Original article

Dietary interventions in mild cognitive

impairment and dementia
George S. Vlachos, MD; Nikolaos Scarmeas, MD, PhD

Dietary intervention is an enticing approach in the fight against cognitive impairment. Nutritional supplements and
dietetic counseling are relatively easy and benign interventions, but research has not yet yielded irrefutable evidence
as to their clinical utility. Heterogeneity in the results of available clinical studies, as well as methodological and
practical issues, does not allow replication and generalization of findings. The paper at hand reviews only randomized
clinical trials of single nutrients, multi-nutrient formulations and dietary counseling in mild cognitive impairment
and dementia of the Alzheimer’s type focusing on both cognitive and functional outcomes. Thus far, folate, vitamin
E, Ω-3 fatty acids, and certain multi-nutrient formulations have shown some preliminary promising results; larger,
well-designed trials are needed to confirm these findings before nutritional elements can be incorporated in recom -
mended clinical guidelines.
© 2019, AICH – Servier Group Dialogues Clin Neurosci. 2019;21:69-82

Keywords:Alzheimer disease; controlled clinical trial; diet; mild cognitive impairment; nutrition; treatment

Introduction highly among such strategies and it has the added benefit
of being acceptable by the majority of the public as more
Dementia is almost always relentless, irreversible, and in- “benign” and potentially free of side effects.
capacitating for the patient, as well as having an equally
burdensome impact on the patient’s social surroundings. Nutritional preventive measures range from supplemen-
Dementia is projected to be a top public health, social, tation of the everyday diet with specific nutrients, to
and fiscal concern in the decades to come, as the posi- changes of dietary habits (ie, enrichment with or avoid-
tive effect of enhanced preventive strategies and public ance of certain food groups/beverages) to compliance
awareness may be offset by global population growth with whole dietary patterns. Evidence for the importance

Copyright © 2019 AICH – Servier Group. All rights reserved. www.dialogues-cns.org

– driven mainly by its increase in low-income countries – of nutrition in cognitive function as a lifelong modifiable
and by population aging in the “developed” world. factor arises from animal models, observational studies,
and clinical trials. Longitudinal studies account for the
Evolution of pharmaceutical treatments is costly and bulk of available data on the relationship between nutri-
requires extensive funding. Additionally, it has been tion and cognition, but they are commonly observational.
proven to be an extremely challenging task. In contrast, Additionally, many of them focus mostly on cognitively
prevention strategies are a lower-cost approach and can normal elderly adults, examining nutrition as a preven-
be implemented on a larger scale. Nutrition ranks very tive measure of future cognitive decline, with relatively

Author affiliations: 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Greece (George S.
Vlachos, Nikolaos Scarmeas); Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of
Neurology, Columbia University, New York, USA (Nikolaos Scarmeas). Address for correspondence: Associate Professor N. Scarmeas, Aiginition Hospital,
72 Vassilissis Sofias Avenue, 11528 Athens, Greece. (email: [email protected])

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Original article
Dietary interventions for cognitive impairment - Vlachos, Scarmeas

fewer investigating potential associations with progno- “herbal remedies,” or other supplements that are not part
sis in already cognitively impaired populations.1 Beyond of routine diet (eg, gingko biloba) were excluded.
observational studies, clinical trials of dietary interven-
tions as a treatment for cognitive impairment are scarce. Relevant literature was identified through the PubMed
However, they are instrumental in shaping the clinicians’ search engine in October 2018; the list of located papers
opinion on the potential of nutrition to be considered in is by no means exhaustive, even though every effort was
the therapeutic armamentarium. The paper at hand is an made toward that end. When the results of a specific trial
attempt to review and summarize selected high-level sci- were reported in more than one paper, we focused on the
entific evidence on the topic of dietary interventions to- seminal publication or the one discussing outcomes of a
wards combating established cognitive dysfunction. more clinical/neuropsychological nature.

