The document discusses the relationship between dietary factors and cognitive decline, emphasizing that dementia is characterized by a gradual decline in cognitive abilities. It outlines modifiable risk factors for cognitive decline, including elevated homocysteine levels and poor dietary habits, and advocates for early intervention through dietary changes as a potential preventative strategy. Furthermore, it highlights the importance of specific nutrients, such as B vitamins and omega-3 fatty acids, in influencing cognitive health and offers insights on the role of oxidative stress and gut microbiota in this context.

1. Nutritional strategies for cognitive
decline
Nina Bailey BSc MSc, PhD RNutr
1

2. Defining dementia
• Dementia is an umbrella term, used to describe a syndrome that can have
many different causes and that is characterised by gradual decline in
cognitive abilities and neuropsychiatric symptoms
• The most common dementia types include Alzheimer’s disease, vascular
dementia, fronto-temporal dementia, Lewy body dementia, Korsakoff's
syndrome, Huntingdon’s chorea and Parkinson's disease
• Processes related to cognitive decline/dementia begin to damage the brain
many years, if not decades, before symptoms become apparent and cause
a progressive decline in functioning as more of the brain is damaged,
making early intervention key to slowing/preventing cognitive decline
Understanding the mechanisms and those dietary factors that influence
cognitive health may provide insight into an optimum time window when
dietary interventions would be most beneficial for changing the course of
the disease

3. Well established risk factors for cognitive decline
Risk factor Modifiable?
Age X
Genetics (i.e., APOε4) X
Overweight/obese 
Hypertension 
High cholesterol 
Dyslipidaemia 
Type II diabetes 
Poor mental or social stimulation 
Poor education status 
Low activity/sedentary lifestyle 
Smoking 

4. Additional nutrient & lifestyle factors
Risk factor Modifiable?
High HbA1c (with or without diabetes) 
Poor adherence to Mediterranean diet 
Low omega-3 intake/ fish consumption 
Low intake of B vitamins 
Low vitamin D exposure/ intake/ status 
Low antioxidant intake 
High oxidative stress 
High alcohol consumption 
Low intake of polyphenols 
High stress/ cortisol/ HPA axis activity 
Poor sleep quality/ sleep deprivation 

5. ‘New’ environmental
stressors
Reactive Hypoglyceamia Immune System Activation
High calorie diet
Muscle/fat ratio
Bosma-den Boer, M. M., M. L. van Wetten, et al. (2012). "Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and
medication prevent our body from recovering." Nutr Metab (Lond) 9(1): 32.

6. Free radicals, reactive oxygen species (ROS) & oxidative stress
Many neurodegenerative diseases are characterised by aggregates and inclusions of
aberrant proteins
Degradative pathways such as the ubiquitin proteasome system, are responsible for
the clearance of toxic protein aggregates
ROS can modify proteins,
leading to protein unfolding
and aggregation
Alzheimer's
disease
Parkinson's
disease
Huntingdon’s
disease
Frontotemporal lobar
degeneration
Amyloid-β α-synuclein Ataxins Tau
Abnormal misfolding and aggregation
Neurodegeneration
ROS
Aging
APOε4
Inflammation
Neuronal dysfunction Neuronal death
Proteasome inhibition
(degrades unneeded or damaged proteins)
Homocysteine
Pollution
Stress
Injury/trauma/infection
Metabolism
Li J, O W, Li W, Jiang ZG, Ghanbari HA. Oxidative stress and neurodegenerative disorders. Int J Mol Sci. 2013 Dec 16;14(12):24438-75.

7. Neurotrophins play a role in the maintenance, repair and genesis of
neurons including serotonergic and noradrenergic neurones
Brain-Derived Neurotrophic
Factor (BDNF) is involved in
neuronal survival and
synaptic plasticity, and
considered to be an
important biomarker for
cognitive decline as well as
for psychiatric conditions
such as depression and
bipolar disorder

8. Activation of tryptophan 2,3-dioxygenase
(TDO), present in liver and brain, is up regulated
by cortisol whilst cytokines (such as IL-1. IL-6
and TNF-α) activate IDO and kynurenine
monooxygenase (KMO)
Not only are serotonin levels reduced as a
result of the diversion of tryptophan but
elevated quinolinic acid production has
neurotoxic effects via agonist actions on
N-methyl-D-aspartate receptors (NMDA)
triggering neuronal apoptosis
Elevated quinolinic acid accumulation in certain
areas of the brain tissue is linked to cognitive
issues
Oxenkrug, G. F. (2010). "Tryptophan kynurenine metabolism as a
common mediator of genetic and environmental impacts in major
depressive disorder: the serotonin hypothesis revisited 40 years
later." Isr J Psychiatry Relat Sci 47(1): 56-63.
The kynurenine (KYN)/tryptophan ratio and cognitive function
The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is a
main tryptophan metabolic pathway and shares tryptophan with the serotonin
(5-HT) pathway

9. Elevated homocysteine
(poor recycling)
 Elevated homocysteine levels damage
cells directly by promoting oxidative
stress
 Reduced glutathione production
results in compromised detoxification
 Reduced methyl donor production
The methylation cycle supplies methyl groups for a large number of methylation-
dependent reactions, including those involved in the synthesis of substances including
creatine, choline, carnitine, coenzyme Q10, melatonin and myelin proteins
Low SAMe levels also result in a reduction in neurotransmitter production
Methylation is a fundamental process required for normal cell division and DNA repair
Compromised methylation is also implicated in accelerated ageing!!

