36 ‘Holes in the Roof’ The Dawn of the Era of Treatable and Preventable Alzheimer’s Disease

Reading Time: 15 minutes

currentCoverSummary review by Antony Haynes BA, RNT, promoted by attendance to a lecture presented by Professor Dale Bredesen MD, Augustus Rose Professor, Director, Easton Center for Alzheimer’s Disease Research, UCLA Founding President, Buck Institute

On Saturday 14th March 2015, Dr Dale Bredesen presented information, slides, and short videos on the subject of Alzheimer’s disease at the Cavendish Conference Centre 2015 CAM Conference. He presented the prevalence of Alzheimer’s disease (AD), and the predicted number of sufferers in the years to come, the impact on society that this will / would have, some examples of his patients who had reclaimed their memories, and the fact that there are currently no known cures. Hundreds of millions of dollars have been spent in an attempt to develop medications but none have been successful.

“It’s a metabolic problem that is destroying your brain” says Dr Bredesen.

The most evident symptoms of AD were identified as being poor memory, being easily overwhelmed and getting lost.

Dr Bredesen declared that it is a mistake to use mono-therapy for a multifactoral condition such as AD, and as drug therapy is very clearly mono-therapy and bound to fail. AD is a metabolic disorder and the disordered metabolism needs to be corrected, and this potentially involves many points of simultaneous intervention, as many he suggests as 36 metabolic imbalances, or more.

Dr Bredesen adopted an integrative, wholistic approach to AD, which reflects a functional medicine approach. Dr Bredesen is himself familiar with and knows personally many eminent doctors and clinicians who are practicing and teaching functional medicine, including Dr David Perlmutter, Board Certified Neurologist. For us in the audience, this notion to approach AD from a multi-factoral basis is simply common sense, but it is heartening to meet a medical doctor who is doing just that.

We learned that specific genes do play a role in the risk of developing AD, and he named ApoE4, whether it is heterozygous or homozygous, as having a 10-12 fold increased risk of developing AD if an individual carries 2 sets of ApoE4 (i.e. homozygous). ApoE4 strongly influences retention and forgetting processes. We were given a brief history in evolution as it was explained how there were potential benefits to humans who had ApoE4 since this was related to an inflammatory response, which was crucial to our survival in the short term. The constant expression of these genes is not helpful when we get older.

Dr Bredesen shared with us that it, the development of AD, is all about biological signalling and we can influence this biological signalling with food choices, lifestyle choices and by optimising levels of hormones and nutrients. It’s not all about the build up of Alpha-β peptide in the brain. It has to do with the balance between the cells that remember and the cells that cause us to forget, specifically the balance between synaptoclastic and synaptoblastic activity. Many, many things can and do contribute to this balance.

With modern technology, it is now possible to identify the onset of AD earlier and this provides a valuable opportunity to engage in the many nutritional and lifestyle choices. Dr Bredesen then introduced us to the ‘roof with 36 holes’ metaphor, with each one of them needing to be filled in order to achieve the best outcome, and even reverse AD.

Based on the hypothesis that AD results from an imbalance in an extensive plasticity network, the therapy he says should address as many of the network components as possible, with the idea that a combination may create an effect that is more than the sum of the effects of many monotherapeutics.

The ‘36 holes’ represent 36 mechanisms explained in more detail in his recent paper published in aging.[1] it is my intention to provide clarity on those 36 mechanisms which are the target of the comprehensive therapeutic programme that Dr Bredesen has been engaging his patients in.

35 Mechanisms
1. Decrease Aβ production
2. Increase Aβ degradation
3. Decrease Aβ oligomerization
4. Increase BDNF (Brain Derived Nerve Factor)
5. Increase NGF (Nerve Growth Factor)
6. Increase G-CSF
7. Increase ADNP
8. Decrease p-tau
9. Decrease homocysteine
10. Build synapses
11. Decrease 4/2
12. Increase Aβ breakdown
13. Increase A/G Ratio (Albumin/Globulin)
14. Decrease Inflammation
15. Inhibit NF-kB
16. Increase GSH (glutathione)
17. Increase antioxidants
18. Decrease Iron (& decrease copper, increase zinc – target of Zn : fCu is 100:10-15)
19. Increase CBF
20. Increase ACh
21. Increase α 7 signaling
22. Increase Aβ transport
23. Increase Aβ clearance
24. Decrease ApoE4 effect
25. Increase GABA
26. Decrease NMDA
27. Optimise hormones
28. Increase vitamin D
29. Decrease pro-NGF
30. Decrease caspase-6
31.  Decrease N-APP
32. Increase Memory
33. Increase Energy
34. Increase Mitochondrial function
35. Increase Mitochondrial protection


