MEDICAL NUTRITION THERAPY

Alzheimers Disease as
Type-3 Diabetes
Nutrition Therapies
Brian Devonshire

Abstract: Alzheimers Disease (AD) is the number one form of dementia in developing
countries. AD and Diabetes are closely associated and they both share many of the same
treatment strategies. Diabetes and obesity are closely linked as well. Formation of beta-
amyloid (A) plaques and neurofibrillary tangles (NFTs) is accelerated in the presence of
obesity and insulin-resistance. As a result, possible medical nutrition therapies for AD
include; prevention of obesity and diabetes management. This paper will discuss the
pathophysiology of AD development and some of the avenues for treatment of AD by targeting
both obesity and diabetes such as: weight management through physical activity, diabetic
medications and diet patterns like the Mediterranean diet; as well as the associated benefits
with each.

1
 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 2

Introduction

Alzheimers Disease as Type-3 Diabetes

AD, a neurodegenerative disorder which is a characterized by severe memory loss, is

generally accepted to be Type-3 Diabetes. The term first being coined by Suzanne de la Monte

and her colleagues as they noticed that AD exhibits characteristics from both Type-1 and Type-2

Diabetes; insulin production deficiency and insulin resistance, respectively.1

Prevalence and Risk Factors

AD is currently the most common form of dementia in elderly individuals in the United

States.2 There are two main types of AD; Familial (FAD) and Sporadic (SAD) or Late Onset

Age-Related (LOAD). SAD is the more common form of the two and risk increases

exponentially after age 65.2 Other risk factors include; compromised blood-brain barrier, immune

dysfunction and malnutrition.3 Development of AD is also much more likely in Type-2 Diabetics

and obesity is a major risk factor associated with Type-2 Diabetes.4 Genetics factors include

mutations in; Amyloid Precursor Protein (APP) and Presenilin 1 and 2 which are proteins

involved in proteolytic events that degrade beta-amyloid plaques.5

Pathophysiology

In AD, several physiologic and metabolic abnormalities have been observed including; beta-

amyloid plaques, neurofibrillary tangles and metabolic abnormalities associated with diabetes and other

chronic diseases like; insulin resistance, brain insulin deficiency, impaired glucose utilization and

increased oxidative stress. (Figure 1). This section will discuss the pathophysiology of: beta-amyloid

plaques & neurofibrillary tangles (1), and insulin resistance (2).

 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 3

Alzheimers
Disease

Low brain insulin Chronic Inflammation

levels

Advanced Glycation Oxidative Stress

End Products

Insulin Resistance

Hyperglyceridemia

Hypertyglyceridemia

Diabetes Mellitus

Figure 1: Potential mechanisms of diabetes causing Alzheimers Disease

1. Beta-amyloid Plaques & Neurofibrillary Tangles

Diagnosis of AD is determined mainly by the presence of beta-amyloid (A) plaques and

neurofibrillary tangles (NFT). Accumulation of A plaques are neurotoxic and lead to; oxidative

stress, chronic inflammatory responses and formation of NFTs.6 These NFTs are a result of

defective tau proteins which are used to stabilize neuron microtubules.

Hyperphosphorylation of Tau prevents binding to tubulin the proteins that make up

microtubules and, as a result, negatively affects proper neuron function.7 It has also been

shown that decreased GLUT 1 and GLUT 3 production in the brain is correlated with increased

Tau phosphorylation, meaning altered glucose transportation as seen in diabetic patients and

the resulting abnormal brain glucose metabolism may lead to NFTs.8,9

4 B. Devonshire

2. Insulin Resistance:
As was mentioned previously, type-2 diabetic patients experience a higher risk of AD 4,

this indicates a relationship with the development of AD and insulin resistance. For what follows,

it is important to note that a study published in 2008 by De la Monte 1 showed that Type-2

Diabetes was not sufficient to cause AD, although it could possibly serve as a cofactor in its

pathogenesis or progression.