10. Role and benefits of a healthy methylation cycle
 Neurotransmitter production:
o Mood
o Memory
o Learning
o Gut function
 Antioxidant activity:
o Increased glutathione production
o Reduced free radical production
 Cardioprotection:
o Reduced risk of cardiovascular disease and
stroke
 Detoxification:
o Improved liver function
o Increased energy
o Improved sleep
 Neuroprotection
 Improves cell signalling
 Anti-inflammatory
 Normal cell cycle
 Reduced risk of bone loss and fracture
 Improved fertility
 Anti-ageing

11. Homocysteine and cognitive decline
Prospectively, elevated homocysteine is associated with cognitive decline, white matter damage,
brain atrophy, neurofibrillary tangles and dementia, and is a strong modifiable risk factor for
vascular dementia and Alzheimer's disease
•77 cross-sectional studies on >34,000 subjects and 33 prospective studies on >12,000 subjects
have shown associations between cognitive deficit or dementia and high homocysteine and/ or
low B vitamin status (Smith 2008)
•Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective
agents against cognitive decline were poorly designed by including subjects unlikely to benefit
during the trial period
•In contrast, trials in high-risk subjects, which have taken into account the baseline B-vitamin
status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are
consistent with modification of the Alzheimer's disease process
Benefits of intervention are most apparent in those individuals with high homocysteine and low
B-vitamin status
Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008 Jun;29(2 Suppl):S143-72. Review.
Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211-39

12. Homocysteine and dementia risk factors
• Elevated homocysteine is also associated with cardiovascular
disease, diabetes, major depression and cognitive decline
• As levels of homocysteine in the blood are directly influenced by
levels of the B-complex vitamins (folate, vitamin B6 and vitamin B12),
supplementation with these key nutrients offers preventive
strategies for a number of conditions related to high homocysteine
• Studies have shown that supplementing with B6, B12 and folate
successfully lowers homocysteine
Clarke R, Harrison G, Richards S; Vital Trial Collaborative Group. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress
and homocysteine in people at high risk of dementia. J Intern Med. 2003 Jul;254(1):67-75.
.
Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation
(HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease N Engl J Med. 2006 Apr 13;354(15):1567-77
Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M.
Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations.
Expert Rev Neurother. 2009 Sep;9(9):1393-412.

13. ESSENTIAL TO BRAIN
STRUCTURE AND MASS

14. In the transsulfuration pathway,
homocysteine can be catabolised to the
most important intracellular antioxidant
glutathione, with vitamin B6 as a cofactor
In the transmethylation pathway,
homocysteine can be transformed to SAMe,
with vitamin B12 and folate as cofactors
(SAMe is a universal donor of methyl
groups, which are used for fatty acid and
phospholipid production)
SAME (S-adenosylmethionine)
During high oxidative stress, the one-carbon cycle shifts away from the methylation
pathway and production of methyl groups needed for PUFA production,
neurotransmitters and DNA methylation, to the transsulfuration pathway, resulting in
synthesis of the major intracellular antioxidant glutathione
Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular
disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.
The impact of oxidative stress on the one-carbon cycle and long-chain fatty acids

15.  Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the
aged population
 Main pathological features of AD include β-amyloid (Aβ) accumulation and hyper-
phosphorylation of the microtubule-associated protein tau, leading to the
neuropathological hallmarks of AD, senile plaques and neurofibrillary tangles
 Amyloidogenic Aβ peptides are generated by sequential proteolytic processing of
the amyloid precursor protein (APP) involving β- and γ-secretase activity
 DHA has been shown to reduce Aβ production in vitro and in animal models of AD
 DHA is decreased in post-mortem AD brains, and AD patients have reduced blood
DHA levels
 DHA has therefore become of major interest for nutritional intervention in AD
Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and
Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.

