Dale Bredesen’s book The End of Alzheimer’s gives us a novel approach to first understanding, and then treating Alzheimer’s.
It differs from the approach typically taken by doctors and pharmaceutical companies, whereby they prescribe one or two drugs to help. Bredesen’s protocol instead identifies 36 different mechanisms contributing to Alzheimers decline, then gives the reader a blueprint for identifying which issues affect them individually, and how to fix them.
In 2018 Dale co-published a paper demonstrating reversal of cognitive decline in 100 patients, which helps adds credence to the claims.
Of course 36 mechanisms is a LOT – but not everyone will have issues with all 36. There is a general set of guidelines for optimal health that apply, which covers:
- Stress reduction
After that, the challenge for each individual is to figure out what what their core problems are (using testing), then addressing them.
For example, person A may have thyroid or hormonal issues they need to prioritize, whilst person B may need to prioritize their glucose/insulin regulation (type 2 diabetes).
In this post we will look at 4 key areas to achieve a big picture understanding of the protocol:
- What is Alzheimers? Understanding this gives context and background for Bredesen’s approach
- Basics of how we can treat it? Diet, Supplements, Exercise, Sleep, Stress
- Using Alzheimer’s Subtypes for Diagnosis – What are they and how do they inform a diagnosis?
- Individual Testing – What do we need to test?
- Individual Solutions – Once test results are in, what do we do?
Read on to learn more…
- 1. What is Alzheimer’s?
- 2) Diet, Supplements, Exercise, Sleep & Stress
- 3) Using Alzheimer’s Subtypes for Diagnosis & Treatment
- 4) Individual Testing – What do we need to test?
- 5) Individual Solutions – Once test results are in, what do we do?
1. What is Alzheimer’s?
In this section we will explore the biological backdrop for how Alzheimer’s occurs, based on Dale’s research. If you want to skip this section you can, but I’d suggest it’s worth making the effort to at least get a high level overview. Much as when when you go to a mechanic with an car engine problem, it helps to understand how the car works. Similarly with treating Alzheimer’s, it helps to understand Dale’s hypothesis for how it occurs, so you understand the why behind his treatment methodology.
- Alzheimer’s disease, named after Alois Alzheimer who discovered it in the early 1900s, is a neurodegenerative disease, characterized by 3 hallmarks in the brain; cerebral cortex thinning, amyloid plaques and neurofibrallary tanges.
- The amyloid plaques are largely made up of a peptide called amyloid-beta (aβ) – which is likely used by the brain for a purpose, such as selective downsizing of damaged or unhealthy neurons. However, when too much amyloid-beta accumulates, this causes widespread death and dysfunction of neurons. So what’s causing this oversupply of amyloid-beta?
- Amyloid beta is made from a molecule called amyloid precursor protein (APP), which is a dependence receptor attached to nuerons. After it’s produced by neurons it is cut by molecular scissors called proteases. They either cut at 3 sites along APP or at 1 site. If they cut at 3 sites, it produces 4 peptides; sAPPβ (soluble APP beta), Jcasp, C31 and amyloid-beta. Or if it’s cut at 1 site, it produces sAPPα and αCTF.
- The result of 3 cuts (sAPPβ, Jcasp, C3 & amyloid-beta) are peptides that cause loss of synapses, shrivelling of the connection between neurons and activation of the nueron’s suicide programme. These are pro-Alzheimer’s peptides 👎
- Vice-versa, the result of 1 cut (sAPPα and αCTF) are peptides that maintain synaptic connections and block neuron’s suicide program. These are anti-Alzheimer’s peptides 👍
- The upshot, is that to reduce your risk of Alzheimer’s disease, you want to minimize production of the pro-Alzheimer’s peptides, and maximize production of the anti-Alzheimer’s peptides. Bredesen’s protocol is designed to do this.
- Dale’s research has identified 36 different mechanisms that can steer APP towards the pro-Alzheimer’s route.
If Dale’s theory is correct, then it helps us understand why drugs created to clear amyloid plaques haven’t solved Alzheimer’s. In order to clear existing amyloid, it means that the APP has already gone down the pro-Alzheimer’s path, rather than creating trophic factors that support healthy neurons.
