This is the most important column I’ve ever written. The message is quite complex–dozens of new health parameters to test for and to optimize, all of them interacting in ways that will require new training for MDs. The message is also as simple as it can be: There is a cure for Alzheimer’s disease. You can stop reading right here, and buy two copies of Dale Bredesen’s book, one for you and one for your doctor: The End of Alzheimer’s.

Dr Bredesen’s spectacular success is easily lost in a flood of overly-optimistic, early hype about any number of magic cures. This is an excuse for the New York Times, the Nobel Prize committee, and the mainstream of medical research, but it’s no excuse for me. I’ve known Bredesen for 14 years, and I’ve written about his work in the past. His book has been out for a year, and I should have written this column earlier.

I suspect you’re waiting for the punch line: what is Bredesen’s cure? That’s exactly what I felt when I read about his work three years ago. But there isn’t a short answer. That’s part of the frustration, but it’s also a reason that Bredesen’s paradigm may be a template for novel research approaches cancer, heart disease, and aging itself.

The Bredesen protocol consists of a battery of dozens of lab tests, combined with interviews, consideration of life style, home environment, social factors, dentistry, leaky gut, mineral imbalances, hormone imbalances, sleep and more. This leads to an individual diagnosis: Which of 36 factors known to affect APP cleavage are most important in this particular case? How can they be addressed for this individual patient?

Brain cells have on their surface a protein called APP, which is a dependence receptor. It is like a self-destruct switch whose default is in the ON position. The protein that binds to the receptor is a neurotrophin ligand, and in the absence of the neurotrophin ligand, the receptor signals the cell to die.

APP cleavage is the core process that led Bredesen down a path to his understanding of the etiology of AD 16 years ago. APP is Amyloid Precursor Protein, and it is sensitive to dozens of kinds of signals, adding up the pros and the cons to make a decision, to go down one of two paths. It can be cleaved in two, creating signal molecules that cause formation of new synapses and formation of new brain cells; or it can be cleaved in four, creating signal molecules that lead to trimming back of existing synapses, and eventually, to apoptosis, cell suicide of neurons.

In a healthy brain, these two processes are balanced so we can learn new things and we can forget what is unimportant. But in the Alzheimer’s brain, destruction (synaptoclastic) dominates creation (synaptoblastic), and the brain withers away.

On the right, one of the fragments is beta amyloid. Beta amyloid blocks the dependence receptor, so the receptor cannot receive the neurotrophin ligand that gives it permission to go on living. Beta amyloid is one of the 4 pieces, when the APP molecule goes down the branch where it is split in 4.

One of the signals that determines whether APP splits in 2 or in 4 is beta amyloid itself. This implies a positive feedback loop; beta amyloid leads to even more beta amyloid, and in the Alzhyeimer’s patient, this is a runaway process. But positive feedback loops work in both directions–a boon to Bredesen’s clinical approach. If the balance in signaling can be tipped from the right to the left pathway in the diagram above, this can lead to self-reinforcing progress in the healing direction. In the cases where Bredesen’s approach has led to stunning reversals of cognitive loss, this is the underlying mechanism that explains the success.

Amyloid has been identified with AD for decades, and for most of that time the mainstream hypothesis was that beta-amyloid plaques cause the disease. (Adherents to this view have been referred to jokingly as BAPtists.) But success in dissolving the plaques has not led to restored cognitive function. In Bredesen’s narrative, generation of large quantities of beta amyloid are a symptom of the body’s attempts to triage a dying brain.

To tip the balance back toward growing new synapses

Having identified the focal point that leads to AD, Bredesen went to work first in the lab, then in the clinic, to identify processes that tend to tip the balance one way or the other. He has compiled quite a list.

Reduce APPβ-cleavage

Reduce γ-cleavage

Reduce caspase-6 cleavage

Reduce caspase-3 cleavage

( All the above are cleavage in 4 )

( ) Increase α-cleavage ( cleavage in 2 )

) Prevent amyloid-beta oligomerization

Increase neprilysin

Increase IDE (insulin-degrading enzyme)

Increase microglial clearance of Aβ

Increase autophagy

Increase BDNF (brain-derived neurotropliic factor)

Increase NGF (nerve growth factor)

Increase netrin-1

Increase ADNP (activity-dependent neuroprotective protein)

Increase VIP (vasoactive intestinal peptide)

Reduce homocysteine

Increase PPZA (protein phosphatase 2A) activity

Reduce phospho-tau

Increase phagocytosis index

Increase insulin sensitivity

Enhance leptin sensitixity

improve axoplasmic transport

Enhance mitochondnal function and biogenesis

Reduce oxidative damage and optimize ROS (reactive oxygen species) production

Enhance cholinergic neurotransmission

Increase synaptoblastic signaling

Reduce synaptoclastic signaling

Improve LTP (long-term potentiation) Optimize estradiol

Optimize progesterone

Optimize E2:P (estradiol to progesterone) ratio

Optimize free T3

Optimize free T4

Optimize TSH (thyroid-stimulating llormone)