16. DHA has numerous biological properties that might be beneficial in AD neurogenesis
It has been previously demonstrated that polyunsaturated fatty acids (PUFAs), especially DHA, are associated
with a reduced risk of AD caused by decreased Aβ production
However, in epidemiological studies and dietary interventions, the outcomes of DHA-dependent treatment are
controversial
 For example the OmegAD study, found no benefits from a 6-month intervention with 1.7g DHA/0.6g EPA in AD
patients (n=204)
 However, in a subgroup (n = 32) with very mild cognitive dysfunction, a significant (P<.05) reduction in MMSE
decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group –
although this difference disappeared when adjusted for body weight
 “Since our study suggests dose-response relationships between plasma levels of omega-3 FA and preservation of
cognition, future omega-3 trials in patients with mild AD should consider exploring graded (and body weight
adjusted) doses of omega-3 ”
Eriksdotter M, Vedin I, Falahati F, Freund-Levi Y, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Cederholm T, Palmblad J. Plasma Fatty Acid Profiles in Relation to Cognition and
Gender in Alzheimer's Disease PatientsDuring Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study.
J Alzheimers Dis. 2015;48(3):805-12.
Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty
acid treatment in 174 patients with mild to moderate Alzheimer disease:OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;6 3(10):1402-8.
 neurotransmission
 synaptogenesis
 neuronal differentiation
 synaptic plasticity
 neurite outgrowth
 pro-resolvins
(MMSE) Mini-Mental State Examination score

17.  However, DHA is very susceptible to lipid peroxidation and might auto-oxidise
and induce lipid peroxidation resulting in oxidative stress, known to be involved
in AD pathogenesis
 Lipid peroxidation is not only a result of the increased levels of ROS, but also the
oxidation products increase the amyloidogenic processing, resulting in a futile
cycle
 Lipid peroxidation is elevated in human post-mortem AD brains, especially 4-
hydroxy-nonenal (HNE) derived from AA
 However, oxidised DHA can increase amyloidogenic amyloid precursor protein
processing
Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and
Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.
Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A. Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev. 2016 Apr
11;4:CD009002. doi: 10.1002/14651858.CD009002.pub3. Review.

18. Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces
manifold potentially harmful lipoperoxidation (LPO) products, such as
malondialdehyde (MDA; from AA, EPA & DHA), and hydroxynonenals
( HNEs; from AA) and hydroxyhexenals (HHEs; from EPA and DHA)
Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular
disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.

19. Even small amounts of oxidised DHA are sufficient to reverse the beneficial effects of
DHA, emphasising the importance of preventing DHA from oxidation in nutritional
approaches
This might also explain the different results obtained in epidemiological studies
dealing with DHA, where small contamination of oxidised DHA could lead to
negative/neutral study results
Omega-3 should be combined with appropriate antioxidants in high-risk individuals
Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blümel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and
Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54.

20. 4-hydroxynonenal (HNE) is a lipid peroxidation by product, derived from membrane
lipid oxidation by ROS
At physiological or low stress levels the major 4-HNE detoxification step is via
glutathione; if glutathione levels are compromised 4-HNE accumulates, causing
irreversible cell damage
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signalling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.
Oxid Med Cell Longev. 2014;2014:360438.

21. Gut microbiota and cognitive behaviour
Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gut-brain interactions. Mech Ageing Dev. 2014 Mar-Apr;136-137:59-69.
Dysbiosis is known to result in low grade inflammation
Recent studies suggest a significant correlation between the
changes of gut microbiota and cognitive behaviour:
Neurotransmitters including γ-aminobutyric acid (GABA),
glutamate and serotonin are influenced by gut flora
Disruption of gut microbiota by antibiotic treatment also
significantly reduces the level of N-methyl-D-aspartate glutamate
receptor (NMDA) in the hippocampus – important for regulating
neuronal survival, dendrite & axon development and synaptic
plasticity
The development of HPA-axis in germ free mice is abnormal,
leading to altered response to stress and reduced expression of
brain-derived neurotrophic factor (BDNF)

22. Cytokines
(IL-1, IL-6, TNF-α)
Acute Phase Proteins
C-reactive protein (CRP),
Serum amyloid A (SAA)
PLA2/COX2/LOX
NFκB
Receptor mediated pathways
(Toll like receptors [TLR], TNF-α, IL-
1)
Inflammation stimulus (i.e.
tissue injury, infection, heat
stress, psychological stress)
Prostaglandins
Leukotrienes
Thromboxanes
INFLAMMATION
Saturated fatDysbiosis

23. How do we combat cognitive decline?
At present, healthy diets, antioxidant
supplements, the prevention of nutritional
deficiencies and moderate physical activity
could be considered the first line of defence
against the development and progression of
pre-dementia and dementia syndromes
Solfrizzi V, Capurso C, D'Introno A, Colacicco AM, Santamato A, Ranieri M, Fiore P, Capurso A, Panza F. Lifestyle-related factors in predementia
and dementia syndromes. Expert Rev Neurother. 2008 Jan;8(1):133-58. Review.

24. The Mediterranean-style diet was first described in the Seven-Country study
in the 1950s to 1960s in the south of Europe, where adult life expectancy was among
the highest in the world and rates of coronary heart disease, certain cancers and other
nutrition-related chronic diseases were among the lowest (Keys et al. 1986)
• The Mediterranean diet may exert its effects on cognitive health through multiple
biological mechanisms as relationships with reduced risk of coronary heart disease,
hypertension, diabetes, dyslipidaemia and metabolic syndrome have been observed;
these conditions have also been associated with mild cognitive impairment, dementia,
or Alzheimer’s disease
• Higher adherence to a Mediterranean diet may also facilitate metabolic control because
it has been related to improved insulin sensitivity and glucose metabolism
• Higher adherence to a Mediterranean diet helps to dampen oxidative stress – known to
increase ‘naturally’ with age and results in oxidative damage - a state often observed in
the brain of patients with Alzheimer’s disease
Keys et al., The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986 Dec;124(6):903-15.
Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC, Llewellyn DJ. Mediterranean diet, cognitive function, and dementia: a systematic
review. Epidemiology. 2013 Jul;24(4):479-89.

