1. Delaying dementia – a case of
nutritional inadequacies?
Nina Bailey
BSc MSc PhD ANutr

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 causes are most commonly brain disease including Alzheimer’s
disease, vascular dementia, frontotemporal dementia, Lewy body
dementia, Korsakoff's syndrome, Huntingdon’s chorea, Parkinson's
disease
• These diseases begin to damage the brain many years before symptoms
become apparent and cause a progressive decline in functioning as more
of the brain is damaged

3. Treat, prevent or delay?
• In the last few decades, huge advances have been made in
understanding the neurobiology of dementia, leading to an increase in
trials assessing various treatments
• Drugs used to treat dementia are of limited clinical benefit and so do
not treat the underlying cause
• Preventing or postponing the onset of dementia and delaying or slowing
its progression appear to be required options, leading to a consequent
improvement of health status and quality of life in older age

4. Risk factors for cognitive decline and dementia
 Brain function
Higher mental stimulation through education, occupation or leisure is
associated with lower risk
Higher social interaction in later life is associated with lower risk
 Lifestyle factors
Regular physical exercise at all ages is associated with lower risk
Current smoking increases risk
Excessive alcohol use increases risk
Diabetes increases risk
Depression increases risk
Elevated homocysteine levels increases risk
High blood pressure increases risk
Elevated cholesterol increases risk

5. The apolipoprotein E (APOE) gene, on chromosome 19, is the major
genetic source of the common forms of late-onset Alzheimer’s disease
 APOE carries and delivers cholesterol to the nerve cells which use it for the
repair and establishment of new connections
 There are three common variants of the APOE gene:
APOE 3 variant is the most common (neutral)
APOE 2 variant appears to have a protective influence
APOE 4 variant is thought to increase the risk of Alzheimer’s disease
People who inherit one copy of APOE4 are three times more likely to develop
Alzheimer's and people who inherit two copies are 12 times more likely to
develop the disease

6. Mutations in the Amyloid Precursor Protein (APP), Presenilin 1
and Presenilin 2 and inherited Alzheimer's disease
• The APP gene makes a protein that is present on the surface of nerve
cells and may help them grow and move
• The presenilin 1 and 2 genes make proteins that are required for the
correct functioning of the APP protein
• Mutations in any one of these genes can cause the APP protein to be cut
off from the surface of nerve cells, leading to an accumulation in amyloid
plaques which are a hallmark of Alzheimer’s disease

7. Cardiovascular health
Hypertension can cause problems by damaging and narrowing the blood
vessels in the brain, raising the risk of a blood vessel becoming blocked or
bursting, leading to an increased risk of stroke, cognitive impairment and
vascular-related dementia
Hypertension is associated with higher levels of neurofibrillary tangles and
amyloid plaques (poor clearance) and greater hippocampal and cortical
atrophy (loss of neurones)
High blood pressure in mid life rather than late life appears to be associated
with an increased risk of developing dementia (Power et al., 2011)

8. Cardiovascular health
Cholesterol plays an essential role in healthy brain function
High cholesterol in mid life rather than late life appears to be associated with
an increased risk of developing dementia (Anstey et al., 2008)
High cholesterol levels may accelerate the production of beta amyloid,with
autopsy data showing lower midlife cholesterol to be associated with lower
numbers of plaques and tangles (Kivipelto et al., 2006)
Higher HDL is associated with larger hippocampal volume and reduced risk of
cognitive impairment and Alzheimer's disease

9. Elevated homocysteine

10. Elevated homocysteine
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!!

11. Elevated homocysteine
Infertility
Osteoporosis
Inflammatory bowel disease
Chronic fatigue syndrome
Pregnancy complications
Atherosclerosis/heart attack/stroke
Compromised cell cycle control
Diabetes
Neurodegenerative disease
Depression/mood disorders