Optimize piegnenolone

Optimize testosterone

Optimize cortisol

Optimize DHEA (deliydroepiandrosterone)

Optimize insulin secretion and signaling

Activate PPAR-γ (peroxisome proliferator-activated receptor gamma)

Reduce inflammation

Increase resolvins

Enhance detoxification

Improve vascularization

Increase cAMP (cyclic adenosine monophosphate)

Increase glutathione

Provide synaptic components

Optimize all metals

Increase GABA (gamma-aminobutyric acid)

Increase vitamin D signaling

Increase SirT1 (silent information regulator T1)

Reduce NF-κB (nuclear factor kappa-ligllt-chain-enhancer of activated B cells)

Increase telomere length

Reduce glial scarring

Enhance stein-cell-mediated brain repair

This explains why no single drug can have much effect on AD; it’s because the primary decision point depends on a balance among so many pro-AD (synaptoclastic) and anti-AD (synaptoblastic) signals. Addressing them all may be impractical in any given patient, so the Bredesen protocol is built around a detailed diagnostic process that identifies the factors that are most important in each individual case.

Three primary types of AD

Bredesen’s diagnosis begins with classifying each case of AD into one of three broad constellations of symptoms, with associated causes.

Type I is inflammatory. It is found more often in people with carry one or two ApoE4 alleles (a gene long associated with Alzheimer’s) and runs in families. Laboratory testing will often demonstrate an increase in C- reactive protein, in interleukin-2, tumor necrosis factor, insulin resistance and a decrease in the albumin:globulin ratio. Type II is atrophic. It also occurs more often those who carry one or two copies of Apoε4, but occurs about a decade later. Here we do not see evidence of inflammatory markers (they may be decreased), but rather deficiencies of support for our brain synapses. These include decreased hormonal levels of thyroid, adrenal, testosterone, progesterone and/or estrogen, low levels of vitamin D and elevated homocysteine. Type III is toxic. This occurs more often in those who carry the Apoε3 allele rather than Apoε4 so it does not tend to run in families. This type tends to affect more brain areas, which may show neuroinflammation and vascular leaks on a type of MRI called FLAIR, and associated with low zinc levels, high copper, low cortisol, high Reverse T3, elevated levels of mercury or mycotoxins or infections such as Lyme disease with its associated coinfections. (This box quoted from Dr Neil Nathan’s book review)

There’s also a Type 1.5, associated with diabetes and sugar toxicity, a Type IV, which is vascular dementia, and a Type V which is traumatic damage to the brain.

These categories are just a start. The patient will work closely with an expert physician to determine, first, where are the most important imbalances to address, and, second, which of the changes that cna address them are most accessible for the life style of this particular patient.

Success

Bredesen wrote a paper in 2014 about successes in reversing cognitive decline with his first ten patients. As of this writing, he has treated over 3,000 patients with the protocol called RECODE (for REversal of COgnitive DEcline), and he claims success with all of them, in the sense of measurable improvement in cognitive performance. This contrasts with the utter failure of all previous methods, which claim, at best, to slow cognitive decline.

Translation to the millions of Alzheimer’s patients will require training of local practitioners all across the country. A few doctors have already learned parts of the Bredesen protocol, and Bredesen’s website can help you find someone to guide your program, but you will probably have to travel. The first training for doctors is being organized now through the Institute for Functional Medicine.

Implications

This is a new paradigm for how to study chronic, debilitating diseases. Type 2 diabetes comes to mind as the next obvious candidate for reversal through an individualized, comprehensive program. Terry Wahls has pioneered a similar approach with MS. Cancer and heart disease may be in the future.

I’ll go out on a limb and say I think Bredesen’s protocol is the most credible generalized anti-aging program we have. (Blame me for the hyperbole, not Dr Bredesen — he has never made any such claim.) Could we adopt Bredesen’s research method to accelerate research in anti-aging medicine? Perhaps biomarkers for aging (especially methylation age) are approaching a point where they could be used as feedback for an individualized program, but Horvath’s PhenoAge clock will probably have to be 10 times more accurate to be used for individuals. Averaging over ~100 individuals can give this factor of 10 in a clinical trial. Still, we don’t have the kind of mechanistic understanding of aging that Bredesen himself developed for AD before bringing his findings to the clinic; and this is probably because causes of aging are more complex and varied than AD.

Disclaimers: I’m pre-disposed to think highly of Dale Bredesen and his ideas for 3 reasons. He was a friend to me, and gave me a platform when I was new to the field of aging. He believes that aging is programmed. And his multi-factorial approach parallels the research I have advocated for researching other aspects of aging.

Rhonda Patrick interviews Dale Bredesen on FoundMyFitness