25. Randomised controlled trials to assess the effect on cognition of a nutritional intervention using
Mediterranean diet (supplemented with extra-virgin olive oil [EVOO] or mixed nuts) in comparison
with a low-fat control diet
2013 - PREDIMED-NAVARRA trial - 6.5 years nutritional intervention - 522 participants at high
vascular risk (44.6% men, age 74.6 ± 5.7 years at cognitive evaluation)
Measurements: cognitive performance as a main outcome and cognitive status (normal, mild
cognitive impairment [MCI] or dementia) as a secondary outcome. Global cognitive performance was
examined by Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT)
2015 -Prevención con Dieta Mediterránea nutrición intervención trial - 6.5 years nutritional
intervention 447 participants at high cardiovascular risk (47.9% men, mean age 66.9 years at cognitive
evaluation)
Rates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State
Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest
from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory
Scale, and the Colour Trail Test
In older populations, compared to a low fat diet, a Mediterranean diet supplemented with olive oil
or nuts is associated with improved cognitive function.
Martinez-Lapiscina, E.H.; Clavero, P.; Toledo, E.; Estruch, R.; Salas-Salvado, J.; San Julian, B.S.; Sanchez-Tainta, A.; Ros, E.; Valls-Pedret, C.; Martinez-Gonzalez, M.A. Mediterranean diet improves cognition: The
PREDIMED-NAVARRA randomised trial. J. Neurol. Neurosur. Psychiatry 2013, 84, 1318–1325.
Valls-Pedret, C.; Sala-Vila, A.; Serra-Mir, M.; Corella, D.; de la Torre, R.; Martínez-González, M.Á.; Martínez-Lapiscina, E.H.; Fitó, M.; Pérez-Heras, A.; Salas-Salvadó, J.; et al. Mediterranean diet and age-related
cognitive decline: A randomized clinical trial. JAMA Intern. Med. 2015, 175, 1094–1103.

26. Olive oil
Fruit
Vegetables
Oily fish
Nuts & seeds
Legumes &
cereals
Monounsaturated fat (oleic
acid)
Antioxidants
(i.e. polyphenols)
Vitamin A,B,C & E
Vitamin D
Omega-3 fatty acids
(ALA, EPA & DHA)
Minerals
(i.e. selenium, iron &
iodine)
Amino acids
(i.e. taurine, tyrosine &
tryptophan)
Moderate red
wine
Lean meat
Moderate dairy
Neuronal survival
Energy metabolism
Neurotrophins
Neurotransmission
Membrane fluidity
Cell membrane
integrity
Glucose transport
Nutrient synthesis
Nutrient metabolism
Gene expression
Methylation
Cerebral blood flow
Blood pressure
Oxidative damage
Neuronal cell death
Neuroinflammation
Free radicals
Healthy brain
Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

27. Fish consumption, cognitive decline and dementia
Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFAs), which are a
main component of cell membranes
The physiological roles of omega-3 PUFA in the brain include regulation of cell membrane
fluidity, dopaminergic and serotonergic transmission, regulation of cellular signal
transduction, brain glucose metabolism, eicosanoid synthesis, gene expression and cell cycle
control
 High fish consumption tends to be inversely associated with cognitive impairment and
decline (Kalmijn 2000)
 Elderly people who eat fish or seafood at least once a week are at lower risk of
developing dementia, including Alzheimer's disease (Barberger-Gateau et al. 2002)
 Meta analysis of 21 studies (181,580 participants) with 4438 cases identified during
follow-up periods (2.1-21 y) found increased fish and omega-3 fatty consumption was
associated with a statistically significant lower risk of dementia, AD, MCI and PD (Zhang et al.
2016)
Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study.
BMJ. 2002 Oct 26;325(7370):932-3.
Kalmijn S. Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies. J Nutr Health Aging. 2000;4(4):202-7.
Review.
Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis
of 21 cohort studies. Am J Clin Nutr. 2016 Feb;103(2):330-40.

28. In 1992, the BNF Task Force on Unsaturated
Fatty Acids suggested a desirable
population intake for EPA and DHA of
0.5% of energy, which equates to about
8g/week (1.14g/day) for women and
10g/week (1.42g/day) for men,
equivalent to 2-3 medium servings of
oil-rich fish per week
For a 77kg individual to raise their omega-3
index from 4.2% to 8% they would
need a daily dose of 16mg/kg omega-3
(equivalent to 1.25g) (Flock et al. 2013)
Current UK omega-3 recommendations
450mg EPA and DHA daily (2 portions fish weekly, of which one should be oily)
Mean consumption of oily fish (all age groups) was below the recommended one portion (140g) per week
(rolling programme for 2012 and 2013 to 2013 and 2014) and equivalent to 13–29 grams per week in
children and 54–87 grams per week in adults
Figure source: Stark KD et al. 016
Is omega-3 ‘deficiency’ a global burden?