Method Results

Literature on dietary treatment for neurodegenerative Scientific papers fulfilling the criteria outlined above are
disorders other than Alzheimer disease (AD) and its pro- presented in Tables Ia and Ib in detail. The earliest iden-
dromal stage, mild cognitive impairment (MCI), is quite tified papers date back as far as 1991, albeit in recent
limited. There is some evidence on the role of dietary in- years larger and better designed studies have emerged.
tervention in cognitive symptoms after stroke or coincid-
ing with diseases increasing vascular risk (eg, diabetes Almost all identified randomized controlled trials (RCTs)
mellitus), but the anticipated complex interplay between were double-blind and compared an intervention against
degenerative, inflammatory, and vascular mechanisms a placebo group; eighteen trials tested the therapeutic
might prevent any attempt to coalesce data into meaning- effect of nutrition on (usually mild-to-moderate) AD
ful conclusions. We therefore decided to focus on cogni- and ten on MCI. Diagnosis was established according to
tive impairment due to clinically suspected underlying various sets of international criteria, although in some
AD pathological changes. studies diagnostic methodology and baseline sample
characteristics are not clearly presented. About half of
A large part of published data in the field comes from ob- the studies involved a single micronutrient and the rest a
servational and retrospective studies; we opted to restrict micronutrient combination. We did not detect any RCTs
our search to controlled clinical trials reported in English, with the aforementioned characteristics on the effect of
with an initial sample of at least 50 subjects with MCI trace elements, vitamin D, coenzyme Q10, curcumin,
or AD and an intervention spanning at least 24 weeks in caffeine, olive oil, whole foods, food groups, or whole
duration, as neurodegenerative processes evolve slowly diets on cognitive impairment.
and nutritional treatment effects are expected to be low
in magnitude. In order to collect evidence with as high A summary of the main findings of the studies
practical value as possible, we encompassed only trials by intervention category
with clinical, neuropsychological, or functional end points
and not biochemical or neuroimaging changes, as cor- B vitamins
relation of such changes with everyday outcomes is often B vitamins are usually studied as a complex related main-
indistinct. No limit was imposed on publication year. ly to energy production in neurons and lowering of homo-
cysteine levels. The B-complex has been studied in MCI
We included in our search all types of intervention (eg, in- in two RCTs. A study from the United Kingdom reported
gestion of a certain nutrient/food as well as dietary coun- cognitive improvement mainly in those with high base-
seling/training and adherence to a certain diet). Nutrition- line homocysteine2; further analysis showed an interac-
al intervention as both single and “add-on” treatment was tion with baseline Ω-3 fatty acid plasma concentrations:
accepted. Only therapeutic attempts related to chemical only those with higher initial Ω-3 levels benefited from
compounds found in food were included, eg, vitamins, B vitamin supplementation.3 A Dutch study examined a
minerals, antioxidants as well as whole foods/food groups. possible effect in quality of life (QoL) and reported essen-

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tially no change.4 In AD there is one study in subjects with and Australia20 reported positive cognitive outcomes in
mild-to-moderate AD (and normal baseline vitamin B12 subjects with MCI. Two studies were conducted in mild
and folate levels) that did not find any effect5; oddly, de- to moderate AD: one Swedish study showed a small ben-
pression was more common in the active treatment group. efit only in the population with very mild cognitive dys-
function (slower decline)21; less agitation was reported in
Folate has been studied as a solitary intervention: cogni- APOE-ε4 carriers and a lower depression score in non-
tive improvement in general intelligence, attention span, APOE-ε4 carriers in the same study.22 Another study from
and visuospatial metrics within 6 months has been re- the United States reported improved cognitive metrics
ported in MCI6; two studies on patients with AD under only in non-APOE-ε4 carriers23 (APOE: apolipoprotein E).
acetyl-cholinesterase inhibitors (AChEI) reported either
an increase in Mini-Mental State Examination (MMSE) Phosphatidylserine
with no change in Activities of Daily Living (ADL)7 or Phosphatidylserine, a component of cell membranes, has
the exact opposite result regarding MMSE and ADL.8 been studied in two diverse populations: a somewhat
poorly designed study in people with at least moderate
Antioxidants cognitive decline24 reported cognitive benefits, while
Chemical compounds characterized as antioxidants are a another study in mild to moderate AD25 that evaluated
diverse group. Vitamins C and E were studied in a simple phosphatidylserine plus cognitive training as part of a
study in subjects with MCI for 1 year 9; no difference in multidomain intervention reported only transient cogni-
MMSE was noted. tive amelioration.

Vitamin E has been studied extensively. One study in AD Multi-nutrient formulations

concluded that vitamin E resulted in an MMSE increase in Two distinct multi-nutrient formulations have failed to
subjects who “responded” to it (ie, showed reduced gluta- yield positive cognitive effects: one trial enrolled sub-
thione oxidation – a marker of oxidative stress), but could jects that were normal or diagnosed with MCI 26 and an-
even be detrimental in “non-responders.”10 Vitamin E has other one patients with AD and normal baseline vitamin
also been studied against active comparators: in a large B12 and folate levels.27
study against donepezil for 3 years in subjects with am-
nestic MCI,11 time to progression to AD was not different Other relatively large studies examined the effect of a
in either treatment group compared with placebo, even patented formulation called Fortasyn Connect. In sub-
though vitamin E exerted a positive effect on language jects with MCI,28 no change in a composite neuropsy-
and overall cognition in the first half of the study period. chological score was proven; nonetheless subjects with
Two other large studies examined the effect of vitamin E higher baseline MMSE showed some clinical benefit in
on progression rate in AD against placebo and meman- the form of Clinical Dementia Rating (CDR) stabilization.
tine12 or selegiline13 for up to 4 years and showed slower One study in drug-naïve patients with mild AD showed im-
functional decline with focus on the ADL, even though no provement in a memory composite score29 persisting during
effect was observed on cognitive measures. an open-label, 24-week extension,30 while in patients with
mild-to-moderate AD under standard treatment no cog-
Other potential antioxidants studied in AD include soy nitive effect was shown.31 This formulation has also been
isoflavones14 (patients that metabolize them effectively shown to increase the body mass index (BMI) of patients
might show modest cognitive improvement), acetyl-L- with mild AD and improve everyday function in those with
carnitine15,16 (contradictory results) and resveratrol17 lower baseline BMI.32 The safety profile was favorable.
(no clinically meaningful benefit in secondary outcomes
related to cognition). Dietary counseling
One study aimed to identify functional and cognitive
Ω-3 fatty acids benefits of dietary counseling provided to AD patients’
Ω-3 fatty acids are credited with anti-inflammatory and physicians and caregivers and failed to show any change;
neuroprotective properties. Three studies from China18,19 nonetheless the risk of malnutrition was reduced.33