The six principles of the programme developed by Dr Bredesen are as follows:
1.      The goal is not simply to normalise metabolic parameters, but rather to optimise them.
2.      Based on the hypothesis that AD results from an imbalance in an extensive plasticity network, the therapy should address as many of the network components as possible, with the idea that a combination may create an effect that is more than the sum of the effects of multiple monotherapeutics.
3.      Just as for other chronic illnesses such as osteoporosis, cancer, and cardiovascular disease, the underlying network features a threshold effect, such that, once enough of the network components have been impacted, the pathogenetic process would be halted or reversed. Therefore, even though it is not expected that most patients will be able to follow every single step of the protocol, as long as enough steps are followed to exceed the threshold that should be sufficient.
4.      The approach is personalised, based on the contributory laboratory values affecting the plasticity network; and is computationally intensive, since many physiological data points are analyzed, interdependent network-component status is assessed, and many interventions are prioritised to determine the therapeutic program.
5.      The program is iterative, so that there is continued optimisation over time.
6.      For each network component, the goal is to address it in as physiological a way, and as far upstream, as possible.

A Therapeutic System was developed by Dr Bredesen, referred to as Therapeutic System 1.0.

Therapeutic System 1.0
1. Optimise diet: minimise simple CHO, minimise inflammation – patients are given a choice of several low glycaemic, low inflammatory, low grain diets. This aims to minimise insulin & inflammation.
2. Enhance autophagy, ketogenesis by fasting for 12 hours each night, including 3 hours prior to bedtime. This aims to reduce insulin & Aβ levels.
3. Reduce stress – with a personalised programme of yoga or meditation or music, etc. This aims to reduce cortisol, reduce CRF, support the stress axis.
4. Optimise sleep – 8 hours a night, with 1-3 mg of melatonin at night, tryptophan 500 mg 3X per week, exclude sleep apnoea.
5. Take exercise – 30-60 minutes per day, 4-6 days/wk
6. Engage in brain training & stimulation
7. Optimise Homocysteine, < 7, with Me-B12 (Methylcobalamin), MTHF (methylenetetrahydrofolate), P5P (pyridoxal-5-phosphate), TMG (trimethylglycine) if necessary.
8. Serum B12 > 500, with Me-B12 (Methylcobalamin).
9. hs-CRP < 1, A/G > 1.5 with anti-inflammatory diet; curcumin; DHA/EPA; optimise hygiene.
10. Optimise insulin < 7 fasting, HbA1C < 5.5 – diet as above – with aim to minimise inflammation in AD.
11. Optimise hormones: Free T3, Free T4, TSH, Pregnenolone, Progesterone, Oestradiol, Testosterone, Cortisol & DHEA
12. GI Health – with probiotics and prebiotics if necessary
13. Reduce Aβ levels – Curcumin, Ashwaganda
14. Cognitive enhancement – Bacopa monniera, magnesium threonate
15. Vitamin D3 – 25OH-D3 = 50-100ng/ml – optimise levels with vitamin D3, & vitamin K2.
16. Increase Nerve Growth Factor (NGF) – H. erinaceus or acetyl-l-carnitine
17. Provide structural synaptic components: DHA, citicoline
18. Optimise Antioxidants: Mixed tocopherols & tocotrienols, Se, blueberries, NAC, ascorbate, α-lipoic acid.
19. Optimise Zn: fCu ratio – depends on values obtained
20. Ensure nocturnal oxygenation – Exclude or treat sleep apnoea
21. Optimise Mitochondrial function: CoQ or ubiquinol, α-lipoic acid, PQQ polyquinoline quinine), NAC, ALCAR (acetyl-L-carnitine), Se, Zn, resveratrol, ascorbate, thiamine
22. Increase focus – with pantothenic acid for acetylcholine synthesis
23. Increase SirT1 function with resveratrol
24. Exclude heavy metal toxicity – Evaluate heavy metals (Pb, Hg, Cd) – chelate as necessary
25. MCT effects – Coconut oil or Axona

The rationale behind the desired changes are based on the known role of inappropriate inflammation in AD and therefore to reduce inflammation accordingly, & to reduce auto-immune risks, to minimise insulin resistance, to reduce Aβ, to reduce excess cortisol, to reduce excess CRF, & support the hypothalamic adrenal axis, to optimise antioxidant status, to optimise blood glucose balance, to support optimal production of acetylcholine synthesis.

