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White Paper and References Evidence of Associations and Treatment

Recommendations for Genes Analyzed by the

Mindful DNA™ Test.

April 2018


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Table of Contents

(Click on title name to hyperlink to location within document)

Purpose of Document

Categories of Evidence Strength and Definition

Evidence Summaries for Health Impact Claims

ABCA7: ATP-Binding Cassette A7 Protein

ACE: Angiotensin I Converting Enzyme

AKT1: Serine/Threonine Protein Kinase (Protein Kinase B)

ANK3: Ankyrin G

ApoE: Apolipoprotein

BDNF: Brain Derived Neurotrophic Factor

BNP: Brain Natriuretic Peptide

CACNA1C: Cav1.2 Voltage-Dependent L-Type Calcium Channel, α1C Subunit

CD33: Siglec-3, Compliment of Differentiation 33

CHRNA5/3: Cholinergic Receptor Nicotinic Alpha 5, Alpha 3 Subunits

CLOCK: Circadian Locomotor Output Cycles Kaput

COMT: Catechol-O-Methyltransferase

CRHR1: Corticotropin-Releasing Hormone Receptor

CRP: C Reactive Protein

FKBP5: FK506-Binding Protein 5

FTO: Alpha-Ketoglutarate-Dependent Dioxygenase

FUT2: Fucosyltransferase 2

HDAC9: Histone Deacetylase 9

HLA-DQ2.2/4/2.5/8: Major Histocompatibility Complex, Class II, DQ2 and 8

HLA-DQB1: Major Histocompatibility Complex, Class II, DQ Beta 1

IL6: Interleukin 6

LRP1: Low Density Lipoprotein Receptor-Related Protein 1

LRRK2: Leucine Rich Repeat Kinase 2

MC4R: Melanocortin 4 Receptor

MEIS1: Meis Homeobox 1

miR-181: miR-181 MicroRNA Precursor

MTHFR: 5,10 Methylenetetrahydrofolate Reductase

OXTR: Oxytocin Receptor

PCSK9: Proprotein Convertase, Subtilisin/Kexin-Type 9

PPARG: Peroxisome Proliferator-Activated Receptor Gamma

SMARCA4: Catalytic Subunit of the SWI/SNF Chromatin-Remodeling Complex

TREM2: Triggering Receptor Expressed on Monocytes 2


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Evidence Summaries for Key Recommendations

Agmatine

Ashwagandha

Berberine

Bright Light Therapy

Caffeine

Carotenoids

Coenzyme Q10 (CoQ10)

Curcumin

DASH Diet

Exercise and Caloric Restriction

Ferrous Sulfate

Hypertension Management to Reduce the Risk of Dementia

Lithium

L-Methylfolate (5-MTHF)

Magnesium

Mediterranean Diet

Melatonin

Memory and Learning is Modulated by High-Fat, High-Sugar Diet

Mindfulness & Meditation

N-Acetyl-Cysteine (NAC)

Neurofeedback: Quantitative Electroencephalography (qEEG)

Nicotine Replacement Therapy (NRT)

Omega-3 Poly-Unsaturated Fatty Acids (ω-3 PUFA)

Oxytocin

OXTR GG Genotype Greater Response to Social Support

Palmitoylethanolamide (PEA)

Petasite hybridus (butterbur)

Physical Activity Benefits Cognition and Mood

Polysomnography (PSG) & Actigraphy

Prebiotics

Probiotics

Quercetin and Epigallocatechin Gallate (EGCG)

Sodium Butyrate

Vitamin D

Domain Recommendations

COGNITION & MENTAL ACUITY

CARDIOMETABOLIC

GI & IMMUNE

STRESS & EMOTIONAL WELLBEING

INFLAMMATION

SLEEP

References


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Purpose and Intended Use of the Mindful DNA™ White Paper and References

The following is a summary of the key published literature relevant to a variety of genetic variations

analyzed by Mindful DNA. The purpose of this document is to summarize the available information.

Individual patients vary and this information is not intended to replace the clinician’s responsibilities in

clinical decision making.

Categories of Evidence Strength and Definition

The strength of evidence supporting the purported health impacts or mechanisms for each

polymorphism or haplotype (set of polymorphisms) may vary. The strength of the evidence is

categorized numerically 1-4, with 4 indicating stronger evidence for the association reported in Mindful

DNA.

Evidence level category descriptions:

Evidence category Minimum requirements for category

Evidence level 1 Preliminary evidence in at least 1 clinical study published in a peer-reviewed publication in good standing with the scientific community.

No compelling contradictory evidence.

Evidence level 2 Evidence in at least 2 clinical studies published in a peer-reviewed publication in good standing with the scientific community.


Evidence level 3 Evidence in at least 2 clinical studies published in a peer-reviewed publication in good standing with the scientific community.

Well established biological plausibility.*

No compelling contradictory evidence. -OR-

At least 1 large GWASⱡ study or meta-analysis with significant

association in addition to at least one additional clinical study (if GWAS) supporting the association, but without a well-established biological plausibility.

Evidence level 4 At least 1 large GWAS study or meta-analysis with significant association.

At least 1 additional clinical trial (if GWAS).

Well established biological plausibility.*


*Biological plausibility: The mechanism by which the genetic variant confers a health impact correlates

with the function of the expressed protein. Example: Angiotensin converting enzyme (ACE) is involved

in hemostasis and has a mechanism which acts to increase blood pressure. Thus, a genetic variant

which is associated with increased blood pressure and hypertension would have good biological

plausibility.

ⱡGWAS: Genome wide association study.


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Evidence Summaries for Health Impact Claims

ATP-Binding Cassette A7 Protein (ABCA7)

ABCA7 encodes ATP-binding cassette A7 protein. In the brain, ABCA7 is highly expressed in hippocampal

CA1 neurons and microglial cells.4,7 ABCA7 is thought to play a role in Alzheimer’s disease (AD) through

three primary means. First, ABCA7 contributes to efflux of phospholipids and cholesterol, which is

hypothesized to be related to AD pathogenesis through amyloid β related pathways. Second, ABCA7

plays a major role in regulating phagocytosis of apoptotic cell debris. It is highly expressed in microglial

cells in which ABCA7 knockdown leads to ineffective engulfment of apoptotic debris.7 Finally, ABCA7

may be directly involved in amyloid β homeostasis. Meta-analyses have confirmed that the G allele of

the ABCA7 variant tested in Mindful DNA is associated with an approximate 17-20% increased likelihood

of developing AD with one risk allele (C/G).1,11 This variant demonstrates extremely robust associations

with AD, including associations with underlying neuropathology (e.g. neuritic plaque burden and

neurofibrillary tangles), as well as subsyndromal predictors of AD such as mild cognitive

impairment.2,3,5,6,8-10

Evidence Level 4

Angiotensin I Converting Enzyme (ACE)

The angiotensin I-converting enzyme, encoded by ACE, plays a role in the production of angiotensin II

(vasoconstrictor) and the catabolism of bradykinin and kallidin (vasodilators). The ACE enzyme is a key

component of the renin-angiotensin system, a major pathway and therapeutic target involved in the

pathogenesis of hypertension and cardiovascular disease.13 The much studied ACE (Ins/Del)

polymorphism confers increased ACE activity, and has been consistently linked to increased risk of

cardiovascular disease12-21 and metabolic syndrome.22,26 The ACE G2350A variant on the Mindful DNA

test is a well-validated surrogate marker for ACE (Ins/Del).23-25

Evidence Level 4

Serine/Threonine Protein Kinase (Protein Kinase B) (AKT1)

This gene encodes one of three isoforms of protein kinase B (PKB). PKB participates in the signaling of

multiple g-protein coupled receptors, including dopamine signaling, such that decreased AKT function

results in an increased DRD receptor stimulation.27 Cannabinoids interact with AKT1, 29,30 and AKT1

variants have been associated with development of psychotic symptoms in habitual marijuana users.31

The C/C genotype has been associated with a twofold increase in risk of psychotic symptom

development in cannabis users.28 While the AKT1 gene shows a relatively robust association with

psychotic symptoms in cannabis users, all studies focused on patients who reported cannabis use prior

to developing symptoms.

