Functional Nutrition for Alzheimer’s Disease

What is Alzheimer’s disease?

Alzheimer’s disease is a degenerative brain disease that causes progressive dementia and is eventually fatal.

It is estimated to affect 5.7 million Americans (as of 2018) and is the 6th leading cause of death. It is also the leading cause of dementia (involved in up to 80% of all cases) (1).

It is unique from other forms of dementia because people with Alzheimer’s disease have characteristic amyloid-beta protein  (also called beta-amyloid) plaques in their brains and tau-protein tangles within neurons (which are not present in other forms of dementia).

Technically, Alzheimer’s disease can only be officially diagnosed after death, with an autopsy of the brain to look for those amyloid-beta plaques.

Overall, the risk of developing Alzheimer’s disease at some point in life is 10-12% for the average adult or 15-39% for those with a 1st degree relative with the disease (2).

What are some symptoms of Alzheimer’s?

It is believed that differences in brain function associated with Alzheimer’s disease actually begins years before overt symptoms appear (perhaps up to 20 years prior) (345).

Some of these early indicators include reduced levels of beta-amyloid peptides and increased levels of tau protein and phosphorylated tau protein in the cerebrospinal fluid (678).

However, these findings have not yet been translated into mainstream screening tools.

In general, symptoms of Alzheimer’s progress over several years as follows (1):

  • Difficulty remembering things (especially names, events, or conversations)
  • Apathy and/or depression
  • Trouble communicating
  • Disorientation/confusion
  • Poor judgment
  • Changes in behavior and personality
  • Difficulty speaking, then swallowing and walking

Alzheimer’s disease usually affects people later in life (60 years or older), but can also be early-onset and affect someone as early as 30 years old (although early-onset only accounts for less than 5% of cases) (19).

What are some factors associated with increased risk of Alzheimer’s?

The following factors are associated with increased risk of Alzheimer’s disease:

1. Age

The risk of developing Alzheimer’s disease continues to increase with age. In fact, age is considered the biggest risk factor.

Approximately 3% of people between the ages of 65 and 74 have Alzheimer’s, 17% between the ages of 75 and 84 have it, and 32% of people 85+ have it (10).

2. Genetics

Early-Onset Alzheimer’s

There are 3 gene mutations associated with a greater risk of developing early-onset Alzheimer’s disease. These are PSEN1, PSEN2, and APP – all genes involved in the production/processing of amyloid-beta protein (2).

Remember, this form of Alzheimer’s disease is relatively rare, involving less than 5% of all cases, and NOT all of these cases have mutations in these genes. Other factors are also involved.

However, it does appear that anyone with certain mutations in the PSEN1 or APP gene will develop Alzheimer’s disease if they live long enough (these genes have 100% penetrance). In contrast, only about 95% of people with mutations of the PSEN2 gene will develop it (incomplete penetrance) (1112).

Late-Onset Alzheimer’s

The most commonly discussed “Alzheimer’s gene” is ApoE4. This gene can be involved in both early and late-onset Alzheimer’s disease (but since late-onset accounts for 95%+ of all cases, this gene gets the most attention).

The ApoE gene codes for a cholesterol transport protein. It has 3 forms – 2, 3, and 4.

The “3” form is the most common. Only the “4” form is associated with an increased risk of Alzheimer’s (50-70% of people with Alzheimer’s have at least one copy of this gene), while the “2” form might be protective (213).

If you have one copy of the ApoE4 allele, you have a 3x increased risk of developing Alzheimer’s disease. If you have 2 copies, you have an 8-12x greater risk (3).

But it is a very common allele, and having it doesn’t tell you whether you’ll get Alzheimer’s definitively or not. Plenty of people get dementia who don’t have these alleles, and some people who have these alleles never develop it.

Your genes are NOT determinants, just predispositions. Many factors play a role, including things like diet, stress levels, sleep, etc. and these are in our control!!

People should not fear that understanding their genetic information is fatalistic. It’s definitely not.

However, because of concerns about the value of knowing your genotype, ApoE4 testing is not widely used in clinical practice.

3. Poor Cardiovascular Health  

The brain relies on healthy blood vessels to deliver oxygen and nutrients, so it is important to keep this system healthy to prevent dementia.

Smoking and diabetes have both been linked to poor cardiovascular health and increased risk of Alzheimer’s disease (141516). Even high blood sugar levels without full-blown diabetes may increase the risk (17).