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PUBLICATION POPULATION INITIALLY DIAGNOSIS INTERVENTION DURATION INTERVENTION

RANDOMIZED (METHOD) (DAILY DOSAGE) OF INTER- (DAILY DOSAGE)
SAMPLE SIZE VENTION

Bo et al ≥60 yr (mean: 86 MCI according 480 mg DHA & 6 mo 480 mg DHA &
(2017)18 71 yr), Chinese, to the modified 720 mg EPA vs placebo 720 mg EPA vs placebo
community- Petersen criteria (550 mg oleic acid) (550mg oleic acid)
dwelling (MMSE, CDR, ADL)

Ma et al ≥65 yr, 180 MCI according Folic acid 400 μg vs conventional 6 moFolic acid 400 μg vs conven
(2016)6 Chinese, to the modified treatment treatment
community- Petersen criteria
dwelling (MMSE & ADL)

Zhang et al ≥65 yr, 240 MCI according DHA 2 g vs placebo 12 mo DHA 2 g vs placebo
(2017)19 Chinese, to the modified
community- Petersen criteria
dwelling (MMSE, ADL)

de Jager et al ≥70 yr, 271 MCI (TICS-M & Folic acid 0.8 mg, vitamin B6 20 mg Folic acid 0.8 mg, vitamin B6
2 yrs
(VITACOG, English category fluency ± & vitamin B12 0.5 mg vs placebo vitamin B12 0.5 mg vs pl
2011)2 MMSE, subjective
memory complaints
& ADL)

Sinn et al >65 yr, 50 MCI (MMSE, EPA 1.67 g & DHA 0.16 g vs 6 mo
EPA 1.67 g & DHA 0.16 g vs D
(2012)20 Australian, Verbal Paired DHA 1.55 g & EPA 0.40 g vs placebo g & EPA 0.40 g vs place
community- Associates Task)
dwelling

Soininen et al 50-86 yr (mean: 311 MCI (prodromal AD) 125 mL of Fortasyn Connect (DHA 24 125
mo ml of Fortasyn Connect (D
(LipiDiDiet, 71 yr), Finnish, according to the IWG-1 1200 mg, EPA 300 mg, uridine mono - (+12 mo
mg, EPA 300 mg, uridine m
2017)28 German, Dutch criteria phosphate 625 mg, choline 400 mg, optional
phate 625 mg, choline 400 mg
& Swedish, vitamins: B12 3 μg, B6 1 mg, C 80 mg double-blind
B12 3 μg, B6 1 mg, C 80 mg &
outpatients & E 40 mg, folic acid 400 μg, phospholi- extension)
folic acid 400 μg, phospholipid
pids 106 mg, selenium 60 μg) vs placebo selenium 60μg) vs place

Baleztena et al ≥75 yr 99 normal/MCI DHA 250 mg, EPA 40 mg, vitamin 1 yr DHA 250 mg, EPA 40 mg,
(2018)26 (mean: 86.9 yr), (MMSE & Global E 5 mg, phosphatidylserine 15 mg, E 5 mg, phosphatidylserine
Spanish, Deterioration Scale) tryptophan 95 mg, vitamin B12 5 μg, tryptophan 95 mg, vitamin B
institutionalized folate 250 μg & ginkgo biloba folate 250 μg & ginkgo bi
60 mg vs placebo 60mg vs. placebo

Naeini et al 60-75 yr, 256 MCI (MMSE) Vitamin E 300 mg & vitamin C 400 mg 1 Vitamin
yr E 300 mg & Vitamin
(2014)9 Iranian vs placebo vs placebo

Petersen et al 55-90 yr 769 amnestic MCI Vitamin E 2000 IU vs donepezil 10 mg 3 Vitamin

yrs E 2000IU vs donepezil
(ADCS, 2005)11 (mean: 72.9 yr), (delayed recall score, vs placebo; all groups additionally placebo; all groups additionally
US, CDR, MMSE) received vitamin E 15 IU vitamin E 15IU
outpatients

van Uffelen et al 70-80 yr 179 MCI according to For the vitamin intervention: 1 For
yr the vitamin intervention: fo
(2007)4 (mean: 75 yr), the Petersen criteria folic acid 5 mg, vitamin B12 0.4 mg, mg, vitamin B12 0.4 mg, vita
Dutch, (MMSE, TICS, WLT, vitamin B6 50 mg vs placebo mg vs placebo
community- Groningen Activity
dwelling Restriction Scale)

Table Ia. Randomized clinical trials on the therapeutic effect of dietary interventions on mild cognitive impairment (see abbreviations at end of Table).