2.1. Background
Earlier in this article it was stated that Type-1 and Type-2 Diabetes are a result of; insulin

production deficiency and insulin resistance, respectively. Insulin is a protein that regulates glucose

utilization in the body and its receptors are found in both the peripheral tissues and the central nervous

system (CNS). Production of insulin is mainly in the pancreatic beta cells but it is also produced in small

quantities by the brain.10 Deficiency of brain insulin, in AD, is a result of decreased permeation of serum

insulin across the blood-brain barrier.11 Insulin signaling pathways in the brain are mediated by the well-

known phosphoinositide 3-kinase (PI3K)/Akt and Ras/Mitogen Activated Protein Kinase (MAPK)

pathways.

2.2. Insulin Resistance in AD

Regarding those pathways and insulin resistance, studies using animal models with AD

showed that these signaling pathways are over-activated, which causes hyperphosphorylation of

Tau proteins.12 Similarly, other animal studies showed that A plaque accumulation led to

increased insulin resistance in both the brain and peripheral tissues.13 This reinforces what was

mentioned earlier, that the presence of A plaques promotes chronic inflammation and these

inflammatory cytokines impair insulin signaling.6

 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 5

2.3. Insulin Resistance in Diabetes and Metabolic Syndrome

In diabetic patients, chronic hyperglycemia is common and chronically elevated glucose

levels lead to the formation of Advanced Glycosylation End-Products (AGEs). Not only does

hyperglycemia cause the many neuropathies we see in diabetics but these AGEs, specifically, are

neurotoxic and specific cell-surface receptors for AGEs have been found on Ab peptides.14 These

AGEs are important to mention because they affect AD progression and also induce insulin

resistance. A study by Jia et al in 2006, looked at cultured skeletal-muscle tissue of mice and

found that methylglyoxal (MG) a type of AGE formed bonds with insulin and the resulting

MG-Insulin species significantly decreased glucose uptake.15 MG, by itself, did not produce the

insulin resistance observed. In the study, the insulin resistance was due to the formation of AGE-

Insulin species causing disruption of insulin signaling.

Along with hyperglycemia in diabetic patients, we also see dyslipidemia as well, usually

in the obese population. Dyslipidemia, specifically hypertriglyceridemia, can disrupt insulin

signaling inadvertently through the inhibition of pyruvate decarboxylase. Saturated fats (SFAs)

have higher oxidation potential and thus inhibit insulin signaling more. There is clear evidence in

humans that SFAs exacerbate insulin resistance.16

2.4. Insulin Signaling Benefits in AD

When signaling is working properly, insulin also has protective effects. Cell culture

studies of human neurons have shown that insulin is protective against A-plaque related

neuronal cell degradation.17 Other cell culture studies showed that insulin and insulin-like growth

factor-1 (IGF-1) reduces Tau phosphorylation.18 Therefore, not only does insulin regulate glucose

utilization, it also regulates A and Tau protein levels in the brain.

6 B. Devonshire

Treatments for
Alzheimers Disease

Prevention of Obesity

&

Diabetes Management

Weight Management Diabetic Medications

Physical Activity Diet Patterns

Figure 2: Potential treatments for Alzheimers Disease

Potential Treatments for Alzheimers Disease

The pathophysiology of AD development is complex and mainly involves the metabolic

abnormalities resulting from chronic diseases like Type-2 Diabetes and similarly, obesity.

Therefore, recommendations to potentially improve AD-related abnormalities include;

prevention of obesity/diabetes management (1) and diet/nutrition therapies (2). Summarized in

Figure 2 above.

1. Prevention of Obesity / Diabetes Management

Obesity is prevalent in Type-2 Diabetes patients and it has been shown that reducing obesity rates

is feasible in the adult population.19 However, prevention of obesity is critical in the early years of

children and adolescents and systematic reviews have shown promising interventions, including exercise

and diet, for prevention of weight gain regarding this population. 20 Further, it has been shown that the

presence of diabetes worsens functional status in AD patients and obesity is an important factor in both
 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 7

the functional decline 21 and development of Type-2 Diabetes.22 Also considering that insulin has
6,14-18
protective effects against AD and obesity-related impaired insulin signaling has negative effects ;

targeting insulin resistance through the prevention of obesity and management of diabetes may be

therapeutic for AD.

1.1. Weight Management:

There are a few avenues to the prevention of obesity and managing diabetes, including; Exercise

and Weight Management. The use of diabetic medications may also play a role. This section, however,

will discuss the effects of weight and weight management in AD and Diabetes.