What are some low-cost lifestyle changes that can help reduce the risk?

1. Exercise

Exercise appears to be one of the most important protective factors against dementia (181920).

This is probably because exercise improves cardiovascular health and increases BDNF levels (brain-derived neurotrophic factor), which promotes neuronal growth and hippocampal volume (an area of the brain where memories are formed) (21).

No firm guidelines have been developed, but exercising 45-60 minutes at least 3 days per week for 8 months (a mixture of cardio and strength training) has been shown to improve memory in older adults (22).

2. Mediterranean-Style Diet

A Mediterranean-style diet rich in vegetables, fruit, legumes, nuts, whole grains, olive oil, and fish has been linked to reduced risk of Alzheimer’s disease (2324).

Green leafy vegetables and berries appear to be especially protective (25262728).

3. Sleep

Higher quality sleep is linked to lower risk of Alzheimer’s disease (29).

Animal studies have found that amyloid-beta protein increases in the brain with sleep deprivation and that high-quality sleep helps clear these proteins (303132).

4. Mental Stimulation

Having a mentally-stimulating job or higher education has been associated with a reduced risk of Alzheimer’s disease (3334).

Maintaining a healthy social life, reading, writing, doing crossword puzzles, playing card or board games, engaging in stimulating discussions, and listening to music can also help reduce the risk (3536).

Recent advances in understanding:

There has been a lot of discussion recently that the amyloid-beta plaques may be a side effect, not a cause, of the neurodegeneration in Alzheimer’s (37).

We have recently discovered that amyloid-beta is actually an antimicrobial peptide, so it could be produced in response to various infectious agents in the brain.

Because of this, researchers are starting to shift their thinking about the importance of getting rid of these plaques. Maybe amyloid-beta proteins are actually functioning as antibiotics or antivirals (38) ??

But still, there is a correlation between plaque in the brain & risk of cognitive decline. It is just unclear whether they directly cause neuronal damage or are a side effect.

MEND Diet & Lifestyle Intervention (now known as the Bresden Protocol) for Alzheimer’s (39):

Works under the hypothesis that many factors contribute to the development of Alzheimer’s.

We don’t want to target just one, but rather many pathways, to get the best results.

Main principles of the Bresden Protocol:

  1. Want to optimize (not just normalize) all metabolic parameters.
  2. Address as many known pathways that affect neural plasticity as possible.
  3. Theorize that there is a threshold where the brain tips back and forth before neuron-building and neuron-destroying. The goal is to tip it back to neurogeneration (rather than degeneration). Probably don’t need to get every single thing in the protocol right, but if you do enough, you’ll probably hit that threshold.
  4. Personalize & prioritize the protocol based on each person’s lab values.
  5. Check in periodically and make adjustments to the protocol as needed.
  6. Try to address each contributing pathway as far upstream as possible.

The Bresden (MEND) Protocol:

  1. Optimize diet 
    • Reduce simple carbohydrates.
    • Reduce inflammation (LEAP could probably help here!)
    • Patients given diet options to choose from (low grain, low glycemic, low inflammatory, etc.)
    • Goal is to minimize inflammation & reduce insulin resistance.
  2. Enhance autophagy & ketogenesis
    • Fast 12h per night, including 3 hours before bed.
    • Goal is to reduce insulin levels and reduce amyloid-beta levels (one of the proteins that forms Alzheimer’s plaques in the brain).
  3. Reduce stress
    • Personalized interventions, based on lifestyle.
    • Could include yoga, meditation, music, etc.
    • Goal is to reduce cortisol & CRP and decrease activation of the stress axis.
  4. Optimize sleep:
    • 8h of sleep per night.
    • Take 0.5 mg of melatonin by mouth at bedtime if trouble falling asleep (40).
    • 500 mg tryptophan by mouth 3x per week if awakening at night.
    • Address sleep apnea if needed.
  5. Exercise
    • 30 to 60 minutes, 4-6 days per week (4142).
  6. Brain stimulation
    • Memory games, etc. (43).
  7. Homocysteine levels < 7
    • Supplement with methylB12, methylfolate, P5P, or trimethylglycine as needed (44).
  8. Serum B12 > 500
    • Supplement with methylB12 as needed (45).
  9. CRP < 1 and albumin/globulin ratio > 1.5
    • Anti-inflammatory diet should help.
    • Add curcumin & fish oil as needed.
    • Goal is to reduce inflammation.
  10. Fasting insulin < 7 and HbA1c < 5.5
    • Dietary intervention (see above)
    • Reduce risk of T2DM, since there is a link to AD.
  11. Hormone balance
    • Optimize thyroid hormones, estradriol, testosterone, pregnenolone, and cortisol (4647).
  12. GI health
    • Repair if needed.
    • Consider pre and probiotics.
    • Goal is to reduce inflammation and avoid autoimmunity issues.
  13. Reduction of amyloid-beta proteins
    • Consider curcumin & ashwagandha supplements (484950).
  14. Cognitive enhancement
    • Consider bacopa monniera & magnesium threonate supplements (5152).
  15. Vitamin D (25-OHD-3) between 50-100 ng/mL
    • Monitor vitamin D & Vitamin K levels (53).
  16. Increase nerve growth factor (NGF)
    • Consider H. erinaceus and acetyl-l-carnitine supplementation (5455).
  17. Provide synaptic structural components
    • Consider citicoline and DHA supplements (56).
  18. Optimize antioxidant
    • Consider mixed tocopherols and tocotrienols, selenium, blueberries, N-acetyl cysteine, ascorbate, & α-lipoic acid (57).
  19. Optimize zinc to free copper ratios
    • Intervention will depend on individual lab values (58).
  20. Ensure nocturnal oxygenation
    • Address sleep apnea if needed (59).
  21. Optimize mitochondrial function
    • Consider CoQ10 or ubiquinol, alpha lipoic acid, polyquinoline quinone, N-acetyl cysteine, acetyl-l-carnitine, selenium, zinc, resveratrol, ascorbate, and thiamine supplements as appropriate.
  22. Increase focus
    • Pantothenic acid as needed.
    • Goal is to improve acetylcholine synthesis (panthothenic acid is required).
  23. Increase sirtuin 1 function
    • Protects against neurodegeneration (60).
    • Consider resveratrol supplements (61).
  24. Rule out heavy metal toxicity
    • Evaluate mercury, lead, and cadmium levels.
    • Refer to doctor for possible chelation therapy if appropriate.
    • Goal is to reduce the central nervous system effects of heavy metals.
  25. MCT effects
    • Consider adding coconut oil or MCTs or ketones (62).

*Note none of the participants did all of these interventions, but they did enough of them to make a significant difference in their symptoms.

If you would like to become certified in the Bresden Protocol, the Institute of Functional Medicine is now training practitioners to specialize in this area. You can check it out here.

MEND case study results for early stages of cognitive decline (39):

1) 67-year-old woman suffering from memory decline (mother also suffered in her early 60’s and passed away around 80 years old in a nursing home).

  • Followed some but not all of her protocol, and saw significant improvement.
  • Was able to remember phone #’s again, and stay employed as a financial analyst.
  • At age 70, she was still doing fine & working at her job.
  • At one point when she fell ill and went off the protocol, noticed her symptoms returning. They went away again when she restarted the protocol.

2) 69-year-old man with progressive memory decline over the last 11 years, showing early signs of Alzheimer’s disease.

  • Heterozygous for ApoE4 gene.
  • Trouble remembering numbers and faces, needed prompting by assistants at work. Could no longer add columns of numbers quickly in his head like he could his whole life.
  • After 6 months he was vastly improved. His rapid cognitive decline had halted, could recognize faces again and work independently, and regained the ability to add numbers in his head.

3) 55-year-old attorney with progressive memory loss over the last 4 years.

  • Started leaving the stove on when left the house, was confusing her schedule at work, started recording conversations and taking notes, but then forgot the password for her iPad to access them. Was trying to learn Spanish but couldn’t remember anything new.
  • 5 months on the protocol she no longer needed to take notes or record conversations, she could work well again, started to learn Spanish, and was taking up a new legal specialty. Her children noticed she stopped getting lost mid-sentence or asking them about conversations that never happened.

Newer study released in 2016 (63):

  • Showed significant improvement in hippocampal volume after 10 months, reductions in inflammatory markers, reduced insulin levels, and increases in vitamin D levels on the MEND protocol. Improvement in behavior began showing up after 3 months on the protocol.
  • Some of the patients met criteria for Alzheimer’s disease at the start of the study, and by the end of the protocol, no longer met the criteria!

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