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NTERVENTION MAIN OUTCOME TYPE OF RESULT POSITIVE/ OTHER FINDINGS/COMMENTS

AILY DOSAGE) (MOSTLY MAIN NEGATIVE
PRIMARY) OUTCOME STUDY

480 mg DHA & Differences in BCAT Cognitive Improvement in total BCAT + Olive oil as placebo. BCAT scores improved
mg EPA vs placebo scores, perceptual speed, in both groups; working memory not changed
550mg oleic acid) space imagery efficiency in females
& working memory

d 400 μg vs conventional Difference in Cognitive Improvement in Full Scale + Unblinded RCT

treatment IQ & WAIS-RC IQ, Digit Span & Block
scores Design

HA 2 g vs placebo Difference in Cognitive Greater increase in + Corn oil as placebo

WAIS-RC Full-Scale IQ, Information
& Digit Span scores

.8 mg, vitamin B6 20 mg &Changes in cognitive Cognitive & No effect for MMSE, ± In subjects with high baseline total
B12 0.5 mg vs placebo and clinical status functional HVLT-DR, category fluency homocysteine, improvement in all metrics
or CDR, IQCODE;
stabilization of CLOX
scores

& DHA 0.16 g vs DHA 1.55 Difference in GDS, Cognitive & Improvement in Initial Letter ± LA 2.2 g as placebo
EPA 0.40 g vs placebo QoL, cognition QoL Fluency in the DHA group
(focusing on memory & in GDS in both active
& executive function) treatment groups

ortasyn Connect (DHA 1200 Difference in Cognitive NS ± Reduced increase in CDR-SoB in the active
300 mg, uridine monophos - composite NTB treatment group; the effect was more pronounced
g, choline 400 mg, vitamins: score in those with higher baseline MMSE. The control
6 1 mg, C 80 mg & E 40 mg, group had slower cognitive decline than
0 μg, phospholipids 106mg, anticipated in this study
um 60μg) vs placebo

mg, EPA 40 mg, vitamin Difference in Cognitive NS − Improvement in memory subscale of MMSE
phosphatidylserine 15 mg, MMSE in well-nourished subjects
95 mg, vitamin B12 5 μg,
50 μg & ginkgo biloba
0mg vs. placebo

300 mg & Vitamin C 400 mg Difference in Cognitive NS −

vs placebo MMSE

000IU vs donepezil 10 mg vs Time to conversion Cognitive & NS for all time − Positive effect of vitamin E on the executive,
groups additionally received to AD (according to functional intervals language & overall cognitive scores for the first
vitamin E 15IU the NINCDS- 18mo (The risk of progression to AD was lower
ADRDA criteria) in the donepezil group than in the placebo group
in the first 12 mo; this effect was evident for the
whole 3 yr in APOE-ε4 carriers)

min intervention: folic acid 5Difference in D-QoL QoL NS − The same subjects were randomized to a parallel
n B12 0.4 mg, vitamin B6 50 & SF-12 scores exercise intervention. No cognitive outcomes.
mg vs placebo (overall & health- Baseline QoL scores above the general popu-
related QoL) lation average. Detrimental effect of vitamin
supplementation on D-QoL-belonging

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PUBLICATION POPULATION INITIALLY DIAGNOSIS INTERVENTION DURATION INTERVEN

RANDOMIZED (METHOD) (DAILY DOSAGE) OF INTER- (DAILY DOS
SAMPLE SIZE VENTION

Cenacchi et al 65-93 yr, Italian, 494 Moderate to severe Brain cortex-derived phosphatidylserine 6 mo 480 mg DH
(1993)24 inpatients & cognitive decline 300 mg vs placebo 720 mg EPA vs
institutionalized (MMSE, Global (550mg oleic
Deterioration Scale)

Dysken et al 53-96 yr 613 Mild to moderate AD Vitamin E 2000 IU vs memantine 20 mg 6 mo-4 yrs Folic acid 400 μg vs
(TEAM-AD VA, (mean: 78.8 yr), (MMSE) vs both vs placebo (mean: 2.27 yr)
2014)12 >95% male, US,
on AChEI

Sano et al Mean age 341 Moderate AD Selegiline 10 mg vs vitamin E 2000 IU 2 yrs DHA 2 g vs p
(ADCS, 1997)13 >72 yr, US, (CDR of 2) vs both vs placebo
outpatients

Scheltens et al ≥50 yr, Dutch, 259 Mild AD according to 125 ml of Fortasyn Connect 24 wks Folic acid 0.8 mg, vita
(Souvenir II, German, the NINCDS-ADRDA (as above) vs placebo vitamin B12 0.5 m
2012)29 Belgian, criteria (MMSE)
Spanish, Italian
& French,
drug-naïve

Spagnoli et al >40 yr 130 AD according to Acetyl-L-carnitine 2 g vs placebo 1 yr EPA 1.67 g & DHA 0.1
(1991)15 (mean: >74 yr), DSM-III (Organic Brain g & EPA 0.40 g
Italian Syndrome scale)

Chen et al >60 yr, Chinese, 162 AD (MMSE) Folic acid 1.25 mg vs placebo 6 mo 125 ml of Fortasyn Con
(TFA-AD, on donepezil phate 625 mg, choline 4
2016)7 5-10 mg

Connelly et al mean age 57 AD according to the Folic acid 1 mg vs placebo 6 mo DHA 250 mg, EPA 4
(2008)8 76.27 yr, NINCDS-ADRDA E 5 mg, phosphatidy
Scottish, criteria tryptophan 95 mg, vit
outpatients, folate 250 μg & gi
on AChEI 60mg vs. pl

Freund-Levi mean age 204 Mild to moderate AD DHA 1.72 g & EPA 0.6 g vs placebo for 6+6 mo Vitamin E 300 mg & V
et al 74 yr, Swedish, according to DSM-IV 6 mo, open-label extension for 6 mo
(OmegAD, outpatients, on (MMSE)
2006)21 AChEI

Gleason et al >60 yr 65 AD, mostly early Purified soy isoflavone glycosides 6 mo

(2015)14 (mean: 76.3 yr), 100 mg vs placebo
US, commu-
nity-dwelling,
on AChEI ±
memantine

Table 1b. Randomized clinical trials on the therapeutic effect of dietary interventions on Alzheimer disease (see abbreviations at end of Table).

