Preventing Cognitive Decline: The Bredesen Protocol & Beyond

The Roof With Thirty-Six Holes

Dale Bredesen — neurologist, former professor at UCLA, and author of The End of Alzheimer’s — uses a metaphor that reframes everything we think about cognitive decline. Imagine you have a roof with thirty-six holes in it. Conventional medicine develops a drug to patch one hole. The rain still pours in through the other thirty-five. The drug “fails” in clinical trials — not because it didn’t work, but because one patch can’t fix a roof with that many leaks.

This is why every single-target Alzheimer’s drug has failed or shown minimal benefit. Aducanumab, lecanemab — they target amyloid plaques, one hole. The disease keeps progressing because amyloid is a consequence of upstream processes, not the cause.

Bredesen’s ReCODE (Reversal of Cognitive Decline) protocol isn’t one drug. It’s a personalized, multi-target, functional medicine approach that identifies and addresses each patient’s specific combination of holes. His published case studies (Bredesen 2014, 2016) documented cognitive improvement in 9 out of 10 patients — results no drug trial has come close to matching.

This isn’t fringe science. It’s what happens when you treat a multifactorial disease with a multifactorial approach.

Alzheimer’s as Metabolic Disease

In 2008, Suzanne de la Monte at Brown University published research demonstrating that Alzheimer’s disease involves brain-specific insulin resistance. She coined the term “Type 3 diabetes.” The brain becomes unable to efficiently use glucose, its primary fuel. Neurons starve in the midst of plenty.

The evidence has only grown stronger since:

• People with Type 2 diabetes have double the risk of Alzheimer’s
• Insulin resistance precedes cognitive symptoms by decades
• Brain PET scans show reduced glucose metabolism (hypometabolism) in Alzheimer’s-vulnerable regions years before symptoms
• Intranasal insulin trials (Craft 2012) showed cognitive improvement
• Ketones bypass the broken glucose pathway and fuel the brain directly

This metabolic understanding is foundational. It means that everything we know about preventing and reversing insulin resistance — diet, exercise, sleep, stress management, targeted nutrients — applies directly to brain protection.

Bredesen’s Three Subtypes

Not all cognitive decline looks the same at the molecular level. Bredesen identified three primary subtypes, each requiring different interventions:

Type 1: Inflammatory (Hot)

Driven by chronic systemic inflammation — elevated hs-CRP, IL-6, TNF-alpha. Often associated with infections (oral pathogens like P. gingivalis, herpes simplex, Lyme), gut permeability, metabolic syndrome, and ApoE4 genotype. The brain’s immune system (microglia) becomes chronically activated, creating a neurotoxic environment.

Key interventions: Resolve the inflammatory sources. Heal the gut (5R protocol). Treat chronic infections. Anti-inflammatory nutrition (Mediterranean/ketogenic hybrid). Omega-3 DHA 1-2g daily. Curcumin 1000mg daily. Resolve dental infections.

Type 2: Atrophic (Cold)

Driven by insufficient trophic (growth) support — low nerve growth factor, BDNF, estradiol, testosterone, thyroid hormone, vitamin D. The brain doesn’t have enough building blocks and growth signals to maintain synapses. Often seen in perimenopausal/postmenopausal women and men with low testosterone.

Key interventions: Hormone optimization (bioidentical estradiol, progesterone, testosterone as indicated). Optimize thyroid (free T3 is critical). Vitamin D to 50-80 ng/mL. BDNF-boosting strategies (exercise, curcumin, lion’s mane). Adequate protein and nutrients.

Type 3: Toxic (Vile)

Driven by exposure to toxins — mycotoxins (from mold), heavy metals (mercury, lead, arsenic), organic pollutants, biotoxins. These patients often have a history of mold exposure, amalgam fillings, or occupational chemical exposure. Imaging may show diffuse cortical atrophy rather than the typical hippocampal pattern.

Key interventions: Identify and remove the exposure. Test for mycotoxins (urine mycotoxin panel), heavy metals (provoked urine or blood), organic pollutants. Detoxification support: glutathione (liposomal 500-1000mg or IV), binders (activated charcoal, bentonite, chlorella), sauna, adequate hydration.

The ApoE4 Factor

The ApoE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s. Carrying one copy increases risk 3-4 fold; two copies increase it 12-15 fold. About 25% of the population carries at least one copy.

But ApoE4 is not a death sentence — it’s an amplifier. It amplifies the consequences of poor metabolic health, inflammation, and toxic exposure. Conversely, it amplifies the benefits of intervention. ApoE4 carriers who adopt comprehensive lifestyle changes may reduce their risk more dramatically than non-carriers, because they have more to gain from each intervention.