Evidence level 2 (CC genotype)


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Ankyrin G (ANK3) ANK3 belongs to a family of scaffolding proteins known as the ankyrins and plays a role in the

maintenance of sodium ion channels.41 A variation in this gene, the T allele, can potentially lead to

abnormal clustering of sodium channels and dysfunction in action potential firing.41 Genome wide

association studies (GWAS) have shown a correlation between this variation and disorders characterized

by mood instability and lability.32-35,39,40,42,43 Many studies indicate that this variant is associated with

changes in anatomical connections that may be related to cognitive and affective symptoms.35-38,44 More

specifically, this variation has been associated with anhedonia, altered novelty seeking, impaired

threat/stress signal processing, diminished cognition, working memory, and reduced integrity of white

matter tracts.34,36,38,45

Evidence level 4

Apolipoprotein (ApoE)

Apolipoprotein (ApoE) is a multifunctional protein with central roles in lipid metabolism, neurobiology,

and neurodegenerative diseases.48 It has three major isoforms (ε2, ε3, and ε4) with different effects

on lipid and neuronal homeostasis. The ε2 allele is the rarest form of APOE and carrying even one copy

appears to reduce the risk of developing Alzheimer's by up to 40% (resilience).46,52 ε3 is the most

common allele and doesn't seem to influence risk. The ε4 allele, present in approximately 10-15% of

people, increases the risk for Alzheimer's and lowers the age of onset. Having one copy of ε4 (ε3/ ε4)

can increase risk by 2 to 3 times while two copies (ε4/ ε4) can increase the risk by approximately 12 to

15 fold.47,49-51 However, like all variants on Mindful DNA, this is not deterministic. Up to 50% of

individuals with two ε4 alleles (high risk) have been observed to survive to age 80 without having

developed Alzheimer's disease.53,54

Evidence level 4

Brain Derived Neurotrophic Factor (BDNF)

BDNF regulates neuronal differentiation, migration, survival, and synaptic plasticity.67 Expressed in the prefrontal cortex (PFC) and hippocampus, BDNF has been implicated to play in role in etiology of several psychiatric disorders and the biology of learning and memory.61 It has been shown to influence synaptic plasticity by modulating hippocampal long-term potentiation.67 The Val66Met polymorphism is associated with reduced BDNF secretion, depression, and altered stress reactivity.55-59 Several studies indicate that physical activity may improve cognition and working memory in Met allele carriers and may be implemented as therapy, if clinically indicated.60,62-66 Evidence level 4

Brain Natriuretic Peptide (BNP)

BNP, encoded by NPPB, plays a role in regulation of circulatory volume, plasma renin-aldosterone concentrations, natriuresis, and maintenance of blood pressure. Elevated serum BNP levels stimulate natriuresis and diuresis as well as promoting peripheral vasodilation. Plasma BNP and NT-proBNP levels are used as biomarkers to aid in the diagnosis and prognosis of heart failure.75 Studies have repeatedly shown that the T381C polymorphism is associated with significantly increased expression of BNP.69-71,76


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Individuals with this polymorphism may benefit from this increased expression as it is associated with decreased blood pressure and decreased risk of hypertension,73,75 type 2 diabetes,68,72,74 and cardiovascular disease.70,77 Seidelmann et al. further showed that the C/C genotype resulted in lower rates of all-cause mortality and cardiovascular death in a 23-year follow up of 11,361 subjects.75

Evidence level 4

Cav1.2 Voltage-Dependent L-Type Calcium Channel, α1C Subunit (CACNA1C) CACNA1C is important in the regulation of calcium signaling; it encodes for an alpha-1 subunit of a voltage dependent calcium ion channel.78 ,79 Several GWAS have identified a variant in this gene, the A allele, to be associated with conditions related to mood instability and lability.80-88 Some studies noted disruptions in cognition among bipolar or schizophrenic patients as a function of rs1006737 status.93-95 Variations in this gene may lead to ion channel dysfunction, resulting in a prolongation of the period during which the pore remains open, leading to increased excitatory signaling.78,82 It has also been reported that this variant is associated with changes in amygdala volume,92 frontal‐hippocampal function,86,91 and this variant also has been hypothesized to be related to glutamate signaling.90 Evidence level 4

Siglec-3, Compliment of Differentiation 33 (CD33)

CD33 encodes a transmembrane glycoprotein that is expressed on the surface of microglia and is an

essential regulator of cell activity. Microglial cells are found in one of two states; monophagocytic or

neuroinflamatory. The monophagocytic state increases microglial clearance of amyloid and other

debris, whereas the neuroinflamatory state leads to oxidative stress and neuronal damage. CD33 can be

thought of as an “off switch” for the monophagocytic state.96 The A allele (resilient allele) of the CD33

variant on the Mindful DNA test confers reduced surface expression of CD33. Thus, ratio of

monophagocytic to neuroinflamatory microglial cells will be higher, with increased clearance of amyloid

and decreased risk of Alzheimer’s disease. The CA substitution confers an approximate 10% reduced

risk of developing late onset Alzheimer’s disease, as reported across multiple studies and recent met-

analyses.97-101

Evidence level 4

Cholinergic Receptor Nicotinic Alpha 5, Alpha 3 Subunits (CHRNA5/3)

Nicotine selectively binds to nicotinic acetylcholine receptors (nAChRs), partially encoded by CHRNA5

and CHRNA3, which opens an ion channel exerting its physiological effects. The receptors activate

neurons in the dopaminergic reward pathway and can facilitate nicotine dependence and addiction with

chronic exposure.102 Studies have shown that the functional variant at rs16969968 (D398N) is associated

with reduced receptor function.103 The A allele at rs16969968 has been shown to be associated with an

increased risk for nicotine dependence.104 Two other variants, rs578776 and rs588765, have been shown

to effect the mRNA expression levels of CHRNA5.105 The combined effect of the three variants may alter

the risk for nicotine dependence and smoking habits.106 Further, individuals at an increased risk that are

homozygous for the risk allele may have a higher chance of relapsing following smoking cessation.


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These individuals are more likely to reverse the risk of relapse using nicotine replacement therapy.107 An

opposing effect has been shown for the minor allele (A) at rs578776, where the variant is associated

with protection against nicotine dependence.108 Depending on the mRNA expression levels of

CHRNA5/3, which is influenced, in part, by the rs588765 allele, the overall risk for nicotine dependence

can be further increased.105 Saccone et al. confirmed the associations of nicotine dependence in a

meta-analysis of 34 studies involving current and former smokers (N=24,807).106

Evidence level 4

Circadian Locomotor Output Cycles Kaput (CLOCK)

CLOCK is one of the core genes involved in the “molecular clock,” governing circadian rhythm in the

body. CLOCK encodes the CLOCK transcription factor which is involved in a transcriptional/translational

feedback loop encompassing multiple genes that work to regulate circadian activity across a number of

biological functions including energy balance and metabolism. CLOCK variants have been associated

with obesity and eating behavior traits.109 The T3111C variant confers increased expression,110,111 as well

as an increased risk of obesity and metabolic syndrome.112-116 In some studies, the C allele was also

associated with diurnal preference and emotional eating behavior, both of which are postulated to play

a role in the observed increased risk of metabolic syndrome.117-120 Of note, the association between the

T3111C polymorphism and metabolic syndrome has not been observed in children or those with

comorbid cardiovascular disease, possibly due to confounding variables in these populations.121,122

Evidence level 3

Catechol-O-Methyltransferase (COMT)

COMT is an enzyme responsible for breakdown of dopamine in the frontal lobes of the brain,123 which is

critical for memory, attention, judgement, and other executive functions.127 The Val66Met variant

results in varying capacity of the enzyme to degrade dopamine.123,128 The Met allele results in reduced

enzymatic activity, while the Val allele results in increased activity.123,128,133 Patients who have normal

levels of dopamine degradation possess one increased and one decreased function allele (Val/Met).

Patients with the Val/Val genotype display elevated enzyme activity and increased dopamine

degradation; conversely, patients with the Met/Met genotype display reduced enzyme activity and

decreased dopamine degradation. Clinical studies have shown that the Val/Val genotype may have

negative influence regarding cognitive function, memory, retention, motivation, and judgement.123-126

Studies have shown that individuals with the Met/Met genotype may perform better on cognitive tasks,

including working memory and reward-learning,129-132 but may also be at increased risk of cognitive

perseveration, PTSD, OCD (in men), and addictive behavior.134-138

Evidence level 3

Corticotropin-Releasing Hormone Receptor (CRHR1)

CRHR1 encodes for the corticotropin-releasing hormone (CRH) receptor, which contributes to the HPA-

axis modulation of neuroendocrine and behavioral responses to stress. CRHR1 is essential for the

activation of signal transduction pathways that activate mesolimbic and hypothalamic-pituitary axis


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(HPA) responses to many types of stress.141 Whereas CRHR1 helps establish the initial HPA axis response

to a stressful episode, the FKBP5 protein assists in terminating the stress response.140,142 The exact

mechanism by which the CRHR1 variant, analyzed by Mindful DNA, impacts stress response is not fully

understood. However, the G allele is associated with significantly increased cortisol in response to

stress,140,142 poor working memory,139,144 and increased rates of adult depression in the context of child-

hood trauma or maltreatment.143,145

Evidence level 3

C Reactive Protein (CRP)

CRP encodes for C-reactive protein, an acute phase reactant that is produced in response to

inflammation and tissue damage, and is a predictor of cardiovascular disease.147-149 To clarify whether

CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various

genetic CRP variants. Although CRP was associated with risk, those with a high CRP due to genetic

variation (including the variant analyzed by Mindful DNA) had no increased risk of cardiovascular disease

(CVD) compared to those with a normal or low CRP.150 This spurred two large meta-analyses which

confirmed that polymorphisms that cause an increase in serum CRP are not associated with increased

risk of CVD.146,151 Thus, although the T allele of the CRP variant is consistently associated with increased

serum CRP levels,146,152,153 this does not necessarily confer the risks normally associated with elevated

CRP. Interpretation of serum CRP levels should be made with the foreknowledge that T carriers may

have elevated baseline levels in excess of normal parameters that may not be associated with

cardiovascular or inflammatory pathology.