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INTERVENTION MAIN OUTCOME TYPE OF RESULT POSITIVE/ OTHER FINDINGS/COMMENTS

(DAILY DOSAGE) (MOSTLY MAIN NEGATIVE
PRIMARY) OUTCOME STUDY

480 mg DHA & Differences in Plut- Cognitive & Improved motivation, + Corn oil as placebo. No adjustment
720 mg EPA vs placebo chik Geriatric Rating functional learning & retrieval for potential confounders. Very few AEs
(550mg oleic acid) Scale (behavior) and
the Buschke Selective
Reminding Test
(cognition)

olic acid 400 μg vs conventional Difference in Functional Subjects receiving vitamin E + Subjects receiving vitamin E showed a delay in
treatment ADCS-ADL had slower decline than ADL deterioration by 6.2 mo; caregiver time
those receiving placebo increased least in the vitamin E group compared
to the memantine group. No effect on secondary
cognitive measures

DHA 2 g vs placebo Time to the Cognitive & Delayed progression in all + Vitamin E delayed institutionalization;
occurrence of death, functional three active treatment groups improvement in IADL. No effect on cognitive
institutionalization, measures. Falls & syncope more frequent
loss of the ability in the active treatment groups
to perform basic ADL
or CDR of 3

c acid 0.8 mg, vitamin B6 20 mg Difference

& in Cognitive Increase of the score in the + Patients in the active treatment group
“trajectory of change”
vitamin B12 0.5 mg vs placebo active treatment group also received other vitamins, minerals,
of the memory trace elements & macronutrients.
function domain Positive safety profile
z-score of the NTB

1.67 g & DHA 0.16 g vs DHA 1.55Difference in Cognitive & Slower rate of deterioration + No major AEs
g & EPA 0.40 g vs placebo neuropsychological functional in the BDS
& clinical measures

ml of Fortasyn Connect (DHA 1200

Difference in MMSE Cognitive & Increase in MMSE, ± Single-blind RCT
625 mg, choline 400 mg, vitamins:
& ADL functional no difference in ADL

HA 250 mg, EPA 40 mg, vitamin Number of good Cognitive & Improvement in IADL ± Patients with a higher baseline DSST score
5 mg, phosphatidylserine 15responders
mg, per NICE functional & social behavior, responded better based on MMSE
ptophan 95 mg, vitamin B12(difference
5 μg, in MMSE, no difference in MMSE
folate 250 μg & ginkgo biloba behavioral &
60mg vs. placebo functional
assessments)

min E 300 mg & Vitamin CDifference

400 mg in MMSE Cognitive NS ± The active treatment & placebo included vitamin
vs placebo & ADAS-cog E 4 mg; placebo included LA 2.4 g. Reduction
was shown in the MMSE decline rate in subjects
with very mild cognitive dysfunction

Differences in Cognitive NS ± Treatment groups did not differ in

neuropsychological APOE-ε4 status or dietary intake of isoflavones.
battery scores APOE-ε4 genotype did not influence response.
focusing on memory Only effective metabolizers showed
& executive function improvement in verbal fluency
& speed dexterity

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PUBLICATION POPULATION INITIALLY DIAGNOSIS INTERVENTION DURATION INTERVEN

RANDOMIZED (METHOD) (DAILY DOSAGE) OF INTER- (DAILY DOS
SAMPLE SIZE VENTION

Lloret et al Spanish 57 AD according to the Vitamin E 800 IU vs placebo 6 mo Folic acid 400 μg vs
(2009)10 NINCDS-ADRDA
criteria

Aisen et al >50 yr 409 Mild to moderate AD Folate 5 mg, vitamin B6 25 mg & 18 mo DHA 2 g vs p
(ADCS, (mean: 76.3 yr), (MMSE) vitamin B12 1 mg vs placebo
2008)5 US,
outpatients

Heiss et al 48-79 yr, 80 Mild to moderate Social support vs cognitive training 6 mo vitamin B12 0.5 m
(1994)25 German, AD according to the vs cognitive training & pyritinol
outpatients NINCDS-ADRDA 1200 mg vs cognitive training &
criteria (MMSE) phosphatidylserine 400 mg

Quinn et al Mean age: 402 Mild to moderate AD DHA 2 g vs placebo 18 mo EPA 1.67 g & DHA 0.1
(ADCS, 76 yr, (MMSE) g & EPA 0.40 g
2010)23 US,
outpatients

Salva et al Mean age 946 Mild to moderate de- Teaching and training of physician 1 yr 125 ml of Fortasyn Con
(NutriAlz, >78 yr, mentia (AD) according and caregiver on health and nutrition mg, EPA 300 mg, uri
2011)33 Spanish, to DSM-IV (MMSE) vs usual care phate 625 mg, choline 4
outpatients