12. Homocysteine and dementia
• High values of plasma homocysteine and low levels of vitamin B12
and folate are frequently present in Alzheimer’s patients (Coppede
2010)
• Deficiencies of B vitamins (folate, vitamin B6 and vitamin B12) and
elevated homocysteine levels have been associated with increased
risk of cognitive impairment, Alzheimer’s disease and vascular
dementia (Herrman & Obeid 2011)
• Elevated homocysteine may also increase oxidative stress and the
production of beta-amyloid plaques in the brain (Herrman & Obeid
2011

13. Homocysteine and dementia risk factors
• Elevated homocysteine is also associated with cardiovascular disease,
diabetes and major depression
• As levels of homocysteine in the blood are directly influenced by
levels of the B-complex vitamins (folic acid, 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 folic acid
successfully lowers homocysteine (VITAL 2003; Schnyder et al., 2002;
Lonn et al., 2006; Stanger et al., 2009)

14. Using B vitamins to lower homocysteine as a method to reduce
dementia risk
• Clinical trials in older adults have not shown that increasing B vitamin
intake or using supplements reduces the risk of cognitive decline or
dementia; however, some trials demonstrated slowing of brain atrophy
and improvement in some domains of cognitive function
• It is possible that if such supplementation were begun in midlife, when
chronic elevations in homocysteine could be prevented, they would be
more beneficial, although further research is required to determine this

15. Diabetes, especially type 2, and metabolic syndrome appear to be risk
factors for cognitive impairment and dementia
• Meta-analysis finding suggests that diabetes may be associated with
a 47% increased risk of any dementia, a 39% increased risk of
Alzheimer’s disease, and a 138% increased risk of vascular dementia
(Lu et al., 2009)
• APOE4 genotype combined with diabetes doubles the relative risk of
dementia compared with diabetes alone (Peila et al., 2002; Xu et al.,
2004)

16. Depression is a common comorbidity in dementia
• A history of depression has been associated with an increased risk of
Alzheimer's disease
• A review of epidemiological studies reported that a history of
depression was associated with around double the risk of Alzheimer's
(Ownby et al., 2006)
• Depression is associated with increased inflammation and high
cortisol, both of which have a detrimental impact on brain structure
and function

17. Comorbidity
Dementia
Diabetes
CardioDepression

18. • Dementia is NOT a normal part of ageing, although the risk of
developing dementia increases with age
• Many nutrients, micronutrients and metabolic enzymes known
to be essential for substrate metabolism, substrate utilisation
and energy transfer are known to reduce with age
• Deficiencies in a number of nutrients and micronutrients have
been observed in dementia patients, including omega-3 fatty
acids, vitamin A, vitamin B12, vitamin D, folate, iron, vitamin E
and vitamin C (Lopes da Silva et al., 2013)

19. Oxidative damage and mitochondrial decay in ageing
• Oxidative stress-induced damage in the brain is thought to contribute to
cognitive impairments in ageing humans
• Oxidative stress and lipid peroxidation are believed to be contributing
factors leading to neuronal loss and mitochondrial dysfunction in Parkinson's
disease and may play an early role in the pathogenesis of Alzheimer's
disease
• Several studies show that there is an emerging link between individual
stress and intracellular oxidative stress as measured by
inflammatory cytokine (TNF-α), glycosylated haemoglobin (HbA1C) and
malondialdehyde (MDA) and low levels of enzyme antioxidants superoxide
dismutase (SOD) and glutathione peroxidase (GPX) (Padurariu et al, 2009)

20. • Cognitive decline is correlated with synaptic loss and many of the
components required to maintain optimal synaptic function are
derived from dietary sources
• As synapses are part of the neuronal membrane and are continuously
being remodelled, the availability of sufficient levels of nutritional
precursors to make the phospholipids required to build neuronal
membranes may have beneficial effects
• Oxidative damage, inflammation, demyelination, impaired processing
and metabolic deficits are all associated with the ageing brain
• Could a cocktail of multiple antioxidants with anti-inflammatory
agents be beneficial in the prevention of neurodegenerative disease?