Key modifications for ApoE4 carriers:

• Lower saturated fat intake (ApoE4 carriers have impaired lipid clearance)
• Higher omega-3 DHA (the brain’s preferred structural fat)
• More aggressive insulin sensitivity management
• Earlier and more frequent screening
• Ketogenic approaches may be particularly beneficial (providing alternative brain fuel)
• Alcohol has a stronger negative impact — minimize or eliminate

Key Interventions: The Evidence Base

Ketones and MCT Oil

When glucose metabolism fails in the Alzheimer’s brain, ketones provide a rescue fuel. The brain’s ketone transporters remain intact even when glucose transporters are impaired.

Fortier et al. (2019) published in Alzheimer’s & Dementia showing that 6 months of MCT oil supplementation increased brain ketone metabolism and improved cognitive scores in MCI patients. Stephen Cunnane’s group at the University of Sherbrooke has demonstrated repeatedly that ketone availability directly correlates with cognitive function in aging.

Protocol: MCT oil (C8 caprylic acid is most ketogenic) — start with 1 tsp daily, increase gradually to 1-2 tbsp daily. Or a well-formulated ketogenic diet (under 20-30g net carbs). Or periodic fasting to generate endogenous ketones.

Exercise

Erickson et al. (2011) published in PNAS that one year of aerobic exercise increased hippocampal volume by 2% in older adults — effectively reversing 1-2 years of age-related volume loss. The control group lost 1.4% over the same period. This is the only intervention consistently shown to grow the hippocampus.

Exercise works through multiple mechanisms: increases BDNF (brain-derived neurotrophic factor), improves insulin sensitivity, reduces inflammation, promotes neurogenesis, enhances cerebral blood flow, and clears amyloid through enhanced glymphatic function.

Minimum effective dose: 150 minutes/week moderate aerobic + 2 sessions resistance training. More is generally better for brain health, up to the point of overtraining.

Sleep and the Glymphatic System

Xie et al. (2013) discovered in Science that the brain has its own waste clearance system — the glymphatic system — that becomes 60% more active during sleep. It flushes out metabolic waste, including amyloid-beta and tau, through cerebrospinal fluid channels that expand when you’re asleep.

One night of sleep deprivation measurably increases brain amyloid burden (Shokri-Kojori 2018). Chronic poor sleep is one of the strongest modifiable risk factors for Alzheimer’s.

Non-negotiables: 7-9 hours of quality sleep. Screen for and treat sleep apnea (it independently increases Alzheimer’s risk). Sleep hygiene basics: consistent schedule, cool dark room, no screens 1 hour before bed, no caffeine after noon, no alcohol (it fragments sleep architecture even if it helps you fall asleep).

Omega-3 DHA

DHA (docosahexaenoic acid) comprises 40% of brain polyunsaturated fatty acids. It’s structural — literally building material for neuronal membranes and synapses. Low omega-3 index correlates with smaller brain volume and accelerated cognitive decline.

Dosing: 1-2g DHA daily (often combined with EPA). Target omega-3 index >8% (measurable via blood spot test). Algal-based DHA is available for those avoiding fish.

Lion’s Mane Mushroom

Mori et al. (2009) conducted a double-blind, placebo-controlled trial showing that lion’s mane (Hericium erinaceus) significantly improved cognitive function in older adults with mild cognitive impairment over 16 weeks. The effect disappeared 4 weeks after stopping — suggesting ongoing supplementation is needed.

Lion’s mane stimulates nerve growth factor (NGF) synthesis through its unique compounds hericenones and erinacines. NGF is critical for the survival and function of cholinergic neurons — the exact population that degenerates in Alzheimer’s.

Dosing: 500-3000mg daily of fruiting body extract, or 1-3g of whole mushroom powder. Look for extracts standardized to hericenones/erinacines.

Additional Neuroprotective Compounds

Phosphatidylserine: 100-300mg daily. A phospholipid critical for neuronal membrane integrity and cell signaling. FDA allows a qualified health claim for cognitive function.

Citicoline (CDP-choline): 500-1000mg daily. Provides both choline (acetylcholine precursor) and cytidine (supports membrane phospholipid synthesis). Better evidence than alpha-GPC for sustained cognitive support.

Bacopa monnieri: 300-450mg daily (standardized to bacosides). Ayurvedic nootropic with meta-analysis evidence for memory improvement (Kongkeaw 2014). Takes 8-12 weeks for full effect.

Gotu kola (Centella asiatica): 500-1000mg daily. Traditional Ayurvedic and Chinese herb for brain longevity. Enhances mitochondrial function in neurons and promotes dendrite growth (Gray 2018).

Metals, Toxins, and the Brain

The brain is uniquely vulnerable to toxic accumulation because of its high metabolic rate, high lipid content (toxins are lipophilic), and relatively poor detoxification capacity compared to the liver.