29. Higher information processing speed and less impulsivity in those
with a higher Omega-3 Index

30. Omega-3 increases blood flow to the brain supplying oxygen and fuel delivery, are
essential for neurotransmitter production and function, memory, learning, cognition,
and brain and neurone cell structure
Benefits restricted to those with sub-optimal omega-3 intake!!

31. Omega-3 and cognitive decline
• Meta-analysis examined the neuropsychological benefit of omega-3 in
randomized RCTs including healthy people, Alzheimer's disease and milder forms
of cognitive impairment (e.g. cognitive impairment no dementia [CIND])
• ApoE-ε4 status (genetic risk factor for AD) appears to be a predictor of response to
omega-treatment (no protective response)
• Omega-3 fatty acid treatment was associated with a small, but significant, benefit
for immediate recall and attention and processing speed in subjects with CIND but
not in healthy subjects or those with AD (similar findings from OmegAD study)
“Nevertheless, the present findings suggest that the effects of omega-3 on
cognitive decline are not uniform, and that there is a need to identify potentially
responsive populations”
Furthermore it is likely that nutrients work synergistically rather than in isolation!
Mazereeuw G, Lanctôt KL, Chau SA, Swardfager W, Herrmann N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol
Aging. 2012 Jul;33(7):1482.e17-29.

32.  Steps to reducing cognitive decline:
Reduce oxidative damage
Increase antioxidant enzymes
Decrease homocysteine levels
Manage blood pressure
Modulate inflammation
Increase cellular energy
Optimise neuroprotection
Enhance neurogenesis
Support cell membrane integrity
Optimise neurotransmitter levels
Early intervention is key to successful outcomes

33. National Diet and Nutrition Survey
• Only 8% of 11-18 year olds, 27% of 19-64 year old, and 35% of those ages 65+ are meeting the
5-a-day for fruit and vegetable consumption
• Mean consumption of oily fish in all age groups remained well below the recommended one
portion (140g) per week. Mean consumption was equivalent to 13–29 grams per week in
children and 54–87 grams per week in adults
• Key nutrient ‘deficiencies’ (or lower than average intakes) are vitamins A & D and iron. Women
and girls appear to be under the recommendations for riboflavin and zinc intake. Many adults
appear to be under-consuming magnesium, selenium and potassium
• Actual blood levels of iron, B12 and Vitamin D appear low
• Low iron levels (leading to anaemia) particularly relevant in girls/ women aged 11+
• All age groups are failing to meet the guidelines for fibre intake (18g daily)
• All age groups are exceeding guidelines for both saturated fat and free sugars (used to be
known as non-milk extrinsic sugars)
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/551352/NDNS_Y5_6_UK_Main_Text.pdf

34. Non enzymic antioxidants
Vitamins A, C, & E
Phenols
Polyphenols
- flavonoids
- isothiocyanates
- stilbenes
- phenolic acids
- lignans
- carotenoids
- resveratrol
Enzymatic antioxidants
require:
Selenium
Vitamin D
Copper
Manganese
Magnesium
Zinc
Amino acids (i.e. taurine)
Brain proteins, lipids and
DNA are vulnerable to
oxidative damage
Prevent, inhibit, repair ROS damage
Metabolism and exogenous
damage contribute to the
formation of ROS
Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013 May;24(5):725-43.

35. Product recommendations
35

36. Brain structure & function
with antiinflammatory
benefits
Potent
antioxidant
Homocysteine
control
Supports
cognitive
health
Supports
cognitive
health
Supplement recommendations

37. Those who habitually consume diets low in omega-3, children with low literacy
ability and malnourished and older adults with age-related cognitive decline
and mild cognitive impairment seem to benefit most from dietary intervention
with omega-3

38. DHA is for memory and
learning if intake is low
EPA in excess of DHA for cognitive
performance, in particular attention
Individuals with the
lowest base line levels
tend to be the best
‘responders’
‘DHA only’ often resulted in detrimental effects
to cognition (increased peroxidation?)
Many benefits of
omega-3 are associated
with cardiovascular
benefits such as
increased blood flow
>1month intervention needed for
benefits to be seen
Benefits of EPA associated with
reduced neuroinflammation
(lowers IL-1, Il-6 and TNF-a)
EPA restores a
healthy
(KYN)/tryptophan
ratio
Normal growth and
survival of dendritic
neurones
Omega-3 increases BDNF