Evidence level 4

FK506-Binding Protein 5 (FKBP5)

Stress response is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA triggers release of cortisol from the adrenal cortex that enters the bloodstream to act on target organs, thereby facilitating the “Fight or Flight” response.161,164,165 This process is tightly regulated by a negative feedback loop involving glucocorticoid receptors (GR). FKBP5 is a negative regulator of GR function, and changes in FKBP5 expression can have significant effects on HPA function.156,158-160 The T allele of the FKBP5 variant on the Mindful DNA test confers increased expression of the protein and dysregulated cortisol response to stress. This has been shown to potentiate the risk of depression, disassociation, and posttraumatic stress disorder following traumatic experiences such as injury or childhood trauma.154,155,157,162,163,166 Evidence level 4

Alpha-Ketoglutarate-Dependent Dioxygenase (FTO)

The FTO gene encodes an alpha-ketoglutarate-dependent dioxygenase, which is responsible for

methylation of amino acid and RNA nucleosides.167 It is unclear why variants in this gene result in

increased rates of metabolic syndrome, yet the TA variant analyzed by Mindful DNA maintains one of

the most robust and significant genetic links with metabolic syndrome yet discovered, with the largest

analysis showing a 0.39 kg/m2 change in BMI per copy of the A allele (p = 4.8x10-120)174 This finding has


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been replicated across multiple populations. Additional evidence links the A allele with increased risk of

metabolic syndrome, including increased risk of obesity, type 2 diabetes, and cardiovascular disease,

possibly modulated by decreased satiety168-177

Evidence level 4

Fucosyltransferase 2 (FUT2) FUT2 encodes fucosyltransferase 2 that has been shown to affect the composition of intestinal microbiota due to the addition of an important fucose moiety to luminal surface receptors allowing bacterial attachment and growth.184,185 Multiple studies have linked the two polymorphisms analyzed by Mindful DNA (rs1047781 AT and rs601338 GA) with “non-secretor” status, meaning the variant confers altered fucosyltransferase activity. The non-secretor genotype confers altered vitamin B12 absorption and increased risk of Crohn’s disease,179-181 primary sclerosing cholangitis,178,183 celiac disease and inflammatory bowel disease.182 This is likely due to dysregulation of gut microbiota, as evidenced by several studies showing lower diversity of beneficial gut bacteria in non-secretors compared to secretors.183,186-188 Evidence level 3 (rs1047781) Evidence level 4 (rs601338)

Histone Deacetylase 9 (HDAC9)

HDAC9 is a member of a large family of genes that encodes proteins responsible for deacetylation of histones and, therefore, is involved in the epigenetic modification and transcriptional regulation of DNA. It inhibits myogenesis and is involved in cardiomyocyte and vascular smooth muscle cell development.192 The CT variant analyzed by Mindful DNA results in the thickening of the carotid intima-media, which is an independent predictor of stroke.191,194 Accordingly, the T allele is associated with an increased risk of stroke and coronary artery disease across multiple large studies and meta-analyses.189,190,193,195-197 Evidence level 4

Major Histocompatibility Complex, Class II, DQ2 and 8 (HLA-DQ2.2/4/2.5/8)

Celiac disease is an immune-mediated, gluten-induced disorder that presents primarily with

gastrointestinal symptoms, but may also lead to systemic complications.198 Celiac disease has a well-

established profile of diagnostic biomarkers and a genetic basis.199 The human leukocyte antigen (HLA)

haplotypes DQ2 and DQ8 (HLA-DQ2 and HLA-DQ8, respectively) are necessary for the development of

celiac disease, although not all individuals positive for DQ2 and DQ8 develop the disease.200 These

haplotypes refer to a set of HLA variants that encode heterodimers of major histocompatibility complex

(MHC) class II T cell antigens.201 Variants tend to occur in the antigen-binding site of these proteins. The

DQ2 and DQ8 haplotypes are key to binding gluten and mediating the immune response, allowing the

development of celiac disease.199 One of the earliest studies to suggest the association of specific HLA-

DQ heterodimers with celiac disease found that 90-95% of celiac patients carried the DQ2.5

haplotype.202 Mindful DNA utilizes “tagging SNPs”, that is, polymorphisms which predict the presence or

absence of the HLA phenotypes (DQ2.2, DQ2.5, DQ4 & DQ8) that confer an increased risk of celiac

disease. The validity of these tagging SNPs is supported across numerous studies.203-211

Evidence level 4


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Major Histocompatibility Complex, Class II, DQ beta 1 (HLA-DQB1)

Narcolepsy is a sleep disorder marked by excessive daytime sleepiness and cataplexy (muscle weakness

or paralysis triggered by strong emotion).212 There is evidence that the disorder has an autoimmune

etiology, as much of the strong genetic associations have been found in a region of the genome that

encompasses genes associated with the immune system, including those related to the human

leukocyte antigen (HLA) system.213 Many studies have shown that greater than 90% of individuals with

narcolepsy carry the HLA-DQB1*0602 allele. Conversely, it has been reported that 12-38% of the

general population unaffected by narcolepsy also carry this allele.214-216 Observed differences in the

levels of cerebrospinal fluid hypocretin (neuropeptides involved in the regulation of sleep and arousal)

between individuals positive and negative for HLA-DQB1*0602, along with evidence from several

immunological studies, suggest that the risk allele may cause disruption of the hypocretin pathway,

leading to an autoimmune reaction targeting hypocretin-producing neurons. In this way, the allele is

thought to influence the susceptibility to develop narcolepsy.217,218 The HLA-DQB1*0602 allele has also

been shown to be associated with increased susceptibility for developing multiple sclerosis, another

disease of the central nervous system, likely by a similar pathogenesis.219

Evidence level 4

Interleukin 6 (IL6)

Interleukin-6 (encoded by the IL6 gene) is secreted by T cells and macrophages to stimulate the acute

phase response (immune response), and is a primary determinant of hepatic production of C-reactive

protein, a marker of inflammation and tissue damage.220,221 The role of IL6 in the body is complex and

has been classified as both a pro- and anti-inflammatory cytokine, depending on cellular context. In

muscular tissue, it acts to acutely reduce inflammation222 but may also play a role in the deleterious,

pro-inflammatory cascade seen in chronic inflammation.223,224 The G174C polymorphism confers

reduced expression of IL-6. Healthy controls with the CC genotype showed significantly lower IL-6

plasma levels than G allele carriers.225 This variant has been implicated in a wide range of diseases with

an inflammatory etiology, including vascular dementia, chronic arthritis, inflammatory bowel conditions,

and fatigue, but with very few replications.226-229 However, a recent meta-analysis of 21 case-control

studies confirmed an association between G174C and periodontitis, an inflammatory condition affecting

the gingiva and teeth.230 C allele (resilient allele) carriers were found to have reduced odds of developing

periodontitis by 32% [OR 0.68 (0.56-0.83). P=0.049]. Of note, periodontitis has been proposed to be a

significant source of systemic inflammation and is an independent risk factor for cognitive decline and

dementia.231-233

Evidence level 2

Low Density Lipoprotein Receptor-Related Protein 1 (LRP1)

Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in intracellular signaling,

particularly in vascular tissues, and regulates glucose metabolism in the brain and signaling of NMDA

(glutamate) receptors. LRP1 may play a role in vascular homeostasis.235,241,242 The TC variant analyzed

by Mindful DNA has been linked to a decreased risk of migraine in multiple GWAS and case-control


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studies in Caucasian populations.235,237-240 In the larger studies, individuals carrying the C allele were 10-

27% less likely to have migraines.234,236, 238-240,243

Evidence level 4

Leucine Rich Repeat Kinase 2 (LRRK2)

The biological function of LRRK2 has not been clearly elucidated but investigators believe that it may be involved in regulating peroxidase activity, which is essential for preventing oxidative stress and neuronal degeneration. It is highly expressed in the putamen and substantia nigra; areas of the brain that are susceptible to degeneration in Parkinson’s disease.249 The G2019S variant causes an amino acid change from glycine to serine that may result in decreased peroxidase activity, oxidative cellular damage, and neurodegeneration.244 Clinical studies have consistently associated this variant with an approximate 10-fold increased risk of developing Parkinson’s disease.245,247,248 A recent GWAS identified this SNP as the leading genetic risk factor for the disease.246

Evidence level 3

Melanocortin 4 Receptor (MC4R)

NOTE: The MC4R variant on the Mindful DNA test is a different polymorphism than that analyzed by the Genecept Assay®. The information provided below applies ONLY to the MC4R variant listed in Mindful DNA report.