21. Inflammation and dementia
• Inflammation factors are known to be associated with a higher
risk for Alzheimer's disease and cognitive decline (Halliday et al.,
2000)
• Two large-scale prospective studies showed baseline blood
levels of inflammatory markers are associated with higher risk of
incident Alzheimer's disease (Schmidt et al., 2002; Engelhart et
al., 2004)

22.  Steps to reducing dementia risk:
Reduce oxidative damage
Increase antioxidant enzymes
Decrease homocysteine and cholesterol levels
Manage blood pressure
Modulate inflammation
Increase cellular energy
Optimise neuroprotection
Enhance neurogenesis
Support cell membrane integrity
Optimise neurotransmitter levels

23.  Steps to reducing dementia risk:
Reduce oxidative damage
Alpha lipoic acid
Vitamin E
Vitamin C
Carnosine
Coenzyme Q10
Regulators of antioxidant systems
Superoxide dismutase (SOD) (copper, zinc, manganese & selenium)
Glutathione (Vitamin B6, cysteine)

24. 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 and
acrolein
(lui, 2007; Moreira et al., 2007; Maczurek et al., 2008; Salinthone et al., 2008)

25. Carnosine is a naturally occurring antioxidant and metal chelator
• Inhibits lipid peroxidation and the formation of advanced glycation end
products (AGEs) which have been implicated in the progression of
diseases including dementia, cardiovascular disease and stroke
• Inhibits protein glycation and DNA/protein cross-linking which protects
against a beta-amyloid accumulation (Alzheimer’s disease), and alpha-
synuclein accumulation (Parkinson’s disease)
• Carnosine also plays a vital role in carrying fatty acids from the cytosol
into the mitochondria where they are oxidised for energy

26. Coenzyme Q10 has a dual function as it is essential for generating
energy in mitochondria whilst also being a powerful anti-oxidant and
anti-oxidant recycler including vitamin E, vitamin C and lipoic acid
• Its ability to quench free radicals helps to maintain the structural
integrity and stability of mitochondrial and cell membranes
• Supplementation with CoQ10 may have benefits for Huntington's and
neurodegenerative diseases such as Parkinson's and Alzheimer's
• Coenzyme Q10 has been shown to be neuroprotective and dose-
dependently inhibits the formation α-synuclein and β-amyloid fibrils
(Spindler et al., 2009)
• Coenzyme Q10 also has major implications for cardiovascular health

27. Optimising the diet
• At present, for older subjects, 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 predementia and dementia syndromes
• 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)

28. Mediterranean diet
• Dietary patterns characterised by higher intake of fruits, vegetables,
fish, nuts and legumes, and lower intake of meats, high fat dairy and
sweets/sugars seem to be associated with lower risk of cognitive
impairment and dementia (Gu et al., 2011)
Several studies have found a lower risk of dementia is associated with
higher intake of fruit and vegetables and higher adherence to the
Mediterranean diet (Solfrizzi et al., 2011)

29. Mediterranean diet
• A study of 1433 older people showed 6.5% of cases of mild cognitive
impairment or dementia to be attributable to low fruit and vegetable
consumption Ritchie et al., 2010)
• Increasing fruit and vegetable consumption and eliminating depression
and diabetes are likely to have the biggest impact on reducing the
incidence of dementia (Ritchie et al., 2010)
• Another study showed an 88% lower risk of any dementia and 92%
lower risk of Alzheimer’s disease in those with an overall healthy diet at
midlife, compared to those with an unhealthy diet (Eskelinen et al.,
2011)

30. Mediterranean diet
• A 2011 systematic review found that a Mediterranean diet appeared
to be more effective than a low-fat diet in bringing about long-term
changes to cardiovascular risk factors, such as lowering cholesterol
level and blood pressure (Nordman et al., 2011)
• Adherence to the Mediterranean diet may affect not only risk for
Alzheimer’s disease but also subsequent disease course (Scarmeas et
al., 2007)