Shah et al ≥50 yr 527 Mild to moderate 125 ml of Fortasyn Connect 24 wks DHA 250 mg, EPA 4
(S-Connect, (mean: 76.7 yr), AD according to the (as above) vs placebo E 5 mg, phosphatidy
2013)31 US, commu- NINCDS-ADRDA tryptophan 95 mg, vit
nity-dwelling & criteria (MMSE) folate 250 μg & gi
outpatients, on 60mg vs. pl
stable doses of
AChEI and/or
memantine

Sun et al >50 yr 89 Mild to moderate Vitamins: B12 0.503 mg, B6 5 mg, 26 wks Vitamin E 300 mg & V
(2007)27 (mean: 75 yr), AD according to folic acid 1 mg, B3 10 mg, B2 2 mg,
Taiwanese, DSM-IV-TR B1 3 mg, B5 1 mg, C 100 μg, A 4000
outpatients, on (MMSE, CDR) IU & D3 400 IU, iron ferrous 60 mg,
AChEI, with calcium carbonate 250 mg,
normal serum iodine 100 μg, copper 150 μg vs placebo
levels of vitamin
B12 & folic acid

Table Ib. Randomized clinical trials on the therapeutic effect of dietary interventions on Alzheimer disease (see abbreviations at end of Table).

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INTERVENTION MAIN OUTCOME TYPE OF RESULT POSITIVE/ OTHER FINDINGS/COMMENTS

(DAILY DOSAGE) (MOSTLY MAIN NEGATIVE
PRIMARY) OUTCOME STUDY

olic acid 400 μg vs conventional Difference in Cognitive & Increased MMSE score ± No difference in other scores
treatment MMSE, BDS, functional in respondents vs non-
Clock Drawing Test respondents, reduced in
non-respondents vs placebo

DHA 2 g vs placebo Difference in Cognitive NS (incl. secondary − Adverse events involving depression more
ADAS-Cog outcomes measures) common in the active treatment group

vitamin B12 0.5 mg vs placebo Difference in Cognitive Transient positive effects − Unblinded RCT
MMSE & other at 8 wks, mainly in the
neuropsychological phosphatidylserine group
tool scores

Rate of change
1.67 g & DHA 0.16 g vs DHA 1.55 Cognitive & NS − Corn or soy oil as placebo. APOE-ε4 noncarriers
g & EPA 0.40 g vs placebo in ADAS-Cog & functional showed benefit in ADAS-Cog & MMSE scores
CDR-SoB

Difference in
ml of Fortasyn Connect (DHA 1200 Functional NS − Unblinded RCT. No difference in secondary
ADL-IADL
g, EPA 300 mg, uridine monophos- scores cognitive outcomes
625 mg, choline 400 mg, vitamins:

HA 250 mg, EPA 40 mg, vitamin Difference in Cognitive NS − Good safety & tolerability, high compliance
5 mg, phosphatidylserine 15 mg,ADAS-Cog to treatment
ptophan 95 mg, vitamin B12 5 μg,
folate 250 μg & ginkgo biloba
60mg vs. placebo

min E 300 mg & Vitamin C 400Difference

mg in Cognitive NS −
vs placebo ADAS-Cog (incl. secondary outcomes
measures)

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PUBLICATION POPULATION INITIALLY DIAGNOSIS INTERVENTION DURATION INTERVEN

RANDOMIZED (METHOD) (DAILY DOSAGE) OF INTER- (DAILY DOS
SAMPLE SIZE VENTION

Thal et al ≥50 yr, 431 Mild to moderate Acetyl-L-carnitine 3 g vs placebo 12 mo,

(1996)16 US, AD according to open-label
outpatients the NINCDS-ADRDA extension
and DSM-III-R criteria for 12 mo
(MMSE)

Turner et al >49 yr 119 Mild to moderate Resveratrol 500 mg to 2000 mg 52 wks

(ADCS, (mean: >69 yr), AD according to the vs placebo
2015)17 US NINCDS-ADRDA
criteria (MMSE)

Table Ib. Randomized clinical trials on the therapeutic effect of dietary interventions on Alzheimer disease.

Each publication is identified by its first author and year of publication; if it was part of a broader clinical program or is known by an
acronym they are also noted. The level of available information on the studied population differs; every effort was made to provide
a short, but meaningful delineation. All presented studies are double-blind RCTs, unless stated otherwise. When reported, the set
of criteria used to diagnose patients is presented, together with the main standardized neuropsychological tools that were used for
diagnostic classification (in parentheses). When the primary outcome of a trial was not clinical, neuropsychological, or functional, it
is omitted and clinical/neuropsychological/functional secondary outcomes are presented; the study is categorized as positive/inde-
terminate/negative (+/±/−) based on the main and secondary findings in the cognitive and functional domains.