MC4R moderates the effects of leptin, a neurohormone involved with satiety, metabolism, and energy

balance. Variants of MC4R influence body mass index (BMI) and the risk of obesity.250 The TC variant

tested on the Mindful DNA test was identified as the strongest genetic association with increased BMI in

a 2008 meta-analysis consisting of over 16,000 subjects.251 This finding has been replicated consistently

across varying populations, with indications that the risk is mediated by increased food consumption,

likely resulting from decreased satiety signaling.252-255 Interestingly, more recent studies have further

shown that C allele carriers may be particularly likely to reap the benefits of adhering to a

Mediterranean diet to reduce the increased risk of diabetes conferred by this genotype.252,256 Similarly,

the Graff et. al. meta-analysis showed that the BMI-increasing effect (of the C allele) was 33% less in

active individuals than in inactive individuals.255 Thus, the genetic predisposition to obesity conferred by

this genotype, may be ameliorated with therapeutic lifestyle and dietary interventions.

Evidence level 4

Meis Homeobox 1 (MEIS1)

MEIS1 encodes a homeobox protein that is part of a regulatory network that is involved in spinal motor neuronal connectivity. The TG variant analyzed by Mindful DNA is strongly correlated with an increased risk of developing restless leg syndrome (RLS), a sensorimotor disorder characterized by unpleasant or uncomfortable sensations in the legs and an irresistible urge to move them, particular at night.257 The G allele has been associated with an approximately 30-70% increased likelihood of developing RLS.258-260,262-266 Both RLS and periodic limb movements of sleep are associated with increased rates of hypertension.261

Evidence level 4


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miR-181 MicroRNA Precursor (miR-181)

MicroRNAs (miR) modulate gene expression by regulating messenger RNA (mRNA). miR-181 has been shown to be involved in the development of neurons by promoting spine formation and reducing dendrite branching and axon growth, possibly through an immunomodulatory mechanism.267,270 It is expressed in the nucleus accumbens (NAc) and hippocampus; the brain regions involved with pleasure, reward, and motivation.269,271 The A allele of mir-181 is a resilience allele, conferring decreased expression of miR-181a/b in the brain. This is associated with greater NAc reactivity to positive emotional stimuli, enhanced fear inhibition, and has been identified in two recent GWAS studies to be associated with positive emotion reactivity, spiritual well-being, and affect.268,269 Positive affect is associated with favorable psychological and physical outcomes in multiple longitudinal studies.272-274 Evidence level 3

5,10 Methylenetetrahydrofolate Reductase (MTHFR)

MTHFR is an enzyme responsible for catalyzing the conversion of folic acid to methylfolate. Methylfolate is the active form of folic acid, a vital precursor for the synthesis of norepinephrine, dopamine and serotonin.275 Two variations are tested within this gene. The T allele of the C677T variant and the C allele of the A1298C variant lead to reduced enzymatic activity of MTHFR, resulting in inefficient folic acid metabolism and production of methylfolate.276 Several studies have shown these variations are associated with depression, bipolar disorder, and schizophrenia.277 Studies in psychiatric patients analyzing the therapeutic efficacy of exogenous administration of L‐methylfolate have found superior outcomes when SSRI/SNRI treatment was supplemented with L‐methylfolate compared with SSRIs/SNRI treatment alone.278-281 A 2016 study with a methylfolate B‐vitamin complex showed depression remission rates of 42% as monotherapy when MTHFR genotype was taken into consideration.282 Preliminary data also suggest that biomarkers related to L‐methylfolate synthesis and/or metabolism may identify patients who would benefit from supplementation with L‐methylfolate.283

Evidence level 4

Oxytocin Receptor (OXTR)

Oxytocin is a neurohormone involved in sociality and empathy in adults, as well as emotional bonding

between parents and infants.287,289 A common variant in the gene that expresses oxytocin receptor

(OXTR) has been broadly linked to socially related personality traits and behaviors.286,291 Several large

studies have indicated that G allele homozygotes have greater measures of sociality than A allele

carriers.287,292-294 Accordingly, A allele carriers tend to experience less negative pressure from an adverse

social environment, but also tend to benefit less from positive social reinforcement and

support.284,285,288,290 Conversely, G allele homozygotes may be more influenced by their social

environment, which confers an increased risk of maladaptive behaviors in the context of social stress

such as childhood maltreatment or significant social pressure.285,292,294,295

Evidence level 3


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Proprotein Convertase, Subtilisin/Kexin-Type 9 (PCSK9)

PCSK9 expresses an enzyme that is strongly linked with lipoprotein homeostasis. Downregulation of

PCSK9 results in an increased expression of low-density lipoprotein receptors which, subsequently,

results in an increased metabolism (clearance) of cholesterol and LDL particles in the blood.301,302,307

Thus, it is not surprising that genetic variants which result in decreased expression of PCSK9 are

consistently associated with decreased cholesterol and LDL levels.296-299,303-305,308 Specifically, the C allele

of the TC missense variant analyzed by Mindful DNA not only results in decreased serum LDL, but has

also been linked to decreased risk of coronary artery disease (CAD) and myocardial infarction (MI) in

Caucasians.298,303,306,308 This association has not been observed in those of Asian or African descent.300,309

Evidence level 4

Peroxisome Proliferator-Activated Receptor Gamma (PPARG)

PPARG encodes a nuclear receptor that regulates gene expression and affects peroxisome activity,

playing a significant role in fatty acid oxidation and metabolism.310,311 The variant G allele at rs1801282

(Pro12Ala) has been shown to alter the ability of PPARG to bind target gene promoters. The reduced

binding function affects the ability of PPARG to regulate fatty acid metabolism, contributing to

dysregulated lipid levels.312 Multiple studies have demonstrated that C/G and G/G genotypes are

associated with decreased risk of type 2 and gestational diabetes compared to the C/C genotype.313-316

Conversely, a meta-analysis of 32,000 individuals found an association of C/C genotype with insulin

resistance and increased fasting glucose levels.317 A number of association studies and meta-analyses

have repeatedly demonstrated an association of C/G and G/G genotypes with increased body mass

index (BMI) and obesity.318-320 In contrast, individuals with the C/C genotype may be more likely to

benefit from physical training for weight loss.321-322 However, individuals with C/G and G/G genotypes

may have a health advantage compared to those with C/C genotype when adhering to a Mediterranean

diet; G allele carriers show reduced telomere shortening and overall greater telomere length following

dietary intervention with the Mediterranean diet.323

Evidence level 4

Catalytic Subunit of the SWI/SNF Chromatin-Remodeling Complex (SMARCA4)

The protein expressed by SMARCA4 is involved with epigenetic regulation, which can affect the rate of

gene transcription. SMARCA4 lies in close proximity to LDLR, the gene that expresses the low-density

lipoprotein receptor. Many studies of the polymorphism analyzed by Mindful DNA erroneously link this

SNP directly to LDLR, likely due to its close proximity as well as the strong influence of this

polymorphism on cholesterol and serum LDL.330,336,338,339 More importantly, the GT polymorphism has

been consistently linked across multiple studies with cardiovascular pathology, with the G (major) allele

conferring increased risk of early-onset myocardial infarction and coronary artery disease in Caucasian

and Asian subjects,324,327-329,331-334,337,339 but not in those of African descent.325,326 The link with

cardiovascular pathology may be due to the apparent effect of this polymorphism on serum LDL and


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cholesterol. However, SMARCA4 has also been shown to affect vascular smooth muscle cell

proliferation, which may therefore also play a significant role in vascular pathology.335

Evidence level 4

Triggering Receptor Expressed on Monocytes 2 (TREM2)

TREM2 is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation and

plays an essential role in removing neural debris.343,345 Homozygous loss-of-function mutations in TREM2

have been associated with an autosomal recessive form of early-onset dementia.344 The TREM2 variant

analyzed by Mindful DNA confers an amino acid change from arginine to histidine at position 47 of the

protein (R47H). This reduces protein function and confers an approximately 3-fold risk of developing

Alzheimer’s disease in Caucasians, presumably due to decreased activation of the mophagocytic state of

microglia and increased neuroinflamatory activity.340-342

Evidence level 4

Key Recommendation Summaries

Agmatine

Preclinical data suggests that agmatine may help reduce the harmful effects of cortisol and stress.476

Prolonged treatment with high dose glucocorticoids (50 mug/kg/day) produced noticeable

neuronal structural changes in rats, such as the diminution and disarrangement of dendrites

and neurons in the hippocampus and prefrontal cortex. Simultaneous treatment with agmatine

(50 mg/kg/day) prevented these morphological changes. These results demonstrated that

agmatine has neuroprotective effects against structural alterations caused by glucocorticoids in

vivo.