Obesity and Risk of AD and Diabetes

There is a clear association with obesity and increased risk of AD. A study in 2008 showed that

middle-aged, obese men and women showed increased risk of AD as well as being underweight. 23

Another study in 2003 showed that, in women over age 70, each 1 point increase in BMI increased risk of

AD by 36%.24 Later, a 2011 meta-analysis reinforced these findings stating, underweight, overweight

and obesity in midlife increase dementia risk. 25

Along with decreasing risk of AD, prevention of obesity through weight management also plays a

significant role in diabetes management. A recent review in 2014 showed that weight loss delayed onset

and decreased risk of developing Type-2 Diabetes in pre-diabetes. The author concluded that, Physicians

should encourage weight loss in all overweight patients with or at risk of T2DM. 26 It was also

mentioned that weight loss improves glycemic control, which can prevent the negative effects of

hyperglycemia and ultimately, AGEs.14,15

1.2. Exercise / Physical Activity:

Considering weight management has such an influential role in diabetes, weight management

interventions, specifically involving PA, may also benefit in reducing AD progression. This is because,

exercise or PA, is a critical factor in weight management. This section will discuss PAs role in

obesity/diabetes management and AD.

8 B. Devonshire

Physical Activity in Obesity and Diabetes Management

As for exercise in diabetes management, many studies and reviews have shown that lifestyle

interventions; including physical activity, reduces both obesity and specifically, diabetes. 27-29 Particularly,

one relatively large study with over 5000 participants showed that intensive lifestyle interventions;

including diet changes (calorie restrictions) and 175 minutes of physical activity per week, actually led to

remission from Type-2 Diabetes to Pre-Diabetes and in some cases, complete remission. 29

Physical Activity in AD
There are no randomized control trials (RCTs) showing that exercise or physical activity can

prevent or delay the onset of AD, however, there is strong evidence that exercise can improve cognition.

A review in 2012 noted that physical activity counteracts declining hippocampal function in AD

through the induction of neurotrophins and neuroplasticity growth factors. 30 Later in 2014, a study found

similar results however the hippocampal preservation due to PA was only found in individuals at

increased genetic risk for AD.31 More recently, in 2015, a large cross-sectional study confirmed these

results and found not only hippocampal but overall brain-volume increases associated with PA as well as

a lower BMI.32 Many recent reviews of RCTs show that physical activity is; beneficial in all stages of

dementia and improves physical function of people with dementia. 33-34 On the other hand, more recent

systematic reviews by the Cochrane Database in 2013 and 2015 have shown no clear evidence that

physical activity improves cognition in dementia.35,36 However, the authors of the former study caution

interpreting the results as there was substantial heterogeneity in the analysis.

1.3. Diabetic Medications:

Diabetic medications work by; stimulating the pancreas to synthesis more insulin, decreasing the

level of insulin resistance in the body, or delivering insulin directly to the brain via olfactory and

trigeminal nerve channels. Considering that insulin resistance and low brain insulin levels are risk factors

in the development of AD 1,11 and insulin has protective effects in the brain 17,18 , insulin-sensitizing drugs

and intranasal insulin may also be beneficial for AD.

 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 9

Insulin Sensitizing Medications in AD:

Notable medications among this class are Metformin and Thiazolidinediones (TZDs).

Metformin
Metformin is a common drug used in the treatment of diabetes and it mainly works by decreasing

hepatic glucose output and also increases insulin sensitivity to liver and skeletal muscle tissues. A large

Taiwanese study, involving over 100,000 subjects over the age of 50, found that Metformin significantly

decreased risk of dementia by 35% over 8 years. 37 Other studies suggest a slightly higher risk of AD in

long-term Metformin users and worse cognitive performance, while the other diabetic drugs did not

increase risk of AD.38,39

TZDs
TZDs work by inhibiting hepatic glucose output and stimulating peroxisome proliferator

activated recptor gamma (PPARs), leading to both anti-inflammatory and insulin sensitizing effects. A

few studies have shown that TZDs may improve memory and stabilize brain glucose metabolism,

however the majority seem to show no benefit or slowing of clinical progression of AD. 40-43