39. Omega-3 reduces pro-inflammatory mediators
The presence of neuroinflammation is a common feature of cognitive decline and dementia, with
numerous studies linking higher levels of pro-inflammatory products including CRP, IL-6 & TNF-α
as potential risk factors for cognitive decline
Effects of omega-3 on fasting blood levels of CRP, IL-6 & TNF-α
•Omega-3 supplementation has a significant lowering effect on all inflammatory markers (sixty-
eight RCTs with a total of 4601 subjects)
chronic non-autoimmune disease
subjects with chronic autoimmune disease
healthy subjects
Longer duration of supplementation leads to a greater lowering effect (this relationship was
greater for EPA than DHA)
Bourassa K, Sbarra DA. Body mass and cognitive decline are indirectly associated via inflammation among aging adults. Brain Behav Immun. 2016 Sep 19.
Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhøj P, Pedersen BK. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci.
1999 Jul;54(7):M357-64.
Li, K., T. Huang, et al. (2014). "Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor alpha: a meta-analysis." PLoS One 9(2): e88103.
Palta P, Xue QL, Deal JA, Fried LP, Walston JD, Carlson MC. Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women's Health and Aging
Study II. J Gerontol A Biol Sci Med Sci. 2015 Jul;70(7):873-8. doi: 10.1093/gerona/glu132. Epub 2014 Aug 26.
Tegeler C, O'Sullivan JL, Bucholtz N, Goldeck D, Pawelec G, Steinhagen-Thiessen E, Demuth I. The inflammatory markers CRP, IL-6, and IL-10 are associated with cognitive function--data from the Berlin Aging
Study II. Neurobiol Aging. 2016 Feb;38:112-7.

40. Fatty acid absorption
Flooding the body with concentrated high doses of omega-3 can increase
inflammation (more so in nutritionally compromised individuals) due to creation of
non-enzymatic oxidation end products
Antioxidants can reduce the
production of unfavourable LPOs
e.g. the high content of astaxanthin
in krill oil is possibly due to the
presence of unstable free fatty acids
Regular split-dosing with small capsules is
more favourable for delivery of high doses than single large doses
Non-enzymatic oxidation is caused by ROS attack of PUFAs and produces manifold potentially harmful LPOs, such
as malondialdehyde (general LPO measure), 8-isoprostane (LPO generated by AA peroxidation), and
hydroxynonenals (omega-6 PUFA-derived LPOs) and hydroxyhexenals (omega-3 PUFA-derived LPOs).
Assies J, Mocking RJ, Lok A, Ruhé HG, Pouwer F, Schene AH. Effects of oxidative stress on fatty acid- and one-carbon-metabolism
in psychiatric and cardiovascular disease comorbidity. Acta Psychiatr Scand. 2014 Sep;130(3):163-80.

41. Results from intervention trials are ‘cloudy’; it may be that early intervention with
omega-3 may be ideal with regard to preventing cognitive decline rather than
treating cognitive decline!
Research with EPA or that compares EPA and DHA directly is lacking, especially in the
setting of cognitive performance/impairment
It is clear that more experimental data is needed to determine:
The effectiveness of the supplementation in terms of dose, type of -3 PUFA,
duration, and the influence of concurrent omega-3 and -6 PUFA in the basal diet
 The target of omega-3 PUFA action in brain (neurotransmission pathway,
inflammation, neurogenesis, etc)
The specificity of the impacted cognitive traits (memory, attention, emotivity, stress
response, etc)
Implicated mechanisms in order to select specific responsive populations (genotype,
gender, exposure to stress, etc)
All these parameters constitute confounding factors that seem to greatly influence the
results of the numerous reported studies

42.
How to ‘take’ fish oil supplements to minimise peroxidation
end products
Smaller capsules
Unlike our competitors, we keep our capsules small, making them not only easier to swallow but
to encourage and highlight the importance of split dosing where appropriate
Split-dosing
High doses (>1g) of omega-3 should be distributed throughout the day. Not only does this help
with digestion and uptake of the fatty acids within the oil, but it also ensures that blood levels
are sustained throughout the day
Taking the supplements with food
Capsules should never be taken on an empty stomach. Taking EPA/DHA with food (and ideally in
the presence of other dietary oil/fat) will increase the body’s natural ability to digest and absorb
the fatty acids
Inclusion of vitamin E
We add vitamin E to all of our EPA products to protect the free fatty acids from oxidation both
pre- and post-digestion

43. Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index
an early cardiovascular risk indicator
Omega-6 to omega-3 ratio
an established marker of long-term health and chronic illness
AA to EPA ratio
a measure of ’silent’ or chronic inflammation
A personalised plan aims to achieve:
an omega-3 index of more than 8%
an omega-6 to omega-3 ratio of between 3 and 4
an AA to EPA ratio of between 1.5 and 3

44. Free radical
damage and
oxidative stress
Skin
Lungs
Inflammation
Cardiovascular
Brain
Immunity
Ageing
Ubiquinol deficiency alters mitochondria function and lowers
antioxidant status, leading to increased free radical generation

45. A free radical has an electron
missing from its outer shell
X
Ubiquinol donates an
electron to a free radical
X
Ubiquinol donates
electrons to other
antioxidants
‘Recharged’ antioxidants
(i.e. vitamins C & E, lipoic acid) can
donate electrons to free radical
Ubiquinol – the antioxidant/antioxidant recycler