Ashwagandha Ashwagandha may help to reduce elevated cortisol and reduce symptoms of anxiety.475

A total of 64 subjects with a history of chronic stress were randomized to receive 300 mg of ashwagandha root extract or placebo once daily for 60 days. The treatment group exhibited a significant reduction (P<0.0001) in scores on all the stress-assessment scales on Day 60, relative to the placebo group. The serum cortisol levels were substantially reduced (P=0.0006) in the Ashwagandha group, relative to the placebo group.


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Berberine

Berberine, a natural PCSK9 inhibitor available as a supplement, at doses of 500-1000 mg/day, has been

shown to decrease non-HDL cholesterol levels in individuals with dyslipidemia.447-449

There is preliminary evidence that berberine may also improve insulin sensitivity in individuals with the

metabolic syndrome.450

Bright Light Therapy

Bright light therapy appears effective for seasonal affective disorder and non-seasonal major depressive

disorder, and may also be effective in certain disorders of the sleep-wake cycle.430-432

Caffeine

Caffeine consumption associated with decreased risk of developing Parkinson’s disease.371

A systematic review and meta-analysis of published epidemiological studies was conducted to

better estimate the effect of caffeine exposure on the incidence of Parkinson’s disease (PD). The

summary RR for the association between caffeine intake and PD was 0.75 [95% CI: 0.68-0.82],

with low to moderate heterogeneity (I2= 28.8%).

Caffeine consumption reduces the odds of developing PD in those with genetic predisposition conferred

by LRRK R1628P.372

A case control study involving 812 subjects consisting of individuals with PD and healthy controls

was conducted. Regular caffeine intake was associated with an over 5-fold decreased odds of

developing PD amongst those with LRRK2 R1628P risk variant compared to non-caffeine takers

with the same variant. For those with the wild type genotype, caffeine consumption was

associated with a 91% decreased likelihood of developing PD. Caffeine consumption was

associated with a decreased risk of developing PD, but with a particularly pronounced effect in

those with the LRRK R1628P risk variant.

Caffeine offers neuroprotection and prevents neurodegeneration and rescues motor function in

rotenone-induced rat models of Parkinson’s disease.373

Rats were divided into four groups: (1) control, (2) PD model induced by rotenone, (3) protected group

injected with caffeine and rotenone for 45 days (during the development of PD model), and (4) treated

group injected with caffeine for 45 days after induction of PD model. Caffeine protection and treatment

restored the depletion of midbrain and striatal dopamine induced by rotenone and prevented decline in

motor activities and muscular strength.


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Carotenoids

Plasma lutein level is inversely associated with dementia risk.421

1,092 non-demented older participants, from the Three-City-Bordeaux cohort were followed for

up to 10 years (range: 1.8-10.8 years, median: 9.5 years). Dementia and AD were diagnosed by a

committee of neurologists. The concentration of plasma carotenoids (beta-carotene, alpha-

carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin) was determined at baseline.

During follow-up, 199 dementia cases, including 132 AD, occurred. After adjustment for

sociodemographic data, diet quality, and clinical variables, including baseline cognitive

performances, only higher lutein concentration, considered as a function of plasma lipids, was

consistently significantly associated with a decreased risk of all-cause dementia and AD (hazard

ratio (HR)=0.808, 95% CI 0.671-0.973, p=0.024 and HR= 0.759, 95% CI 0.600-0.960, p=0.021,

respectively).

Preclinical evidence suggests that that carotenoids may inhibit amyloid β aggregation by preventing the

formation of the fibril and through disruption of the Aβ aggregates.422

Histone deacetylase (HDAC) inhibitors, including carotenoids and other flavonoids such as beta

carotene, luteolin, and lycopene, have been associated with reduced risk of stroke.423

In a systematic review, recent studies indicated that high dietary intake of six main carotenoids (i.e.,

lycopene, beta-carotene, lutein, zeaxanthin, and astaxanthin) was associated with reduced risk of stroke

and cardiovascular disease.

Serum lycopene levels are inversely associated with risk of stroke.424

In a meta-analysis of lycopene and stroke risk, the pooled analysis of seven prospective studies, with

116,127 participants and 1,989 cases, demonstrated that lycopene decreased stroke risk by 19.3%

(RR=0.807, 95% CI=0.680-0.957) after adjusting for confounding factors. Circulating lycopene was

associated with a statistically significant decrease in stroke risk (RR=0.693, 95% CI=0.503-0.954).

Dietary lycopene intake is inversely associated with cardiovascular disease.425

Measures of lycopene intake were assessed for subjects from the Framingham Heart Study (N=5,209)

who were followed for over 10 years to characterize the relation between lycopene intake and

incidence of cardiovascular disease (CVD, n=314), coronary heart disease (CHD, n=171) and stroke

(n=99). Using an average of three intake measures with a 9-year follow-up, lycopene intake was

inversely associated with CVD incidence (HR 0.83, 95% CI 0.70, 0.98). Using an average of two intake

measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR

0·74, 95% CI 0.58, 0.94).

Astaxanthin, a dietary carotenoid found in shellfish and cold-water fish, has been shown to inhibit

HDAC9 in a preclinical study.426


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Coenzyme Q10 (CoQ10)

Supplementation with CoQ10, 100 mg twice per day, may modulate BNP levels and help support healthy

blood pressure.441

Supplementation with CoQ10, 100-150mg, daily has been shown to significantly reduce both the

severity and frequency of migraine attacks over a period of 3-4 months.442,443

Curcumin

Preliminary evidence suggests that curcumin may help prevent cognitive decline in older adults as well

as have immediate benefits on mood and memory, consistent with preclinical evidence suggesting a role

in neuritogenic processes and clearance of tau.397-399

A 12-month, randomized, placebo-controlled, double-blind study investigated the safety and

efficacy of curcumin supplementation to prevent cognitive decline in a population of 96

community-dwelling older adults. The decline in function of the placebo group at 6 months was

not observed in the curcumin treatment group.

In a randomized placebo-controlled trial of 60 healthy, older adults, working memory and mood

were significantly improved following curcumin supplementation, compared to placebo at 4

weeks. Significantly improved scores on sustained attention and working memory tasks were

also observed one hour after administration, compared to placebo.

DASH Diet

Dietary approaches to stop hypertension (DASH) is an effective diet plan to prevent and control

hypertension.433,434

Exercise and Caloric Restriction

Findings from the Food4Me European randomized controlled trial indicate greater weight loss for FTO

risk allele carriers with personalized weight reduction intervention.348

In a stratified randomized trial of personalized weight reduction interventions, including caloric

restriction and exercise, mean reductions in weight and waist circumference at month 6 were

greater for FTO risk allele carriers than for non-carriers [-2.28 kg (95% CI: -3.06, -1.48 kg) and -

1.99 kg (-2.19, -0.19 kg), respectively (P = 0.037); and -4.34 cm (-5.63, -3.08 cm) compared with -

1.99 cm (-4.04, -0.05 cm), respectively, (P = 0.048)].

Assessing gene-environment interaction effects of FTO, MC4R and lifestyle factors on obesity using an

extreme phenotype sampling design: results from the HUNT study.349


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The effects of obesity-promoting minor-alleles of FTO and MCR4, and interactions with lifestyle

factors are age- and gender-related. A greater FTO effect on BMI was observed among men with

a regular intake of artificially sweetened beverages, compared to non-drinkers.