Instead what we really want to do is to start fixing whichever of these 36 different proceses someone has taking place in their body. Analogous to a house with 36 holes in the roof, you can imagine that you don’t need to fix them all, before you start to see benefits.
2) Diet, Supplements, Exercise, Sleep & Stress
Much of the key innovation behind Dale’s protocol is his process for identifying and then mitigating individual risk factors for Alzheimer’s. This involves a wide range of tests, each backed up with mitigation strategies if the test results come back negative.
When you get to that section, you’ll see there’s significant complexity involved. Before we get to that, let’s start by looking at Dale’s suggestion of lifestyle modifications that should be adopted by everyone wanting to prevent or reverse Alzheimer’s.
The “Anti-Alzheimer’s Diet” – Ketoflex 12/3
The Ketoflex 12/3 diet that Dale recommends consists of 3 different parts:
1) Ketosis – The ‘keto’ in ‘ketoflex’
Our our bodies preferential source of energy is glucose, which is derived from carbohydrates, and to a lesser extent, protein. When sources of glucose get low, our bodies switch to what are called ketone bodies, which are produced in the liver using fat stores. Using ketone bodies for fuel is referred to as ketosis, and it turns out that mild ketosis is optimal for cognitive function.
A diet that promotes ketosis is a low carbohydrate diet, targeting less than 50g of net carbs per day. The first step in achieving this is to cut out simple carbohydrates such as sugars, bread, white rice, white potatoes, chips, fries, candy, soft drinks and processed food. In place of them you’ll want to increase your healthy fats with things like avocados, nuts, olive oil and coconut oil.
To ensure you’re staying in ketosis, it is helpful to have a ketone meter. Unfortunately ketone urine tests are unreliable, so you’ll either need to opt for a blood ketone meter (gold standard) or a breathalizer.
2) Flexitarian – the ‘flex’ in ‘ketoflex‘
Dale suggests that this diet should be largely plant based – both cooked and uncooked, incorporating as many colors as possible.
If eating meat, it should be limited to less than 1g of meat per kg of bodyweight. More than that will increase the likelihood that it gets converted into glucose, which we want to avoid.
3) 12/3 – Meal Timing
Fasting is a great tool for inducing ketosis, reducing insulin and increasing cognition. The ’12’ in 12/3 refers to the time window in which meals should be consumed. From the time the last bite of food was consumed in the evening, to the time the first bite is consumed in the morning – 12 hours should be the minimum gap.
The ‘3’ in 12/3 refers to the minimum number of hours food should be consumed before sleep. For example, if you typically go to sleep at 11pm, then you should aim to finish eating by 8pm at the latest. This avoids an insulin spike before you go to bed (something that can contribute to insulin resistance), and allows for your food to partially digest before sleeping, which helps maximise sleep quality.
For those with the ApoE4 genotype should aim to fast for between 14 and 16 hours.
Dale explains that a big benefit of fasting between 12 and 16 hours is that it promotes autophagy, in which cells (including those in the brain) recycle components and destroy damaged proteins and mitochondria – making way for renewal.
More Specifics of the Diet
- Aim to eat the majority of foods with a glycemic index of 35 or lower – these will keep your insulin levels low (important). For a list of glycemic indexes see the Harvard site. You want the majority of foods you’re eating to be organic, seasonal, local and non-genetically modified. See the “dirty dozen and clean 15” list for which foods are important to buy organic (due to pesticides), and which foods are less critical.
- Eat whole fruits and avoid fruit juices – to keep the sugar consumption minimised
- Avoid simple cabohydrates, saturated fats and lack of fibre – for example; cheeseburger, fries and soda
- Minimize or avoid gluten and dairy – Leaky gut and inflammation are 2 of the 36 holes in the roof we want to fix, and gluten and dairy can contribute to this.
- Use plants to help reduce toxins – Plants that contain detoxifying molecules include coriander, cruciferous vegetables (cauliflower, broccoli, cabbage, kale, radish, brussel sprouts, turnips, watercress, kohlrabi, rutabaga, arugula, horseradish, maca, rapini, daikon, wasabi, bok choy), avocados, artichokes, beets, dandelions, garlic, ginger, grapefruit, lemons, olive oil, and seaweed.