The FINGER Study

In support of Dr Bredesen and colleagues’ work, just two days prior to the CAM Conference, on 12th March 2015, a research article was published in The Lancet which described the effects of a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population in Finland (FINGER).[2] The findings from this large long-term, randomised controlled trial suggest that the multidomain intervention could improve or maintain cognitive functioning.

The main hypothesis of this trial was that simultaneous changes in several risk factors (even of small magnitude) would lead to a protective effect on cognition, in at-risk elderly people (60-77 years of age).

The control group (n = 565) received regular health advice. The intervention group (n = 554) received additional intervention components which included nutritional advice, a physical exercise training programme, a cognitive training programme and social activities which were stimulated through the numerous group meetings of all intervention components. Vascular risk monitoring was also undertaken for the intervention group.

Multidomain Intervention – FINGER study
  • Nutritional Advice
  • Exercise Training Programme
  • Cognitive Training Programme
  • Social Activity Programme
  • Vascular risk monitoring


The researchers noted significant effects on the primary outcome which was overall cognition, main cognitive secondary outcomes (executive functioning and processing speed), and other secondary outcomes (BMI, dietary habits, and physical activity).

This FINGER trial provides a first reference, and also a novel and pragmatic model, for dementia prevention trials that can be tested and adapted in various other settings and populations.

MIND Diet Study

Interestingly, in February 2015, there was another paper which focused on the influence of diet upon the development of AD, the conclusion of which was “High adherence to all three diets may reduce AD risk. Moderate adherence to the MIND diet may also decrease AD risk”. The study first began in 1997.[3]

This was a prospective study of 923 participants, ages 58 to 98 years, followed on average 4.5 years, conducted in the Chicago area. Participants were asked to report usual frequency of intake over the previous 12 months of 144 food items.

Nutrient levels and total energy for each food item were based either on natural portion sizes (e.g. slice of bread) or according to age- and sex-specific portion sizes from national dietary surveys. The MIND diet score has 15 dietary components including 10 brain healthy food groups (green leafy vegetables, other vegetables, nuts, berries, beans, whole grains, fish, poultry, olive oil, and wine) and five unhealthy food groups (red meats, butter and stick margarine, cheese, pastries and sweets, and fried/fast food). Olive oil consumption was scored 1 if identified by the participant as the primary oil usually used at home and 0 otherwise. For all other diet score components the researchers summed the frequency of consumption of each food item portion associated with that component and then assigned a concordance score of 0, 0.5, or 1. The total MIND diet score was computed by summing over all 15 of the component scores.


MIND Diet Study – Chicago 15 Dietary Component Scores  
Food Item Food Frequency Max Score
Whole Grains ≥ 3/d 1
Green Leafy Vegetables ≥ 6/wk 1
Other Vegetables >1/d 1
Berries >2/wk 1
Red Meats & Products <4/wk 1
Fish >1/wk 1
Poultry >2/wk 1
Beans >3/wk 1
Nuts >5/wk 1
Fast / fried food <1/wk 1
Olive Oil primary oil 1
Butter, margarine <1T/d 1
Cheese <1/wk 1
Pastries, sweets <5/wk 1
Alcohol, wine 1/d 1
  Total MIND Score 15


The DASH diet scoring was based on seven food groups and three dietary components (total fat, saturated fat, and sodium), each scored 0, 0.5, or 1, and summed for a total score ranging from 0 (lowest) to 10 (highest) diet concordance.

The MedDiet Score was computed based on scoring described by Panagiotakos and colleagues.[4] The scoring uses serving quantities of the traditional Greek Mediterranean diet as the comparison metric. It includes 11 dietary components each scored 0 to 5 that are summed for a total score ranging from 0 to 55 (highest dietary concordance). The researchers found protective relations of this MedDiet Score and cognitive decline in both the MAP study and the Chicago Health and Aging Project.

The dietary patterns in question involved a hybrid of the Mediterranean-DASH diets, called MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) that emphasises the dietary components and servings linked to neuroprotection and dementia prevention. Similar to the Mediterranean and DASH diets, the MIND diet score emphasises natural plant-based foods and limited intakes of animal and high saturated fat foods but uniquely specifies the consumption of berries and green leafy vegetables, and does not specify high fruit consumption (three to four servings per day in the DASH and Mediterranean diets), high dairy (21 servings per day in DASH), high potato consumption (2 servings per day in the Mediterranean), or greater than one fish meal per week (.6 meals/week in the Mediterranean).