FTO genotype and weight loss in diet and lifestyle interventions: a systematic review and meta-

analysis.350

A meta-analysis of 10 studies (comprising 6951 participants) that reported the results of additive

genetic models showed that individuals with the FTO AA genotype had 0.44-kg (95% CI: 0.09

0.79 kg; P= 0.015) greater weight loss than those with the TT genotype following dietary

intervention. Differences in weight loss between the AA genotype and TT genotype remained

significant after adjustment for baseline BMI or body weight. These results suggest that

individuals carrying the homozygous FTO obesity-predisposing allele may lose more weight

through diet/lifestyle interventions than non-carriers.

PPARG genotype predicts weight loss through multidisciplinary therapy (e.g., dietary advice,

counseling, and exercise) to severely obese subjects.322

Genetic predisposition to weight gain was assessed in a sampling of 587 participants of

multidisciplinary obesity treatment program involving dietary advice, psychological counseling,

and increased physical activity. The C/G-G/G genotypes of PPARG were found to predict ≥5%

weight loss after 12 months.

Physical activity is associated with improved mood, cognition, and may slow telomere shortening.351-353

Commercial activity monitors, or “smart” wearable devices, may help to achieve the recommended

physical activity goals.354

Ferrous Sulfate

Individuals with restless leg syndrome (RLS) should be screened for ferritin levels. In those with ferritin

levels ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C.427

Hypertension Management to Reduce the Risk of Dementia

APOE ε4 is associated with hypertension and cardiovascular disease, both of which are independent risk factors for cognitive decline and dementia.451,452

Management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduces the

risk of cognitive decline and may reduce the risk of dementia.453

The World Dementia Council, in collaboration with the Alzheimer’s Association, published a

consensus statement on modifiable risk factors influencing the risk of dementia. The authors

concluded that there was strong evidence that management of cardiovascular risk factors

(diabetes, obesity, smoking, and hypertension) reduces the risk of cognitive decline and

dementia.


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Lithium

Microdose lithium treatment stabilizes cognitive impairment in patients with Alzheimer's disease.400

113 AD patients were randomized to receive 300 MICROgrams lithium (gluconate or carbonate) or placebo for 15 months. The treated group showed no decreased performance in the mini-mental state examination test, whereas the lower scores were observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment and increasing progressively. This data suggest the efficacy of microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.

Lithium increases plasma BDNF.401

Ten subjects with bipolar I disorder were evaluated at baseline, during a manic episode, and after 28

days of lithium therapy initiated at 600mg/day and adjusted to attain therapeutic levels (0.6-

1.2mmol/L). Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were

analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with

lithium monotherapy (510.9±127.1pg/mL) compared to pre-treatment (406.3±69.5pg/mL) (p=0.03).

Lithium has been shown to rescue microglial function and reverse the deleterious impact of TREM2 loss

of function in TREM2 knock-out mice.402

Lithium may have neuroprotective effects through an ANK3- mediated pathway to reduce excessive

glutamate dysfunction.403,404

L-Methylfolate (5-MTHF)

Elevated serum homocysteine, a marker of 5-MTHF deficiency, has been associated with atherosclerosis and depression.477-481 Supplementation with reduced B-vitamins including 5-MTHF significantly reduces depressive symptoms and serum homocysteine levels.482

330 adult patients with MDD (DSM-5) and positive for either MTHFR C677T or A1298C polymorphism were enrolled in a randomized, controlled, double-blind study to assess the safety and efficacy of a reduced B vitamin formulation in the treatment of MDD. Plasma homocysteine levels were measured at baseline and week 8. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate efficacy for MDD. Of the active treatment group, 131 (82.4%) showed a reduction in homocysteine (for a mean in this subgroup of 25%, P < .001). Placebo patients demonstrated a small elevation in homocysteine. Active-treatment patients demonstrated, on average, a 12-point reduction on the MADRS by week 8, and 42% achieved full remission (P < .001).


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Adjunctive 5-MTHF 15 mg/day with an SSRI or SNRI results in significantly increased response rate and reduction in depressive symptoms in patients with MDD.279

Magnesium

Low magnesium (Mg) levels have been associated with hypertension, coronary heart disease, and type 2

diabetes.435

In a meta-analysis of 11 prospective cohort studies, 5 reported results on CHD (38,808 individuals

[4437 cases] with an average 10.5-year follow-up), 3 on hypertension (14,876 participants [3149

cases] with a 6.7-year follow-up), and 4 on T2DM (31,284 participants [2680 cases] with an 8.8-year

follow-up). Comparing the highest to the lowest category of circulating Mg concentration, the

pooled RRs (95% confidence intervals [CIs]) were 0.86 (0.74, 0.996), 0.91 (0.80, 1.02), and 0.64 (0.50,

0.81) for incidence of CHD, hypertension, and T2DM, respectively. Every 0.1 mmol/L increment in

circulating Mg level was associated with a 4% (RR, 0.96; 95% CI: 0.94, 0.99) reduction in

hypertension incidence.

Oral Mg, at a dosage range of 400-800mg/day, has been shown to alleviate the frequency and intensity

of migraine across multiple clinical trials.436,437

500mg/day Mg supplementation increases the quality and duration of sleep in elderly subjects.438

46 elderly subjects were randomly allocated to receive 500 mg of Mg or placebo daily for 8 weeks.

Dietary Mg supplementation brought about statistically significant increases in sleep time (P = 0.002),

sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also

resulted in significant decrease in sleep onset latency (P = 0.02) and serum cortisol concentration (P =

0.008).

Magnesium acts to inhibit calcium ion current at voltage gated calcium channels such as that expressed

by CACNA1C.439,440

Mediterranean Diet

Adherence to a Mediterranean diet reduces the risk of cognitive impairment and Alzheimer’s

disease.385,386

In a meta-analysis (Singh 2014), higher adherence to the Mediterranean diet (MeDi score) was

associated with reduced risk of mild cognitive impairment (MCI) and AD. The subjects in the

highest MeDi tertile had 33% less risk (adjusted HR = 0.67; 95% CI, 0.55-0.81; p < 0.0001) of

cognitive impairment (MCI or AD) as compared to the lowest MeDi score tertile. Among

cognitively normal individuals, higher adherence to the MeDi was associated with a reduced risk

of developing MCI (HR = 0.73; 95% CI, 0.56-0.96; p = 0.02) and AD (HR = 0.64; 95% CI, 0.46-0.89;

p = 0.007).

Olive oil polyphenols may increase the activity of the ATP binding cassette transporter and assist in

cholesterol efflux. Additionally, preclinical evidence suggests that olive oil polyphenols may inhibit Tau


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aggregation into fibrillary tangles; a major contributor to Alzheimer's disease and related

tauopathies.387,388

Adherence to a Mediterranean diet reduces the risk of obesity, type 2 diabetes, gestational diabetes,

dyslipidemia, and cardiovascular disease across multiple populations.389-396

Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are

modulated by diet, being higher when adherence to the Mediterranean diet pattern is low.256

A case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and

3,622 non-diabetic subjects) revealed a gene-diet interaction supporting the Mediterranean diet

(MeDiet) as a risk reducing intervention. When adherence to the MeDiet was low, carriers of

the variant alleles of FTO and MC4R had higher type 2 diabetes risk than wild-type subjects.

However, when adherence to the MeDiet was high, these associations disappeared.

PPARG genotype interacts with a Mediterranean diet to prevent telomere shortening.323

521 subjects (55-80 years) participating in a dietary intervention trial were genotyped. Changes in

telomere length (TL) were assessed over 5 years of a nutritional intervention, which promoted

adherence to the Mediterranean diet (MeDiet). PPARG G allele carriers showed lower telomere

shortening after 5 years compared with the C/C genotype (P=0.031). This association was

modulated by MeDiet, as those G allele carriers who reported better conformity to the MeDiet

exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (≤9.5 g/d) resulted

in increased TL among G allele carriers.

Melatonin

Prolonged release melatonin 2mg has been shown to have positive effects on cognitive functioning and

sleep maintenance in elderly patients with dementia.417,418

Melatonin has also been shown to inhibit amyloid aggregation in animal models of Alzheimer’s

disease.419

Preclinical evidence suggests that melatonin inhibits voltage-gated calcium channels like Cav1.2.420

Memory and Learning is Modulated by High-Fat, High-Sugar Diet

A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor (BDNF), neuronal

plasticity, and learning.367

Animals with increased brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus

have been shown to have accelerated learning within the spatial memory domain. Two months on a

high saturated fat and refined sugar diet were sufficient to reduce hippocampal levels of BDNF and

significantly decrease spatial learning performance.