Intranasal Insulin in AD
The final diabetic drug worth mentioning is Intranasal Insulin. Many randomized case-controlled

trials (RCTs) have shown Intranasal Insulin, with doses of 20-40 IU, improves cognition and memory

recall.44-46 A review in 2012 confirmed these findings and concluded that intranasal insulin improves

memory and cognition in AD, however these benefits are relatively small and warrant further study. 47

2. Diet / Medical Nutrition Therapies

Many of the studies regarding weight and diabetes management, mentioned above, incorporated

diet alterations into their lifestyle interventions as well. 19,20,27-29 One of the major factors involved in

prevention of obesity is weight management and in order to accomplish that, proper diet must be

incorporated. The following section will outline some general diet therapies related to AD, including diet

patterns and specific Macro/Micronutrients that are involved.

10 B. Devonshire

2.1. Diet Patterns:

Many researchers are now beginning to study diet patters, rather than specific nutrients, because

these patterns are thought to better represent how people eat. This section will discuss diet patterns such

as; the Ketogenic diet and the Mediterranean diet.

Ketogenic Diet
A Ketogenic Diet (KD) involves consuming very low levels of carbohydrates, forcing the body to

use its fat stores, creating more ketone bodies and inducing keto-acidosis. The brain can use ketones as

fuel and considering GLUT transporters are deficient in AD, KDs may be beneficial. 48 A review in 2014

looking at KDs in neurodegenerative diseases, like AD, stated that ketone bodies like beta-

hydroxybutyrate protect in-vitro neurons from A toxicity.49 They also mentioned other studies that

showed decreases in A plaques and improved cognition in animals given KDs. The authors also

mentioned that human studies, not specifically on AD, have shown that KDs significantly improve blood

glucose levels and thus reduce detrimental AGEs. However, there is no strong evidence of KDs

usefulness in humans but it appears promising. 49

Mediterranean Diet
The Mediterranean Diet is the most widely studied diet pattern and is characterized by a high

consumption of fruits, vegetables, grains (whole wheat), beans, nuts, olive oil, and lean meat like poultry

and fish. Alcohol is consumed in moderation and red meats are avoided. A meta-analysis in 2010,

including 18 cohort studies, concluded that adherence to the Mediterranean Diet was associated with

significant reduction in neurodegenerative diseases, including AD. 50 Many other studies have as well

shown that higher adherence to the Mediterranean Diet is associated with lower risk of AD and improved

cognition in the elderly.51-54 A later review in 2013, looking at diet in AD, continues to support these

findings.55
 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 11

2.2. Macronutrients:

Carbohydrates
High levels of carbohydrates can lead to increased glycation, the detrimental AGEs, and may lead

to the development of AD.56 However, a prospective study in 2007, looking at 900 subjects for over 6

years, found no association with high-card diets and AD. 57 A later review article in 2011 concluded that:

buildup of AGEs damages neurons, fructose induces 10x more AGEs than glucose and dietary

modifications of fewer highly-processed carbohydrates, relatively more fats and cholesterol is protective

against AD.58

Fats/Lipids:

Medium-Chain Triglycerides
Medium-chain triglycerides (MCTs) can be metabolized into Ketones and used by the brain. A

2011 report mentioned a medical food for AD named, AC-1202 (Axona). AC-1202 is a MCT and has

shown improvements in cognition scores. However, long-term ketosis can be detrimental in

diabetes/obesity, therefore it is recommended do short-term trials. 59

Saturated Fats
A high-fat diet can disrupt insulin signaling and lead to insulin resistance and saturated fats

(SFAs) have a higher potential to induce insulin resistance. 16 A systematic review and a qualitative review,

both in 2014, showed a correlation with diets high in SFAs and AD. 60,61 Further, a 2006 study of 1,449

participants showed that a moderate intake of SFAs increased risk of AD. 62

Omega-3 / Polyunsaturated Fatty Acids (PUFAs)