AChEI: Acetyl-cholinEsterase inhibitor, AD: Alzheimer disease, ADAS-Cog: Alzheimer’s Disease Assessment Scale-cognitive
subscale, ADCS: Alzheimer’s Disease Cooperative Study, ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of
Daily Living, ADL: Activities of Daily Living, AE: Adverse Event, APOE: Apolipoprotein E, BCAT: Basic Cognitive Apti-
tude Tests, BDS: Blessed Dementia Scale, CDR: Clinical Dementia Rating, CDR-SoB: Clinical Dementia Rating-Sum of Boxes,
CLOX: Clock Drawing Task, DHA: Docosohexanoic acid, D-QoL: Dementia Quality of Life, DSM: Diagnostic and Statistical
Manual of Mental Disorders, DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, third edition-Revision, DSM-
IV-TR: Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision, DSST: Digit Symbol Substitution
Test, EPA: Eicosapentaenoic acid, GDS: Geriatric Depression Scale, HVLT-DR: Hopkins Verbal Learning Test revised-Delayed
Recall, IADL: Instrumental Activities of Daily Living, IQ: Intelligence quotient, IQCODE:Informant Questionnaire on Cog-
nitive Decline in the Elderly, LA: Linoleic acid, MCI: Mild Cognitive Impairment, MMSE: Mini-Mental State Examination,
NICE: National Institute of Clinical Excellence, NINCDS-ADRDA: National Institute of Neurological and Communicative Dis-
orders and Stroke – Alzheimer’s Disease and Related Disorders Association, NPI: NeuroPsychiatric Inventory, NS: Non-signifi-
cant, NTB: Neuropsychological Test Battery, QoL: Quality of life, RCT: Randomized controlled trial, SF-12: 12-Item Short Form
health survey, TICS: Telephone Interview for Cognitive Status, TICS-M: Telephone Interview for Cognitive Status-Modified,
US: United States, WAIS-RC: Wechsler Adult Intelligence Scale-Revised Chinese, WLT: Word Learning Test.

Discussion appear to be the best nutritional candidates for further in-

vestigation of potential efficacy in MCI or mild AD. The
Given the body of evidence briefly delineated above, no verdict is still open, as in many cases similar studies result
firm guidance or even recommendation can be offered in inconsistent results or a newer study does not replicate
about any of the proposed dietary interventions for cogni- the findings of a previous one. The complex and –to a
tive dysfunction. Indeed, several high-quality systematic certain extent– unclear, still debatable pathophysiologi-
reviews and meta-analyses found no or insufficient evi- cal mechanisms of cognitive dysfunction in AD may be
dence of benefit.34-44 Be that as it may, folate, vitamin E, among the main reasons for conflicting results. There are
Ω-3 fatty acids, and certain multi-nutrient formulations also multiple methodological and practical issues possibly

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 Original article
Dietary interventions for cognitive impairment - Vlachos, Scarmeas

INTERVENTION MAIN OUTCOME TYPE OF RESULT POSITIVE/ OTHER FINDINGS/COMMENTS

(DAILY DOSAGE) (MOSTLY MAIN NEGATIVE
PRIMARY) OUTCOME STUDY

Difference in Cognitive & NS −

ADAS-Cog & functional
CDR-SoB

Difference in Cognitive & NS (except less decline in −

MMSE, ADAS-Cog, functional ADCS-ADL)
ADCS-ADL, NPI,
CDR-SoB

preventing ascertainment of small treatment effects and analyses. Moreover, in some studies with relatively short
generalization of findings. follow-up periods and consequently frequent visits, appar-
ent stabilization in neuropsychological scores might be
A main observation involves the significant differences in the result of a learning effect that keeps differences under
diagnostic methodology, set or version of diagnostic crite- the statistical significance threshold. Various cognitive
ria used, and dementia stage classification across studies. assessment tools and functional scales were used as out-
In virtually all cases, diagnosis and staging were mostly come measures; some of them may have not been sensitive
clinical, with limited use of objective AD neuroimaging/ enough to detect small changes of mental/functional ca-
neurochemical biomarkers. Heterogeneous (community- pacity or QoL in the population with mildly affected cog-
dwelling elderly, memory clinic outpatients, participants nition. Daily variation of cognition is probably larger than
in day care programs, residents of institutions, etc) and nutritional treatment effects, thereby potentially rendering
ethnically diverse populations were studied. These issues cognitive tests insensitive to them.
hinder generalization of findings.
Studying patients with overt dementia may prevent un-
Regarding study design, we noted generally small sample veiling of the beneficial effect of a nutrient, as the neu-
sizes and perhaps not long enough duration of the inter- ropathologic process may already have been so advanced
ventions, sometimes accompanied by high dropout rates. that all available intervention may be futile. Despite that,
Neurodegeneration evolves very slowly, so treatment ef- positive results were not more common in studies on MCI
fects can be expected to be modest at best; large samples than on AD, highlighting perhaps the utility of applying
and sufficient follow-up are needed to ascertain clinically our intervention at an even more prodromal stage of neu-
and statistically important differences (to place findings rodegeneration, if possible.
from this literature in perspective, many novel drug trials
in this population exceed a sample size of 2000 partici- Great variability was noted in supplement dosage and du-
pants and, in several cases, last for as long as 2 years).45 In ration of administration; different chemical compounds
some trials, biochemical, neurochemical, or neuroimaging were often used for a certain vitamin. Furthermore, results
parameters were selected as primary outcomes; such trials may have been confounded by previous dietary habits or
may not be adequately powered to reveal subtle differenc- concurrent intake of the studied nutrient in food. In some
es that may exist in secondary cognitive and functional studies, olive/corn oil were used as placebo, although they
outcomes, which we consider more relevant in everyday contain unsaturated fatty acids that may exert positive
clinical practice. To further complicate matters, some of effects on cognition.46 In certain Western countries, folic
the findings we report here were derived from post hoc acid fortification programs may complicate detection of a