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Mindfulness & Meditation Meditation reduces cortisol levels, blood pressure, heart rate, triglycerides, and markers of inflammation in a range of populations.469-471

Meditation has also been shown to have a modest beneficial effect on cardiovascular risk.472

N-Acetyl-Cysteine (NAC)

NAC 2,400 mg per day may augment cognitive-behavioral therapy to improve post-traumatic stress

disorder (PTSD) symptoms. 379

Veterans with PTSD and substance abuse disorders (SUD) per DSM-IV criteria (N = 35) were

randomly assigned to receive a double-blind, 8-week course of NAC (2,400 mg/d) or placebo

plus cognitive-behavioral therapy for SUD. Primary outcome measures included PTSD symptoms

(Clinician-Administered PTSD Scale, PTSD Checklist-Military) and craving (Visual Analog Scale).

Participants treated with NAC compared to placebo evidenced significant improvements in PTSD

symptoms, cravings, and depression (β values < -0.33; P values < .05).

NAC 2.4-3.6 grams per day may reduce cigarette cravings and enhance the odds of successful smoking

cessation.382-384

Neurofeedback: Quantitative Electroencephalography (qEEG) Neurofeedback, utilizing qEEG, is an emerging technology that may be useful in alleviating symptoms of post-traumatic stress disorder.473,474

Nicotine Replacement Therapy (NRT)

The CHRNA5/A3 risk haplotype confers decreased odds of smoking abstinence without NRT, but not with NRT.466

2633 treatment-seeking smokers received interventions of: NRT, bupropion, varenicline, placebo (PLA), or combined NRT and bupropion, and five modes of group and individual behavioral therapy. CHRNA5/A3 risk alleles associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the placebo group. Conversely, subjects with the same risk variants had increased abstinence when cessation treatment included NRT.

The CHRNA5/A3 risk haplotype confers up to 2 to 3-fold increased odds of responding to smoking cessation pharmacotherapy.107,467

Cortisol regulation may be significantly impacted by smoking in FKBP5 TT homozygotes, which may make it harder to quit smoking.468


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Omega-3 Poly-Unsaturated Fatty Acids (ω-3 PUFA)

Correlation between ω-3 PUFA consumption and BDNF peripheral levels in adolescents. 355

Serum BDNF levels were assessed in a sample of 137 adolescents. ω-3 PUFA consumption was

estimated using a food frequency questionnaire for adolescents. There was a direct correlation

between ω-3 PUFA consumption and serum BDNF levels, which remained significant even after

accounting for potential confounders [rs=0.172, p=0.043].

Long-chain omega-3 fatty acids improve brain function and structure in older adults.356

65 healthy subjects (aged 50–75 years, 30 females) successfully completed 26 weeks of either

fish oil (2.2 g/day n3-PUFA) or placebo intake. Before and after the intervention period,

cognitive performance, structural neuroimaging, vascular markers, and blood parameters were

assayed. A significant increase in executive functions after ω-3 PUFA intervention compared

with placebo was observed (P=0.023). ω-3 PUFA exerted beneficial effects on white matter

microstructural integrity and gray matter volume in frontal, temporal, parietal, and limbic areas,

and on carotid intima media thickness and diastolic blood pressure. Improvements in executive

functions correlated positively with changes in omega-3-index and peripheral BDNF, and

negatively with changes in peripheral fasting insulin.

Increased serum-DHA decreases the risk of atherothrombotic stroke.357

Supplementation with high-dose (4 g/day) ω-3 fatty acid ethyl esters increases large and small artery

elasticity while decreasing blood pressure and plasma triglycerides in obese adults.358

DHA supplementation prior to the onset of Alzheimer’s disease may reduce the risk associated with

APOE ε4.359

Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several

observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3

supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by

which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA

supplementation in predementia stages of AD. The association of cognitive benefit with DHA

supplementation in predementia, but not AD dementia, suggests that early ω-3

supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers.

DHA supplementation reduces markers of inflammation and dyslipidemia in obese men and

women.360,361

In a double-blind, randomized, crossover, controlled study, 154 subjects with abdominal obesity

and low-grade systemic inflammation consumed 2.7 g/day DHA, 2.7 g/day EPA, or corn oil

(control) for 10 weeks. DHA compared with EPA led to more pronounced reductions in

triglycerides (-13.3% ± 2.3% compared with -11.9% ± 2.2%, respectively; P = 0.005) and

cholesterol:HDL-cholesterol ratio (-2.5% ± 1.3% compared with 0.3% ± 1.1%, respectively;

P=0.006). Additionally, supplementation with DHA compared with supplementation with EPA

led to a greater reduction in several inflammatory markers including CRP and IL6.

1-2 grams of omega-3 fatty acids per day can help decrease symptoms of depression.89,362,363


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The most recent meta-analysis conducted by Mocking et al supported an overall beneficial

effect of omega-3 PUFAs on depressive symptoms in major depressive disorder. Meta-

regression showed that higher EPA dose (β=0.00037 (0.00009-0.00065), P=0.009) and higher

percentage antidepressant users (β=0.0058 (0.00017-0.01144), P=0.044) were significantly

associated with better outcome for PUFA supplementation. This is consistent with an earlier

meta-analysis (Sarris 2012 and Kraguljac 2009) which indicated that omega-3 PUFA

supplementation of 2200 g/day with a high EPA content was effective for depressive symptoms

and bipolar depression, but not mania.

Omega-3 fatty acids suppress transmembrane voltage-gated Na+ and Ca+ currents, supporting utility of

supplementation for CACNA1C and ANK3 polymorphisms which confer dysregulation of excitatory

signaling.364-366

Oxytocin (Exogenous)

Adjunctive administration of oxytocin (OT) has been shown to decrease symptoms of depression when added to prescription escitalopram over 4 weeks.483 Administration of exogenous OT has been shown to increase self-reported spirituality when combined with meditation.484 Midlife male participants (N = 83) were randomly assigned to receive intranasal OT or placebo

prior to 20-minute guided meditation. Results showed that intranasal OT increased self-reported spirituality on two separate measures and this effect remained significant a week later. It also boosted participants' experience of specific positive emotions during meditation, at both explicit and implicit levels

Intranasal OT increases neural responses to social reward in post-traumatic stress disorder.485 Male and female police officers with (n = 35) and without PTSD (n = 37) were included in a double-blind, randomized, placebo-controlled cross-over fMRI study. After intranasal OT (40 IU) and placebo administration, a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback. Under placebo, PTSD patients showed reduced left anterior insula (AI) responses to social rewards (i.e. happy faces) compared with controls. OT administration increased left AI responses during social reward in PTSD patients, such that PTSD patients no longer differed from controls under placebo.

OXTR GG Genotype Greater Response to Social Support

OXTR genotype modulates response to social support, such that those with the G/G genotype benefit more from positive social support, but may be more vulnerable to negative social interactions.486,487

Individuals with the GG genotype evidence higher prosocial temperament and reduced cortisol responses to stress. While GG carriers may be buffered against stressors in the presence of social


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support, they may be more susceptible to such stress in its absence, for example in the face of prior childhood maltreatment. Individuals with this genotype may benefit from increased social support to mitigate the effects of adverse life events.

Palmitoylethanolamide (PEA) PEA, a dietary compound found in egg yolk, was shown to decrease inflammatory markers and signs of

ulcerative colitis in a preclinical model inflammatory bowel disease.465

Petasite hybridus (Butterbur)

Supplementation with 50 to 75 mg of butterbur has been shown to be an effective prophylactic

treatment of migraine.444-446

Physical Activity Benefits Cognition and Mood

Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment

in elderly individuals with different BDNF Val66Met genotypes.346

The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy

adults: a meta-analysis.347

This meta-analysis sought to determine the effect of a single exercise session on concentrations

of BDNF in peripheral blood in order to evaluate the potential role of BDNF in mediating the

beneficial effects of exercise on brain health. In 55 studies that met inclusion criteria,

concentrations of peripheral blood BDNF were higher after exercise (Mean change= 0.59, 95%

CI: 0.46-0.72, P < 0.001). In meta-regression analysis, greater duration of exercise was

associated with greater increases in BDNF.

