale Immediate Number Recall.10 A trial listed
on www.clinicaltrials.gov investigated Cerefolin NAC’s
impact on homocysteine, oxidative stress, and beta-
amyloid; however, the results have not been published.
Adverse effects expected with this product derive
from the individual components, which consist mostly
of gastrointestinal (GI) complaints. Drug interactions
are also associated with the individual ingredients. It
is noted that nitroglycerin and chloramphenicol have
documented major interactions with the NAC portion of
the product, and concomitant use should be avoided.7 At
this time, evidence only supports high-dose B-vitamin
supplementation in AD patients who have low vitamin
levels. While supplementing patients with low folate and/
or B12 levels is recommended to avoid cognitive issues,
it is currently unclear whether any real clinical benefit is
derived from Cerefolin NAC.
Omega-3 Fatty Acid—
Docosahexaenoic Acid
Several epidemiological studies have identified a
beneficial association between the consumption of fish,
a large source of omega-3 fatty acids, with possible
improvements in memory in patients with dementia
and reduced risk of cognitive decline in individuals
initially unaffected by AD.11-13 Docosahexaenoic acid
(DHA) is a type of polyunsaturated omega-3 fatty acid
(PUFA). Its benefit is believed to be from a reduction
in plasma beta-amyloid levels and triglycerides, as well
as decreased inflammatory markers. In a randomized,
double-blind, placebo-controlled trial, DHA, dosed at
1 g twice daily, failed to slow the rate of cognitive and
functional decline in patients with mild-to-moderate
AD measured through ADAS-cog score and Clinical
Dementia Rating.11 However, an exploratory analysis, as
well as epidemiological studies, found clinical benefits
413
New Perspectives
and protective effects in APOE(-) individuals.11,14 A recent
Cochrane review found no evidence of efficacy and had
inconclusive results regarding the tolerability of omega-3
PUFAs in patients with mild-to-moderate AD.12
Common side effects associated with omega-3 fatty
acid supplements are GI disturbances, fishy aftertaste,
clinical bleeding, worsening glycemia, and increase in
low-density lipoprotein cholesterol, which all appear to be
dose-dependent.7 Patients taking omega-3 fish oil who are
receiving antiplatelet or anticoagulant medications should
be monitored closely for signs of bleeding.
Conclusion
Meaningful evidence is lacking for these supplements
commonly used by people with AD. Pharmacists should
continue to monitor the literature supporting these
interventions, given their popularity and acceptance
among those with AD, and those seeking to prevent the
disease.2 However, at this time, there is no definitive
evidence to make any of these supplements a “must have”
addition to the AD patient’s regimen.
At the time of this writing Justin Spence was a 2017 PharmD
candidate, Texas Tech University Health Sciences Center School of
Pharmacy-Dallas/Fort Worth, Dallas, Texas. Monica Chintapenta
was a 2017 PharmD candidate, Texas Tech University Health
Sciences Center School of Pharmacy-Dallas/Fort Worth. Hyanggi
Irene Kwon was a 2017 PharmD candidate, Texas Tech University
Health Sciences Center School of Pharmacy-Dallas/Fort Worth.
Amie Taggart Blaszczyk, PharmD, BCGP, BCPS, FASCP, was
associate professor & division head-Geriatrics, Texas Tech University
Health Sciences Center School of Pharmacy-Dallas/Fort Worth.
For correspondence: Amie Taggart Blaszczyk, PharmD, BCGP,
BCPS, FASCP, Geriatrics, Texas Tech University Health Sciences
Center School of Pharmacy-Dallas/Fort Worth, 5920 Forest Park
Road #500, Dallas, TX 75235; Phone: 214-358-9023; Fax: 214-372-
5020; E-mail: amie.blaszczyk@ttuhsc.edu.
Disclosure: No funding was received for the development of this
manuscript. The authors have no potential conflicts of interest.
© 2017 American Society of Consultant Pharmacists, Inc.
All rights reserved.
Doi:10.4140/TCP.n.2017.412.
414 THE CONSULTANT PHARMACIST   JULY 2017   VOL. 32, NO. 7
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