DIALOGUES IN CLINICAL NEUROSCIENCE • Vol 21 • No. 1 • 2019 • 79

Original article
Dietary interventions for cognitive impairment - Vlachos, Scarmeas

relationship between folate status and cognitive impair- olfaction, eating difficulty, and inadequate nutrition due to
ment. Also, most studies do not report baseline vitamin cognitive impairment itself. Conversely, it is possible that
levels, which may influence the effect of supplemented vi- weight loss might also be a potential risk factor for devel-
tamins on cognition, ie, deficient individuals might show oping AD, via, for example, a deficiency of biologically
greater benefit. Moreover, in many studies, data on con- important micronutrients and antioxidative compounds.
comitant use of drugs commonly prescribed for AD were Body weight changes before and after dementia diagnosis
not provided. These issues, in addition to the omnipresent highlight the importance of acknowledging the full inter-
risk of publication bias (which is com- play between nutrition and cognitive
monly more of a concern for studies function; in fact, nutrition is just one of
of relatively smaller size and power),
As single nutrients many potentially modifiable determi -
make interpretation of the results much may not be potent nants of future cognitive decline.
harder. enough to produce Indeed, recently, interest in more ho-
It seems reasonable to expect that clinically significant listic approaches has increased; mul-
multi-nutrient formulations may be benefits, perhaps future tidomain interventions attempt to im-
more potent; conversely, multi-nutrient pact many lifestyle aspects that have
or whole-diet interventions do not al- research should steer been hypothesized to benefit cogni-
low identification of the specific action toward multi-nutrient, tion. Such interventions encompass not
of each component with a possibility
of unidentified synergistic, neutral,
whole-diet and multi- only nutritional guidance for a healthy
diet, but also coaching on modification
or even antagonistic effects between domain interventions of other important factors (eg, phys-
them. Theoretically, such interventions ical activity), cognitive training, and
might be easier and less expensive, as control of cardiovascular risk. Some of
they do not entail any manufacturing costs, but only ad- the large multidomain interventions (preDIVA,52 MAPT,53
vice/counseling and close follow-up of the subjects’ com- and FINGER54) may have included some subjects who
pliance. It should be noted, though, that RCTs (with the could be categorized into MCI; nevertheless, they most-
characteristics we specified in “Methods”) studying whole ly focused on prevention, which is out of scope for this
foods or diets as treatment for cognitive impairment have manuscript. In the future such approaches in patients with
not been identified; perhaps the scientific community opts MCI or dementia may yield significant results.
for simpler, straightforward experimental designs or the
practical difficulties of implementing such a trial in the As single nutrients may not be potent enough to produce
elderly population with cognitive dysfunction are hard statistically and–more importantly–clinically significant
to overcome. Nonetheless, the existing body of evidence benefits, perhaps future research should steer toward
for the potential preventive benefits of the Mediterranean multi-nutrient, whole-diet, and multidomain interventions
diet, in particular, against cognitive impairment in normal in even larger, homogeneous, community-dwelling sam-
cohorts is substantial; data originating from both RCTs ples with as early disease stages as possible; strict diag-
[PREDIMED (on subjects at high cardiovascular risk)]47 nostic criteria, sufficient follow-up, and consensus on the
and observational studies48-50 show reduction in the rate use of specific functional outcomes could enhance com-
and risk of cognitive decline. More data are certainly need- parison of different trials and improve our understand-
ed in MCI and AD, but until then patients and caregivers ing on the role of diet as a treatment option for cognitive
can be encouraged to follow the Mediterranean diet. impairment. Recent technological breakthroughs might
become invaluable aids to such research, as sensors on
Evidence shows that the BMI decreases prior to AD onset portable hand-held/wearable devices and social me-
and remains stable or increases afterwards.51 Reasons for dia-embedded applications could assist in recording
weight loss in the preclinical stage of AD comprise patho- dietary habits and even collection of biomarkers. Innova-
logical changes in brain areas that regulate weight, disrup- tive techniques, such as metabolomics and cerebrospinal
tion in hormone and neuropeptide levels, apathy, reduced fluid neurobiology, or investigation of novel aspects of

80 • DIALOGUES IN CLINICAL NEUROSCIENCE • Vol 21 • No. 1 • 2019

Original article
Dietary interventions for cognitive impairment - Vlachos, Scarmeas

nutrition (including hydration status and chronobiology ranted. Thus far, folate, vitamin E, Ω-3 fatty acids, and
of food intake) may further unravel hidden associations certain multi-nutrient formulations have shown some
between nutrition and cognitive dysfunction. initial promise; larger, well-designed trials with robust
methodology may hopefully corroborate some of these
Conclusions findings.

Nutrition is an important lifestyle factor related to Disclosure/Acknowledgements: Prof Scarmeas received

cognitive impairment. Clinical studies of the poten- a fee for a single advisory board meeting from Merck
tial utility of dietary intervention in ameliorating mild Consumer Health. Dr Vlachos has no conflict of interest
cognitive impairment and dementia are certainly war- to declare.

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