Mercury: Crosses the blood-brain barrier easily. Sources include dental amalgams, large predatory fish, and industrial exposure. Even “low” levels correlate with cognitive changes. Test with a provoked urine challenge (DMSA or DMPS) for total body burden. Removal: careful amalgam removal by a SMART-certified dentist, chelation under medical supervision.

Aluminum: Found in antiperspirants, antacids, cookware, and municipal water. Accumulates in hippocampal tissue. Minimize exposure; support clearance with silica-rich mineral water (Exley research).

Mycotoxins: Mold-produced toxins (ochratoxin A, trichothecenes, aflatoxins, gliotoxins) are potent neurotoxins. Urine mycotoxin testing (RealTime Labs, Great Plains/Mosaic). Removal: glutathione, binders (cholestyramine, activated charcoal, bentonite clay), and eliminating the mold source.

Insulin Sensitivity as Neuroprotection

Because Alzheimer’s is fundamentally a metabolic disease, optimizing insulin sensitivity is neuroprotection. Period.

Continuous glucose monitoring (CGM): Wearing a CGM for 2-4 weeks reveals hidden glucose spikes that accelerate brain insulin resistance. Target: glucose variability (standard deviation) <20 mg/dL, fasting glucose 72-85 mg/dL, post-meal peaks <120 mg/dL.

Time-restricted eating: 14-16 hour overnight fast. This alone improves insulin sensitivity and generates mild ketosis — providing brain ketone fuel.

Berberine: 500mg 2-3x daily with meals. Activates AMPK, improves glucose disposal, reduces insulin levels. Functions comparably to metformin.

BDNF: The Brain’s Fertilizer

Brain-derived neurotrophic factor is like fertilizer for neurons. It promotes neuronal survival, encourages new synapse formation, and enhances learning and memory. BDNF declines with age, and low levels correlate with depression, cognitive decline, and neurodegeneration.

Exercise is the most powerful BDNF booster. A single session of moderate-intensity exercise can double circulating BDNF levels. This is one reason exercise is the most consistently protective factor against cognitive decline.

Curcumin increases BDNF levels (Cox 2015). The UCLA trial showed that highly bioavailable curcumin (Theracurmin 90mg twice daily) improved memory performance and reduced amyloid and tau PET signals over 18 months (Small 2018).

Lithium orotate at low doses (5-20mg, containing roughly 1-4mg elemental lithium) upregulates BDNF and has neuroprotective properties. Not to be confused with prescription lithium carbonate used for bipolar disorder at 100-1200mg elemental lithium. The low-dose form is available over the counter and shows a favorable safety profile. Nunes et al. (2013) found low-dose lithium slowed cognitive decline in Alzheimer’s patients.

Other BDNF enhancers: Omega-3 DHA, meditation (Cahn 2017), adequate sleep, sunlight exposure, social connection.

Putting It Together: A Prevention Protocol

For someone in their 40s-60s with family history or early signs of cognitive decline:

Test first:

• ApoE genotype
• Fasting insulin, HbA1c, HOMA-IR
• hs-CRP, IL-6
• Homocysteine (target <7 umol/L — elevated homocysteine is directly neurotoxic)
• Vitamin D (target 50-80 ng/mL)
• Omega-3 index (target >8%)
• Full thyroid panel (TSH, free T3, free T4)
• Hormones (estradiol, testosterone, DHEA-S)
• Heavy metals, mycotoxins (if exposure suspected)
• MoCA or CNS Vital Signs for cognitive baseline

Foundation (everyone):

• Exercise: 150+ min/week aerobic + 2x resistance
• Sleep: 7-9 hours, screen for apnea
• Mediterranean-ketogenic hybrid diet (low sugar, high polyphenol, adequate healthy fats)
• Time-restricted eating (14-16h overnight fast)
• Stress management (meditation, breathwork, nature)

Targeted supplementation:

• Omega-3 DHA: 1-2g daily
• Curcumin (bioavailable form): 500-1000mg daily
• Lion’s mane: 1000-3000mg daily
• Citicoline: 500-1000mg daily
• Magnesium threonate: 1000-2000mg daily (specifically crosses BBB — Bhatt 2024)
• Vitamin D3: dose to reach 50-80 ng/mL (typically 4000-8000 IU daily)
• B-complex with methylfolate and methylcobalamin (homocysteine management)
• MCT oil: 1-2 tbsp daily

If toxicity is suspected: Detox protocol — glutathione, binders, sauna, source removal.

If hormonal: Bioidentical hormone optimization under medical guidance.

The brain doesn’t decline overnight. It declines over decades of accumulated insults — each one individually small, collectively devastating. But each insult is also individually addressable. You don’t need to patch all thirty-six holes at once. You just need to start patching.

Which holes in your roof have you been ignoring?