46. Time (hours)
VESIsorb®
Therapeutic level
120mg single dose of VESIsorb® delivered CoQ10 reaches therapeutic levels within 2 hours, reaching maximum
blood plasma levels (6.89 µg/mL) (Cmax)within around 4 hours (Tmax)
In contrast, 120mg single dose of oil-based CoQ10 reaches maximum blood plasma levels (2.44 µg/mL) within 5
hours and fails to achieve therapeutic levels
VESIsorb® increases the bioavailability of CoQ10 by 622%
Oil-based
Cmax
Tmax
VESIsorb® delivered CoQ10 is
absorbed FASTER, reaching
concentrations that are STRONGER
and stays in the body LONGER than
generic delivery methods

47. Managing homocysteine
Highly bioavailable (‘body-ready’) micronutrient actives
Formulated at proven dosages for enhanced efficacy
Strong benefits supported by strong health claims
Offers benefits for cardiovascular health, brain function and
mood balance
Synergistic benefits alongside the Igennus clinical omega-3
range
Small, easy-to-swallow tablets optimised for split-dosing
Split-dosing overcomes bioavailability issues related to
vitamin B12 intake and maintains optimal blood levels of key
B-vitamins
Suitable for vegetarians & vegans
Suitable for adults and children aged 7+

48. Ingredient features
Folate ([6S]-5-methyltetrahydrofolate) vs folic acid
 Quatrefolic®
provides the metabolic reduced folate form utilised and stored in the human body, as (6S)-5-
methyltetrahydrofolate, and may benefit certain genetic defects that influence folate metabolism.

Quatrefolic®
overcomes accumulation of unmetabolised folic acid (UMFA) arising from standard folic acid
supplementation, which has no biological function and whose effects are not yet known.
Vitamin B2 (riboflavin-5-phosphate)
 As with many B-vitamins, riboflavin must be converted to its active form – riboflavin-5-phosphate – in order for
it to be utilised by the body.
As absorption of riboflavin occurs in the upper gastrointestinal tract, a compromised digestive system can
adversely affect the body's ability to convert riboflavin to riboflavin-5-phosphate.
Vitamin B6 (pyridoxal-5-phosphate)
Vitamin B6 exists in 6 forms but only the pyridoxal-5-phosphate form has cofactor activity.
Several inborn errors of B6 metabolism exist, which can compromise vitamin B metabolism to pyridoxal-5-
phosphate.
Pyridoxal-5-phosphate is required for approximately 100 enzymes that are important in the metabolism of
neurotransmitters and other neuroprotective compounds.
Sweeney MR, Staines A, Daly L, Traynor A, Daly S, Bailey SW, Alverson PB, Ayling JE, Scott JM: Persistent circulating unmetabolised folic acid in a setting of
liberal voluntary folic acid fortification. Implications for further mandatory fortification? BMC public health 2009, 9:295.
Surtees et al. “Inborn errors affecting vitamin B6 metabolism” Future Neurol 2006, 5:615
Powers HJ: Riboflavin (vitamin B-2) and health. The American journal of clinical nutrition 2003, 77:1352-1360.

49. 49
A simple, expertly formulated, 1-a-day dual capsule system
Ultra concentrated
Mi ndCar e® omega-3 EPA
& DHA capsules with
vitamins D & E
Precisely formulated to target and support
brain function (250mg DHA plus 410 mg EPA
per capsule) using the body-ready rTG form of
omega-3 that is nature-identical and easily
absorbed by the body
Ultra concentrated
Mi ndCar e® omega-3 EPA
& DHA capsules with
vitamins D & E
Precisely formulated to target and support
brain function (250mg DHA plus 410 mg EPA
per capsule) using the body-ready rTG form of
omega-3 that is nature-identical and easily
absorbed by the body
Mi ndCar e® micronutrient
capsules contain:
full B complex plus zinc,
selenium, vitamin C and
targeted ACTIVES
Target distinct areas of brain health with a
comprehensive blend of synergistic vitamins,
minerals and specialist actives at proven,
effective levels and in super-bioavailable
Mi ndCar e® micronutrient
capsules contain:
full B complex plus zinc,
selenium, vitamin C and
targeted ACTIVES
Target distinct areas of brain health with a
comprehensive blend of synergistic vitamins,
minerals and specialist actives at proven,
effective levels and in super-bioavailable
 Mi ndCar e® is based on cutting-edge nutrition science and combines premium
triglyceride omega-3 fish oil containing 80% active doses of EPA and DHA with
scientifically proven nutrients for various aspects of brain health