PUFAs like EPA or DHA are less saturated than SFAs and thus contribute less to insulin

resistance. They also play a role in anti-inflammatory processes and could of significance for AD. 63 The

previously mentioned observational studies not only found that SFAs increased risk of AD but consuming

moderate amounts of PUFAs decreased risk of dementia and AD. 61,62 A review in 2013 looked at 11

different clinical trials, which tested effects of DHA or EPA on cognitive performance in AD, and
12 B. Devonshire

concluded that supplementation with DHA or EPA generally has no significant effect on cognition;

however 6 studies did show some improvements.55 The differences between observational and clinical

intervention studies may be due to the length of the latter trials not being long enough. Another

explanation for the differences which was offered by the authors of the OmegAD Study in 2014, states

that the potential for Omega-3s to oxidize, and induce lipid oxidation, may counterbalance potential

beneficial effects. 64

2.3. Micronutrients:

Vitamin D
Vitamin D deficiency in obesity is common as a result of excess fat stores sequestering the fat-

soluble vitamin. Vitamin D also plays role in inflammation and may be of concern in AD . Genetic studies

have shown an association with Vitamin D receptors and AD. 65,66 A cross-sectional study in 2014, looking

at 1,658 elderly ambulatory patients, showed an association with Vitamin D deficiency and a substantial

increased risk of AD.67 One study looking at 1,604 men found no significant cognitive improvements. 68

However, another much larger study looking at 5,596 women showed improved cognition scores in

women with adequate Vitamin D intake, suggesting gender associations. 69

B-Vitamins
B-Vitamins such as, B12 or Folate, may play a role in AD by regulating Homocysteine levels,

which have been found to be elevated in AD patients.70 However, current available evidence for B-

Vitamins on AD and cognitive decline is inconclusive. A meta-analysis in 2014, looking at 11 large trials

in 22,000 participants, concluded that lowering of serum Homocysteine through B-vitamins had no

significant effect on cognitive scores.71

Antioxidants
Oxidative stress is a risk factor for developing AD, so it is proposed that antioxidants like Vitamin

E, Vitamin C, Phenols, Carotenoids and the trace mineral Selenium may play a role. One study using in

vivo transgenic mice, showed that Vitamin E (an antioxidant) prevented hyperphosphorylation of Tau. 72

However, in humans, a recent review in 2014 looked at 13 longitudinal cohort studies and 8 clinical trials
 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 13

and concluded that the, Available data does not seem to support the idea that long-term dietary

antioxidant intake can reduce AD risk 55

Minerals:

Iron and Zinc

Iron is a potent source of reactive oxygen species and increases oxidative stress in AD. 73 Irons

oxidative capacity exacerbates A toxicity and it has been shown, in mice neurons, that Zinc can

ameliorate the negative impacts of Iron.74

Calcium
Regarding the treatment for diabetes, Metformin is associated with Vitamin B12 malabsorption

and Calcium is required for its uptake.75 A comparative study in 2000, showed that calcium

supplementation reversed the Metformin-induced malabsorption. 75 This may be of clinical importance for

long-term Metformin users.

Conclusion
Prevention of obesity and management of diabetes through weight management, physical activity

and certain diet patterns show promising beneficial effects in decreasing risk of AD and improvement in

cognition.

Reaching ideal body weight is a critical factor in improving diabetes and thus decreasing AD risk.

Physical activity is recommended for AD patients at 175 minutes/week to improve diabetes risk and

potentially cognition. Adopting the Mediterranean diet is highly recommended. There may be possible

neuroprotective effects with Ketogenic Diets and MCTs, however, caution with long-term trials in

obese/diabetic patients. Patients should strive to avoid SFAs and refined-carbohydrates, especially

fructose, as much as possible. Replacing SFAs with PUFAs like DHA or EPA show promising results in

the long-term.
14 B. Devonshire

Diabetic medications like Metformin or Intranasal Insulin can be useful in decreasing AD risk

and improving cognition, respectively. Calcium supplements should be considered in AD patients using

Metformin, especially in long-term. Vitamin Ds association with AD is genetically and sex-linked and

maintaining adequate levels may lead to improved cognition in women.

B-Vitamins show no significant effect on cognition and there is no data supporting antioxidants in

decreasing AD risk. A handful of studies did show associations with certain micronutrients, however,

studies are contradictory and there needs to be more randomized controlled trials.
 Alzheimers Disease as Type 3 Diabetes: Nutrition Therapies 15

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