- Preference good fats – such as nuts, seeds, olive oil and MCT oil
- Avoid processed foods, instead choose whole foods – use this simple rule: if ingredients are listed, it’s processed. Instead seek fresh, local, organic vegetables
- Eat fish carefully – fish are optional on this diet, but if you’re going to eat them, avoid large predatory fish such as sharks, swordfish and tuna. These accumulate mercury and other heavy metals through the smaller fish they feed on. Instead opt for SMASH fish – salmon, mackerel, achovies, sardines and herring. Where possible, choose wild, not farmed fish – which generally have a better omega-3 to omega-6 ratio and less toxins.
- Include prebiotics and probiotics to encourage good gut health. Probiotics are the bacteria, and prebiotics bacteria’s food. Vegetables are a good source of prebiotics and fermented foods are good sources of probiotics. Examples of probiotics include kimchi, sauerkraut, sour pickles, miso soup and kombucha. Dale acknowledges yogurt as a probtiotic, but suggests that due to its sugar content (lactose) and because it is dairy (pro-inflammatory) it should be avoided.
- Avoid advanced glycemic end products (AGEs) – These are glycotoxins produced by a reaction between sugars and proteins or fats. High levels of AGEs add to the bodies inflammation. To reduce and avoid AGEs use moist heat, shorter cooking times and lower temperatures. Grilling, searing, roasting and frying are all cooking methods that produce AGEs.
Whilst a healthy diet is the base, supplements should be used to optimize nutrition and cognitive protection. Dale recommends the following for everyone with cognitive decline or at risk for cognitive decline. The exception is if laboratory values are optimal for each parameter.
|Vitamin B₁||- 50mg/day|
|Vitamin B₅ - Panothenic Acid||- 100 to 200mg (especially if focus or alertness is an issue)|
|B₆/B₁₂ /B₉ (folate) combo||Use if homocysteine is above 6 mcmol/L||Jarrow - Methyl B-12/Methyl Folate (B9) and Pyridoxal-5-phosphate (B6) Lozenges|
|Vitamin C||If suboptimal vitamin C levels, take 1g/day or for those with copper:zinc ratio above 1:2|
|Vitamin D and Vitamin K2 (MK7)||For vitamin D start with 2,500iu/day, until serum levels reach between 50 to 80 ng/mL|
If taking vitamin D, add K₂ as MK7 at 100mcg/day
|- Thorne - Vitamin D3
- 1,000iu per capsule
- Life Extension - Vitamin K2 Low Dose
- 45mcg per soft gel
|Vitamin E - Mixed tocopherols and tocotrienols||- 800 IU / daily|
- Target vitamin E level of 12 to 20 mcg/mL
|Life Extension Gamma E Mixed Tocopherols & Tocotrienols
- 535 mg per soft gel
|Resveratrol||- 100mg||RevGenetics - Micronized Resveratrol
- 25g / tub
|Nicotinamide Riboside||- 100mg||Tru Niagen
- 300mg / capsule
- Whilst Bredesen's protocol lists 100mg, that seems on the very low end.
Most studies on NR have used significantly more.
|Citicoline||- 250mg/2x day|
- To support synaptic growth and maintenance
|ALCAR (acetyl-L-carnitine)||- 500mg/day|
- To increase nerve growth factor - particularly important for those with type 2
|Ubiquinol|| - 100mg/day|
- To support mitochondrial function
|Jarrow - Ubiquinol
- 100mg per soft gel
|PQQ|| - 10 to 20mg/day|
- To support mitochondrial function (as with PQQ)
|Life Extension - PQQ
- 20 mg / capsule
|Omega 3s||- DHA 1g, EPA 0.5g to 1g||Norwegian Pure-3 DHA
- 2 capsules = 1g DHA, 0.4g EPA
- Currently shipped worldwide from Norway
Nordic Naturals - ProDHA
- 2 capsules = 0.96g DHA, 0.82 EPA
|Whole coffee fruit extract (WCFE)||100mg 1-2x/day for 3 months, then gradually stop over 1 month. Increases BDNF and is useful for those with type 2|
 For B vitamin supplementation in situations where homocysteine is above 6, try using the following doses to ameleorate:
– Pyridoxal-5-phosphate (P5P) form of vitamin B6, 20-50 mg/day
– Methylcobalamin (methyl-B12) and adenosylcobalamin forms of B12, 1mg/day
– Methyltetrahydrofolate (methyl-folate) form of folate, starting with 0.8/day, with a max of 5mg/day
Check your homocysteine again after 3 months to see if homocysteine has dropped to 6 micromoles per liter or lower. It generally will, but if it hasn’t, add 500mg/day of glycine betaine (also called trimethylglycine). Once again, check homocysteine after another three months. If still high, focus on reducing the methionine (the amino acid from which the body makes homocysteine) in your diet by limiting consumption of foods such as nuts, beef, lamb, cheese, turkey, pork, fish, shellfish, soy, eggs, dairy and beans.