The estimated effect was a 53% reduction in the rate of AD for persons in the highest tertile of MIND scores and a 35% reduction for the middle tertile of scores compared with the lowest tertile. The estimated effect was independent of other healthy lifestyle behaviours and cardiovascular related conditions. These data suggest that even modest adherence to the MIND diet score may have substantial benefits for the prevention of AD. By contrast, only the highest concordance to the DASH and MedDiet diets were associated with AD prevention.

Prevention vs Reversal

The Finnish study involved a multidomain approach to prevention which included diet, exercise, increased social activities as well as education in these matters. Whilst it may be true that the changes in the diet and exercise and lifestyle of these at-risk elderly people may well have helped improve a number of the metabolic imbalances identified specifically by Dr Bredesen in his Therapeutic System 1.0, these outcomes were not measured, with only the cognitive performance being used as a determinant outcome.

In the MIND Diet study, there were nutritional variables only and not a multidomain approach that were identified to have a protective effect on developing AD. Of interest, the protective effect was independent of other lifestyle variables such as age, sex, education, physical activity, obesity, low BMI, or histories of stroke, diabetes, or hypertension.

It is likely from the emerging evidence from the Buck Institute that there may well need to be an improvement in more numerous metabolic changes than in those variables identified by the Finnish or Chicago MIND Diet study in order to reverse the symptoms of AD. That is to say, that more needs to be done to reverse AD compared to preventing it.

In 2012, according to Dr Bredesen there were 30 million sufferers of AD in the USA, with it probably being as high as the 3rd leading cause of death behind cardiovascular diseases and cancers, and there is a predicted number of 160 million sufferers of AD in 2050.

With these statistics already showing that as much as 15% of the Western population being affected by AD, and the prediction that AD on its own will bankrupt the medical system if it continues at the same rate within the next two decades or so, let alone at an increased rate, there is a growing awareness of the need to find a solution to the AD and other neuro-degenerative diseases. There is currently no existing cure, and Dr Bredesen maintains that there cannot be a single drug cure due to the multifactorial nature of the condition even though a drug may serve a purpose.

Dr Bredesen has identified the need to patch the named holes in the roof, metabolically speaking, and this is proving itself in his small trial to be remarkably effective within his institute as a proof of principle.


[1] Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014 Sep;6(9):707-17 View Full Paper

[2] Ngandu T et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015 Mar 11. pii: S0140-6736(15)60461-5. doi: 10.1016/S0140-6736(15)60461-5. [Epub ahead of print] View Abstract

[3] Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015 Feb 11. pii: S1552-5260(15)00017-5. doi: 10.1016/j.jalz.2014.11.009. View Abstract

[4] Panagiotakos DB, Pitsavos C, Arvaniti F, Stefanadis C. Adherence to the Mediterranean food pattern predicts the prevalence of hypertension, hypercholesterolemia, diabetes and obesity among healthy adults; the accuracy of the MedDietScore. Prev Med 2007 Apr; 44(4):335–40. View Abstract


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6 Comments. Leave new

  • I am so grateful for your work. My mother suffered from Alzheimer’s for many years and finally passed over a year ago. She always said a cure would be found…but not in time for her. She was correct. Thanks to you and Dr. Perlmutter and others, it is in time for me, my children, and my grandchildren.

  • As a practitioner this is a valuable article on supporting cognitive health, thank you

  • This past year I was diagnosed with MCI. I’m a retired and disabled physician. I studied MCI and became more depressed and suicidal. By study and serendipity I found Dr. Bredesen and his work. I have started to apply it as I can and I know I’m getting smarter!! My brain is improving. I wish that I could afford his RECODE or RECOVERY program but I cannot at this time. Thank you Dr. Bredesen for giving me not only hope but improvement!!

  • Hi there, you refer to Bredesen’s 36 holes model but then list only 35. Is there something missing or have I misread? Thank you

  • Donald E Thibodaux
    July 4, 2023 10:35 am

    This kind of logical thinking by brilliant minds such as Dr. Dale Bredesen, is needed for many other diseases, specifically, ALS (Amyotrophic Lateral Sclerosis). I would appreciate any advise on developing a similar “36 hole” approach for ALS.
    I was diagnosed with Lower Motor Neuron disease (ALS) in December 2019. With hope such as this article, I believe we can beat ALS.

    • We all hope for a similar level of collected research and beneficial outcomes, to date we are unaware of any similar programme.


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