50. MindCare®
BALANCE
Magnesium glycinate and L-
Theanine with their natural
calming effects act as relaxants,
reduce feelings of stress and
reduce anxiety
MindCare®
FOCUS
Acetyl-L-Carnitine, L-Theanine,
taurine and caffeine heighten
mental alertness and support
concentration, memory and
focus
MindCare®
LIFT
Magnesium glycinate and 5-HTP
help to regulate
neurotransmitters required for
mood balance
MindCare®
PROTECT
N-Acetyl L-Cysteine, alpha-lipoic
acid and resveratrol help
protect against
neuroinflammation and
improve and support energy
metabolism in the brain
Highly bioavailable micronutrients (vitamins C , D3 & E; vitamins B1, B2, B3, B5, B6, B7, B12 & folate; minerals zinc & selenium)
support immune & detoxification enzyme-mediated pathways. They support homocysteine recycling required for the production of
neurotransmitters, enhance neurotransmission via regulation of receptors, transporters and ion channels, support natural stress
response pathways, ensure optimal delivery of fuel to the brain, enhance cognition, relaxation, sleep, mental focus and reduce stress
and oxidative stress
Ultra concentrated MindCare® omega-3 EPA & DHA capsule
supports cognitive function, mental performance
MindCare®
micronutrient capsules

51. Supporting antioxidant defences
Alpha lipoic acid is an endogenous antioxidant and essential cofactor for many enzyme complexes
that interrupt cellular oxidative processes
 Increases acetylcholine production by activation of choline acetyl-transferase
 Increases glucose uptake
 Acts as a metal chelator
 Down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF-a
and inducible nitric oxide synthase
 Scavenges lipid peroxidation products such as 4-hydroxynonenal (HNE) and acrolein
Vitamin E
Antioxidant protection
Vitamin C
Further supports detoxification,
provides antioxidant protection
against free radicals
Reduces tiredness and fatigue
Necessary for the proper functioning of the CNS and psychological functioning

52. Vascular processesVascular processes Calcium homeostasisCalcium homeostasis
Oxidative stressOxidative stress
Aβ and Tau
accumulation
Aβ and Tau
accumulation
Inflammation and
immune system
Inflammation and
immune system
NeurotransmissionNeurotransmission
Proposed mechanisms of vitamin D-mediated multi-
targeted effects in cognitive decline
Landel V, Annweiler C, Millet P, Morello M, Féron F. Vitamin D, Cognition and Alzheimer's Disease: The
Therapeutic Benefit is in the D-Tails. J Alzheimers Dis. 2016 May 11;53(2):419-44.

53. Magnesium
• Regulates the CNS via
– neurotransmitter synthesis
– neurone activity
– synaptic plasticity
• Vitamin B6 absorption
• Required by 325 enzymes
(many of which act in the brain)
• Neurone health, synaptic plasticity, learning and memory
Low magnesium levels linked to anxiety, depression, irritability,
insomnia, confusion….
Magnesium as glycinate provides a bioavailable and effective magnesium source
Glycine promotes healthy immune, digestive and central nervous systems, production of
human growth hormones and creatine

54. Zinc
•Essential to the production of neurotransmitters
•Enhances neurotransmission via interaction with receptors, transporters and
ion channels in the neurone and synapse
•Low zinc status is linked to cognitive impairment via epigenetic changes of
the brain-derived neurotrophic factor (BDNF) gene
Selenium
•Up-regulates glutathione production
•Main component of antioxidant enzymes
•Supports proper adrenal function – commonly disrupted by high stress and
poor diet – leads to poor sleep, memory problems and fatigue
• Low selenium status is a risk factor for cognitive decline!
Berr C, Arnaud J, Akbaraly TN. Selenium and cognitive impairment: a brief-review based on results from the EVA study. Biofactors. 2012 Mar-Apr;38(2):139-44.
Hu YD, Pang W, He CC, Lu H, Liu W, Wang ZY, Liu YQ, Huang CY, Jiang YG. The cognitive impairment induced by zinc deficiency in rats aged 0 2 months related to BDNF DNA∼
methylation changes in the hippocampus. Nutr Neurosci. 2016 Jun 22:1-7.

55. Each capsule provides 410 mg EPA, 250 mg
DHA and 1000 iu vitamin D3 for intensive
daily support. The omega-3 is provided in the
superior rTG form, which is body-ready and
delivers higher levels of omega-3 into cells
faster than standard fish oil and krill oil.
This ultra-pure supplement is sourced
from wild, sustainable anchovies and the oil
is purified to remove all trace of mercury,
dioxins and PCBs. Natural lemon oil prevents
fish reflux.
SUPER CONCENTRATED
OMEGA-3
WILD FISH OIL & VITAMIN D3

56. ADVANCED
MULTIVITAMIN &
MINERALS
Pure Essentials Advanced Multivitamin &
Minerals is a comprehensive multi-nutrient
supplement, featuring full spectrum body-
ready methylated B-vitamins and active
mineral forms. Enhanced with a slow-release
delivery system, this supplement steadily
releases nutrients for optimal absorption and
uptake into the bloodstream. This advanced
formula is the ideal all-round multivitamin &
mineral supplement to support optimal
wellbeing.

57. Education Technical
Sophie Tully
Nutrition Education Manager
sophiet@igennus.com
Dr Nina Bailey
Head of Nutrition
ninab@igennus.com
Twitter @DrNinaBailey