Next Dale talks about herbs that provide supportive synaptic function. He recommends the following to be taken daily.
|Ashwagandha||- 500mg, 2x/day with meals. Helps in the reduction of amyloid as well as handling stress.||- Jarrow – Ashwagandha
- 300 mg per capsule
- Pure Encapsulations - Ashwagandha
- 500 mg per capsule
|Bacopa monnieri||- 250mg 2x/day with meals to improve cholinergic function|
|Hericium erinaceus (lion's mane)||- 500mg 1x - 2x/day to increase nerve growth factor, especially for those with type 2 alzheimer's|
|Rhodiola||200mg 1x/day to 2x/day for those with anxiety and stress|
|Shankhpushpi (also known as skull cap)||Taken as 2 or 3 teaspoons or 2 capsules per day to enhance branching of neurons in the hippocampus|
They say that sitting is the new smoking!
Dale advocates for regular exercise to help improve cognition.
Suggesting you want to combine:
- Aerobic exercise – such as jogging or walking or spinning or dancing
- Resistance training – using weights or machines
Ideally training 4-5 days per week, for 45 to 60 minutes in total each day. Emphasizing you should work up to this slowly, stretch lots, and take care of your joints!
If you don’t already have an exercise routine you feel comfortable with, he suggests seeking help from friends, family or qualified personal trainers to get you started.
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3) Using Alzheimer’s Subtypes for Diagnosis & Treatment
Bredesen shows us that the first step when treating Alzheimer’s, or when working to prevent its occurance, is to evaulate your possible risk factors and begin fixing those you’re most at risk for. You will see later in the post that there are a lot of possible tests that can be done. Therefore to aid diagnosis, he breaks Alzheimer’s into 3 subtypes; 1, 2 & 3. Using these delineations allows us to priortize diagnosis methods and treatments that are most applicable.
Type 1 – Inflammatory
Type 1 occurs most often in those with 1 or 2 ApoE4 alleles – which tend to run in families. Most people carry 2 copies of ApoE3 which gives an Alzheimer’s risk of 9%. 75 million american’s (~25% of USA) carry a single copy of ApoE4, and have a risk of Alzheimer’s disease around 30%. 7 million carry 2 copies of ApoE4, pushing their risk above 50%. For those with ApoE4 for who develop Alzheimer’s disease, it is most often the inflammatory subtype.
Begins with a loss of ability to store new information, although long term memories are retained. Abilities we take for granted such as speaking, spelling, calculating are retained. In those with 2 copies of ApoE4, symptoms begin in late 40s – 50s. Forthose with 1 copy – symptoms being in the late 50s or 60s. For those with no copies – symptoms being 60s – 70s. The hippocampus, which converts experiences into long term memory, loses volume, but other parts don’t – at least not early on. However other areas do experience reduced function and speed.
Bredesen’s studies of patients with this form of Alzheimer’s disease have identified a set of biomarkers associated with type 1.
1) Increase in C-reactive prtein – made by the liver as part of an inflammatory response to threats like infections.
2) Decrease in the ratio of albumin to globumin – This ratio decreases with inflammation – and is problematic because albumin helps by clearing toxins and amyloid from the blood.
3) Increase in interleukin-6
4) Increase in tumor necrosis factor
5) Metabolic and hormonal issues – such as insulin resistance.
The good news is that Bredesen says type 1 responds quickest to his protocol.
Type 2 – Atrophic
This is the next most common type of Alzheimer’s disease for ApoE4 carriers – but initiates symptoms about a decade later than type 1.
The presentation is the same as type 1 – loss of ability to form new memories. A key difference is that there isn’t signs of inflammation. “Atrophic” Alzheimer’s disease comes about because supportive signalling for brain synapses is not being provided.