31. What is the Mediterranean diet?
The principal aspects of this diet include:
• High consumption of olive oil, legumes, unrefined cereals, fruits
and vegetables
• Moderate to high consumption of fish, moderate consumption of dairy
products (mostly as cheese and yoghurt), moderate wine consumption
• Low consumption of meat and meat products

32. Mediterranean diet nutrients
• Low in saturated fat
• High in polyunsaturated and monounsaturated fat
• Rich source of quality protein
• Rich in essential vitamins and minerals
• High in omega-3 fatty acids
• Low in omega-6 fatty acids
• High in dietary fibre
• High in antioxidants
• High in polyphenols and flavonoids

33. Fish consumption and dementia
• 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)
• Fish is a unique nutritional package
• Fish is a predominant source of long-chain omega-3 fatty acids

34. Omega-3 and dementia
• Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFA),
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
• Deficiencies in omega-3 fatty acids are observed in dementia patients (Lopes
da Silva et al., 2013)
• A higher plasma EPA concentration is associated with a lower incidence of
dementia (Samieri et al, 2008)

35. • 2012 meta-analysis of 10 studies (including 2,280 subjects)
- EPA and total n-3 PUFAs were decreased in patients with dementia
- levels of EPA, but not DHA or other PUFAs, were significantly lower in
patients with pre-dementia syndrome
- EPA may act as a disease-state marker AND a risk factor for cognitive
impairment (Lin et al, 2012)
• A higher plasma EPA concentration is associated with a lower incidence of
dementia (Samieri et al, 2008)
• High AA:DHA and omega-6:omega-3 is associated with an increased risk of
dementia (Samieri et al., 2008)
• EPA intake is more advantageous than DHA in reducing "brain effort" relative to
cognitive performance (in young adults) (Bauer et al., 2014)
35

36. EPA and brain conditions
• The HPA-axis is the body’s mechanism for dealing with stress
• EPA helps reduce its dysregulation, which plays a role in the onset of
several conditions, including:
⁻ depression
⁻ chronic pain and fatigue syndromes
⁻ neurodegenerative disease such as Huntington’s and Alzheimer's
disease
⁻ reduction in brain grey matter
(Caetano et al, 2007,Burgmer et al, 2009, van Duijn et al, 2010, Puri et al, 2008)
• EPA and not DHA has been shown to reduce the symptoms of these
conditions and support the brain’s natural protective processes
(Salvati et al, 2004; Salvati et al, 2008)
36

37. EPA has several neuroprotective roles in the brain
EPA up-regulates gene expression concerned with neurogenesis
neurotransmission and connectivity, improves endothelial nitric oxide
generation and decreases inflammatory cytokine levels ((Salvati et al, 2004;
Salvati et al, 2008; Calder 1997)
EPA enhances brain acetylcholine levels, and suppresses the production of pro-
inflammatory cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-
6) (McCarty 1999)
The neuroprotective effect of EPA is also in part, thought to be through its ability
to inhibit neuronal apoptosis (Martin et al, 2002; Lonergan et al, 2004)
GLA in conjunction with EPA, is known to decrease inflammatory leukotriene B4,
IL-1 and IL-6 consequently offers cerebral anti-inflammatory effects (McCarty
1999).

38. Reducing the risk of developing dementia
Keep an active mind
Keep fit and active
Eat a Mediterranean-style diet
Look after cardiovascular health
Reduce the risk of developing diabetes

39. Comorbidity
Dementia
Diabetes
CardioDepression

40.  Steps to reducing dementia risk:
Reduce oxidative damage
Increase antioxidant enzymes
Decrease homocysteine and cholesterol levels
Manage blood pressure
Modulate inflammation
Increase cellular energy
Optimise neuroprotection
Enhance neurogenesis
Support cell membrane integrity
Optimise neurotransmitter levels

41. ninab@igennus.com
www.igennus.com
drninabailey.co.uk
01223 421434
07527384229