Polysomnography (PSG) & Actigraphy

In individuals with an ambiguous history of RLS, PSG to assess for periodic leg movements may be useful

to help confirm an RLS diagnosis.428

Actigraphy is indicated as a method to characterize circadian rhythm patterns or sleep disturbances in

individuals with chronic insomnia, including insomnia associated with depression.429,430

Prebiotics

There is strong evidence that a diet including low fermentable oligosaccharides may benefit individuals with irritable and inflammatory bowel disease.459-464


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Probiotics

There is substantial support for the role of probiotics in the maintenance of immunologic equilibrium in the GI tract.454-456

Probiotics such as Lactobacillus may be beneficial in the treatment of initial to moderate periodontitis.457,458

Quercetin and Epigallocatechin Gallate (EGCG)

Quercetin and EGCG significantly decrease catechol-O-methyltransferase activity and expression.374,375

Green tea consumption is associated with lower prevalence of cognitive impairment.376

A cross-sectional data from a community-based cohort consisting of 1003 elderly Japanese

showed that volume of green tea consumption was inversely associated with prevalence of

cognitive impairment. After adjustment for potential confounders, the odds ratios (OR)s for

cognitive impairment associated with different frequencies of green tea consumption were 1.00

(reference) for ≤ 3 cups/week, 0.62 (95% CI: 0.33, 1.19) for 1 cup/day, and 0.46 (95% CI: 0.30,

0.72) for ≥ 2 cups/day (P value for trend =0.0006).

Quercetin is associated with preserved cognitive function over time in a large, multi-ethnic cohort of

middle-aged adults.377

Dietary intake of flavonols was assessed from a large biracial study of 10,041 subjects, ages 45-

64, by analysis of a food frequency questionnaire administered at visit 1 of triennial visits.

Cognitive function was assessed at visits 2 and 4 with the following three cognitive performance

tests: the delayed word recall test, the revised Wechsler Adult Intelligence Scale digit symbol

subtest, and the word fluency test of the Multilingual Aphasia Examination. The change in each

score and a combined standardized change score over 6 years was calculated. Generalized

linear models controlled for age, ethnicity, gender, education level, energy intake, current

smoking, physical activity, body mass index, diabetes, and vitamin C intake. Total flavonols

across quintiles of intake were positively associated with preserved combined cognitive function

(P<.001). This pattern with preserved combined cognitive function was consistent for the three

major individual flavonols in the diet, myricetin, kaempferol, and quercetin (each P<.001). The

positive association with total flavonols was strongest for the digit symbol subtest (P<.001). In

this cohort, flavonol intake was correlated with protected cognitive function over time.

EGCG confers immediate benefits on cognition and mood.378

In a small, double blind, placebo controlled cross-over study (n=31) to assess safety and efficacy

of a purified formulation of EGCG, participants completed baseline assessments of cognitive and

cardiovascular functioning, mood, and a resting state electroencephalogram (EEG) before and

then 120 min following administration of 300 mg EGCG or matched placebo. EGCG

administration was associated with a significant overall increase in alpha, beta and theta

activity, also reflected in overall EEG activity, more dominant in midline frontal and central


MIN-RS-003-V2-042018

regions, specifically in the frontal gyrus and medial frontal gyrus. In comparison to placebo, the

EGCG treatment also increased self-rated calmness and reduced self-rated stress.

Green and black teas are a rich source of polyphenols including epigallocatechin-3-gallate (EGCG) and

theaflavins, which may have neuroprotective as well as anti-oxidant properties.380

Tea drinking is associated with decreased risk of developing Parkinson's disease.381

A meta-analysis of publications evaluating the risk of Parkinson’s disease associated with tea

drinking included 8 studies comprising 1418 cases and 4250 controls. The pooled odds ratio

(95% CI) was 0.85 (0.74–0.98), which suggests a protective effect of tea drinking for the risk of

PD. However, sub-group analysis did not reveal a dose-response relationship between the

volume of tea consumed and effect on risk of developing PD.

Sodium Butyrate

Antidepressant-like effects of sodium butyrate (NaB) may be due to upregulation of BDNF, as

demonstrated in animal models wherein NaB ameliorated the behavioral and physiological markers of

chronic stress.368,369

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota

and gastrointestinal barrier.370

NaB corrected high-fat diet (HFD)-induced gut microbiota imbalance in mice, considerably

elevating the abundance of the beneficial bacteria Christensenellaceae, Blautia and

Lactobacillus. Further, NaB restored HFD-induced intestinal mucosa damage and decreased the

levels of gut endotoxin in serum and liver compared with high fat group. Several markers of

inflammation were reduced in liver or epididymal fat in NaB treated mice.

Vitamin D

Vitamin D may play a key role in blood pressure regulation.405

Improved serum 25(OH) vitamin D concentrations in hypertensive individuals who were vitamin

D insufficient were associated with improved control of systolic and diastolic BP. At baseline,

592 participants (7.3%) were hypertensive; of those, 71% were no longer hypertensive at follow-

up (12 ± 3 months later). There was a significant negative association between BP and serum

25(OH) vitamin D level (systolic BP: coefficient = -0.07, p < 0.001; diastolic BP: coefficient = -0.1,

p < 0.001). Reduced mean systolic (-18 vs. -14 mmHg) and diastolic (-12 vs. -12 mmHg) BP, pulse

pressure (-5 vs. -1 mmHg) and mean arterial pressure (-14 vs. -13 mmHg) were not significantly

different between hypertensive participants who did and did not take BP-lowering medication.

Serum 25(OH) vitamin D level is inversely associated with the risk of developing dementia, including

AD.406-408


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In a meta-analysis of 5 cross-sectional and 2 longitudinal studies comprising 7,688 participants

showed an increased risk of cognitive impairment in those with low vitamin D compared with

normal vitamin D (OR 2.39, 95% CI 1.91-3.00; p < 0.0001).

Lower vitamin D levels have been shown to effect TREM2 expression and are correlated with cognitive

decline and Alzheimer's disease.409,410

Low vitamin D levels have been implicated in depression and anxiety across multiple populations.411-413

Vitamin D strengthens FKBP5-mediated inhibition of glucocorticoid receptor transport.414

In in vitro studies, vitamin D was shown to increase FK506-binding protein 5 (FKBP5) impact on the

phosphorylation status of glucocorticoid receptor in human peripheral blood mononuclear cells,

suggesting that 25(OH) vitamin D may act to attenuate the stress response.

Serum levels of 25(OH) vitamin D are inversely associated with serum CRP, as well as diastolic

dysfunction and severity of coronary artery disease.415,416

Domain Recommendations: COGNITION & MENTAL ACUITY

Diabetes, obesity, smoking status, and hypertension are all significant, modifiable risk factors for cognitive decline. Additionally, treatment of sleep dysregulation has been shown to significantly reduce the risk of dementia. Physical activity and cognitive training interventions may have more immediate benefits. Significant increases to working memory as well as delayed and immediate recall have been observed in individuals following these interventions.346,347,488-492

Domain Recommendations: CARDIOMETABOLIC Diets which increase fiber & unsaturated fats, while limiting intake of refined sugars, salt, and saturated and trans-fats, are widely supported as a powerful method to improve cardiovascular health. Physical activity, whether it’s a daily walk in the park, yoga, or vigorous athletic training, has been shown to be a great benefit to improve health over multiple domains.493-496

Domain Recommendations: GI & IMMUNE The gut microbiome is critical to immune system function. Overuse of antibiotics can contribute to disturbances in the gut microbiome, which can increase the risk of infections as well as inflammatory bowel symptoms. Probiotics and prebiotics increase favorable microbiome composition that contributes to overall health and immune system function. Management of irritable bowel symptoms includes eating smaller, more frequent meals and avoiding trigger foods.497-500


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Domain Recommendations: STRESS & EMOTIONAL WELLBEING Chronic stress can have widespread negative impacts across all other domains. Mindfulness, meditation, yoga, progressive muscle relaxation, tai chi, and other forms of physical exercise are well studied methods to reduce stress. One of the most promising candidates to monitor stress is heart rate variability (HRV). Decreased heart rate variability has been associated with stress-related disorders and increased morbidity and mortality. Interventions that increase HRV, such as mindfulness, may promote stress reduction.501-507

Domain Recommendations: INFLAMMATION Chronic inflammation has been implicated in cancer, cardiovascular disease, metabolic disorder, and cognitive decline. Decreased consumption of saturated fats and increased consumption of omega-3 fatty acids have been shown to reduce inflammation and improve markers of health across multiple domains. The Mediterranean Diet has been demonstrated to reduce the risk of cardiovascular events, stroke, and diabetes. Low-glycemic diets may reduce inflammation, oxidative stress, and markers of insulin resistance.502-515

Domain Recommendations: SLEEP

Sleep dysregulation is a major risk factor for multiple physical and neuropsychiatric disorders, including obesity, cardiovascular disease, dementia, and mood and affective disorders. There are several modifiable factors that can improve sleep. Avoiding alcohol and caffeinated drinks late in the evening can increase sleep duration and quality. Low glycemic load meals with a focus on vegetables and protein and increased physical activity can help maintain alertness and improve sleep quality at night.516-521


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