1) Low hormone levels – including thyroid, adrenal, estrogen, progesterone, testosterone and pregnanolone are sub-optimal.
2) Low vitamin D levels
3) Insulin Resistance
4) High homocysteine – (can also be high with type 1)
Types 1 & 2 Combined (Type 1.5)
Whilst types 1 and 2 often occur in isolation, they can also occur together. Inflammation without tropic support for brain synapses.
1) Chronically high glucose levels – resulting in alteration to various proteins (called glycation) and in inflammation.
2) Chronically high insulin levels – high glucose levels result in high insulin levels. With insulin consitantly high, it no longer operates effectively as a neurotrophic molecule in the brain.
Type 3 – Toxic
Type 3 is caused by toxins and typically strikes people at a relatively young age – with symptoms beginning in the late 40s to early 60s. Often ocurring after great stress. Unlike with types 1 and 2, it doesn’t begin as memory loss, instead it begins with cognitive difficulties involving numbers, speech or organisation.
Whereas the previous types cause “strategic downsizing” within the brain, preserving core functions, but not retaining new input, type 3 is not strategic at all. Both new and old memories are lost, and abilities we take for granted such as mental maths, finding words, reading and speaking can be affected. Depression and attention deficits can also be common.
It is common for type 3 Alzheimer’s disease to be diagnosed as something else, for example, frontotemporal dementia or vascular dementia. Spinal fluid analysis or a PET scan can confirm Alzheimer’s.
1) Affects many brain areas – not only, or predominantly, the hippocampus. With an MRI scan showing that multiple regions of the brain have shrunk.
2) Inflammation of the brain and ‘vascular leak’ – shown by an MRI finding called FLAIR (fluid attenuated inversion recovery) – showing multiple white spots on the MRI.
3) Commonly low zinc, high copper – the ratio of copper to zinc should be about 1, with around 100mcg/dL each. With type 3 it’s common to see serum zinc in the 50s, with copper as high as 170mcg/dL.
4) Initially diagnosed as something else – as mentioned above
5) Hormone dysfunction – Dysfunction in the hypothalamic–pituitary–adrenal (HPA) axis which can show up as low cortisol, high reverse T3 (a thyroid test), low free T3, low pregnanolone, low ostradiol, low testosterone – or other hormone abnormalities.
6) High levels of toxic chemicals in the blood – for example mercury or toxins produced by mould (mycotoxins). To measure the mercury you can’t rely on a blood test – because mercury often gets stored in tissue such as bone or brain. Instead you can use a chelating agent, which will help you excrete the mercury. You would expect to find elevated levels of mercury in the urine whilst chelating.
As mentioned previously – one of the key benefits of this subtyping of Alzheimer’s disease is to aid with treatment priorities, which can save time, money and energy. For example, if the symptoms are pointing towards sub-type 3 Alzheimer’s we can jump to testing for toxins, whereas for types 1 & 2 – testing for toxins would be low or non-priority.
4) Individual Testing – What do we need to test?
|Test||Test Purpose||Optional Tests|
|ApoE Status||Establishing whether ApoE4 carrier, or not||Cheapest method is measuring SNPs via 23andMe or Ancestry. More expensive is whole genome sequencing|
Inflammation vs Cellular Protection Tests
|hs-CRP = < 0.9 mg/dL
IL-6 = < 3 pg/ml (optional)
TNFα = < 6.0 pg/ml (optional)
|Omega-6 to omega-3 ratio (optional)||<3 and >0.5 (so less than 3x omega-6 to omega-3s, but more than 0.5)|
|Albumin to Globulin ratio||≥ 1.8 albumin to globulin
With albumin > 4.5 g/dL
|Homocysteine||< 7 μM|
|Vitamins B₆, B₁₂ and folate||B₆ = 60-100 µg/L
B₁₂ = 500-1500 pg/ml
folate = 10-25 ng/ml
|Vitamins C, D, E||C = 1.3-2.5 mg/dL
D = 50-80 ng/mL
E = 12-20 µg/mL
|Fasting insulin, glucose, hemaglobin A1c||Fasting insulin ≤ 4.5 microIU/ml
Fasting glucose = 70 - 90mg/dL
Hemoglobin A1c < 5.6%
|Body mass index (BMI)||18-25|
|LDL particle number (LDL-p) or small dense LDL (sdLDL) or oxidized LDL||LDL-p = 700-1,000
sdLDL = < 20mg/dL or < 20% of LDL
oxidized LDL = < 60 U/l
|Total Cholesterol, HDL, trigylcerides||Total Cholesterol = > 150 mg/dL (more than)
HDL = > 50 mg/dL
Triglycerides = < 150 mg/dL
|Glutathione||5.0 - 5.5 μM|
|RBC thiamine pyrophosphate||100 - 150 nmol/L|
|- Leaky gut|
- Leaky blood-brain barrier
- Gluten sensitivity
|Ideally all negative - goal is to confirm.
If not negative, then each should be addressed individually.
Trophic Support Tests
|Oestradiol (E2), |
|Oestradiol = 50 - 250 pg/ml
Progesterone = 1 - 20 ng/ml
Oestradiol to Progesterone Ratio = 10:100
(and optimize to symptoms)
|Pregnenolone = 50-100 ng/dL
Cortisol = 10-18 mcg/dL
DHEA-sulfate = 350-430 mcg/dL (women)
or 400-500 mcg/dL (men)
|Total Testosterone = 500-1000 ng/dL
Free Testosterone = 6.5 - 15 ng/dL
|Free T3, |
Free T3 to Reverse T3 Ratio
|Free T3 = 3.2 - 4.2 pg/ml
Free T4 = 1.3 to 1.8ng/dL
Reverse T3 = < 20 ng/dL
TSH = < 2.0 microIU/ml
Free T3 to Reverse T3 Ratio > 20
Toxin Related Tests
Quicksilver Testing Panel (optional)
|Mercury = < 7 mcg/L
Lead = < 2 mcg/dL
Arsenic = < 7 mcg/L
Cadmium = < 2.5 mcg/L
Quicksilver Testing < 50th Percentile, a figure they provide when you get their test results (optional)
|- Copper to Zinc Ratio|
- Ceruloplasmin (optional)
|- Copper to Zinc Ratio = 0.8 to 1.2
- Zinc = 90 to 110 mcg/dL (or red blood cell zinc = 12-14 mg/L)
- Copper minus 3x Ceruloplasmin ≤ 30
|(Checking for chronically activated immune system indicators)|
|(Checking for chronically activated immune system indicators)
- C4a = < 2830 ng/ml
- TGF-β1 = 2380 pg/ml
- MSH = 35 to 81 pg/ml
|HLA-DR/DQ||HLA-DR/DQ = Benign Result|
Metals Tests (excluding the heavy metals listed as toxins)
|RBC-magnesium||5.2 to 6.5 mg/dL|
|Copper = 90 to 110 mcg/dL
Zinc = 90 to 110 mcg/dL
|Selenium||Selenium = 110 - 150 ng/mL
|Potassium||Potassium = 4.5 to 5.5 mmol/L|
|Calcium||Calcium = 8.5 to 10.5 mg/dL|
|CNS Vital Signs, BrainHQ or equivalent||>50th percentile for age, improving with practice|
|MRI with volumetrics|
Retinal Imaging (optional)
|- Hippocampal, cortical volume percentiles steady (or increasing) for age, >25th percentile (Neuroreader or NeuroQuant are product options)
- Retinal Imaging to check for amyloid plaques (optional)
|Sleep study||AHI (Alpha Hypopnea Index) = < 5/hr|
|Gut, oral, nasal||No pathogens|
5) Individual Solutions – Once test results are in, what do we do?
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So this is quite a long article, and it’s just a summary of Dale’s fantastic book ‘The End of Alzhimer’s’. To get the full details, if you haven’t already, I’d recommend buying it.
To recap on the above, this is one suggestion for how to process all this information:
- Step 1 – you can get started right away with Dale’s general suggestions for things like diet, exercise and sleep in section 2 above
- Step 2 – next you’ll want to try and identify your individual risk factors for Alzheimer’s. As explained above, Dale has identified 36 potential issues, and you want to find which of these are your particular weak points (we’re all different)
- Step 3 – Work to mitigate your weak points, meanwhile working on building habits from section 2
Personally I found the amount of potential testing that needs doing a bit overwhelming, so you might too. In order to get further support with this you can sign up to one of Dale’s official programs (ReCODE or ReVERSE) via their website at Apollo Health.