Alzheimer

1/12/2017
First Reversals of
Cognitive Decline in
Alzheimer’s Disease and
Systems Therapeutics,
its President Obama,
Precursors, MCIandand
the End ofSCI
Alzheimer’s
Disease
Dale E. Bredesen, M.D.

Augustus Rose Professor
Easton Laboratories for Neurodegenerative
Disease Research
UCLA
Founding President, Buck Institute
“There is nothing that will prevent, reverse, or

slow the progress of Alzheimer’s disease.”
“Everyone knows someone who is a cancer

survivor; no one knows an Alzheimer’s
survivor.”
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1/12/2017
30,000,000
patients in 2012
3rd leading cause (James, B. D. et al. Contribution of Alzheimer disease to
mortality in the United States. Neurology 82, 1045-1050, doi:10.1212/WNL.
0240 (2014)
Pres. Obama and NAPA, 2011
160,000,000
patients in 2050
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Women at the epicenter

of the epidemic
•65% of patients
•60% of caregivers
•More common than breast cancer
0
Cures
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Alzheimer’s Disease (AD) Therapeutic Landscape
  A production
APPROVED
  A aggregation
 Donepezil (Aricept)
  A clearance
 Rivastigmine (Exelon)
  Tau aggregation/phosph
 Galantamine (Razadyne)
 Cholinergic drugs
 Tacrine (Cognex)
 Others
 Memantine (Namenda)
PHASE 3 PHASE 2 PHASE 1

 Solanezumab  ELND005  PBT2  AL-108  GSK933776
 NIC5-15  PF04360365  AF102B
 MABT5102A
 Bapineuzmab  Valproate  Bryostatin-1  Nicotinamide
 Talsaclidine
 EHT-0202  NP12  ACC001  UB311
 Alzemed   Antioxidant
 BMS708163  Lithium  AN1792  R1450  Begacestat
 Semagacestat  Statins  ABT089  NGF  CAD106
 V950  PF3084014
 AZD3480  SB742457
 Flurizan  Dimebon  E2012
 Huperzine-A  PRX03140  CTS21166
 Rosiglitazone  EGCg  EVP6124  PUFA  MK0752
 MEM3454  TTP448
 Phenserine  CHF5074
 PF-04447943
 Clinical Trial in AD terminated
“Game of Throwns” (243/244)
R.I.P. R.I.P. R.I.P.

Semagacesta Rosiglitazone
Dimebon x2
t
R.I.P. R.I.P.
Bapineuzumab
AN-1792 Alzhemed Flurizan Rember
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http://www.youtube.com/watch?v=
uAlkCMfTASQ
-DE_zCSZhWY
UaQPtykWpgk&feature=related
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Alzheimer’s: A Sad State of Affairs
•PATIENTS often do not seek medical care because they have

been told there is nothing that can be done, and they fear loss of
driver’s license, the stigma of a diagnosis, inability to obtain
long-term care, and ultimately nursing home placement. Thus
they often present very late in the process.
•PRIMARY CARE PROVIDERS often do not refer, since they

realize that there is no truly effective therapy. Therefore, they
typically simply start donepezil (Aricept), often without a firm
diagnosis.
•SPECIALISTS often put the patients through hours of

neuropsychological testing, expensive imaging, lumbar
punctures, and then have little or nothing to offer therapeutically.
20th century evaluation of cognitive decline
• “MRI of the brain and blood for CBC, metabolic panel,

thyroids, B12.”
• “I asked the patient and his wife to keep an eye on his
disabilities to manage money, medications and
transportation.”
• “I prescribed donepezil 5mg once per day.”
• No genetics (no ApoE status, TREM2, CD33, NALP1, PS1,
etc.), no hs-CRP or IL-6 or anything re inflammation, no
homocysteine, no fasting insulin, no hormonal status,
nothing re toxin status, nothing re innate immune system
status, nothing on gut health, no microbiome, no blood-brain
barrier analysis, no MRI volumetrics, etc., etc., etc…
• Prescribing donepezil without diagnosis.
• BMI was 33—nothing even noted, no plan to address this.
• Pre-diabetes, a key risk factor—nothing to address this.
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Classical medicine: breaking through to AD cure?
67 y.o. woman with 2-yr history of progressive cognitive decline
• Mother died with dementia, onset age 62.

• Unable to navigate on freeway.
• Could not remember what she had read.
• Unable to prepare reports for work.
• Unable to recall even 4-digit numbers.
• Retinal scan positive for amyloid (greater than London pt.).
• Treated with MEND (metabolic enhancement for
neurodegeneration).
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1/12/2017
70 y.o. man with 12-yr history of accelerating memory loss
• ApoE4 positive (heterozygote)

• FDG-PET scan typical of AD (temporoparietal reduced Glu)
• Neuropsych testing 2003, 2007, 2013
• Progressive loss: CVLT from 84%ile to 3%ile
• Unable to remember lock combination, faces, schedule
• Difficulty at work, and with numbers; Dx—early AD
• Improvement at 6 months: co-workers, schedule, faces, nos.
• Wife notes accelerated decline completely stopped.
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Proof of Improvement on ReCODE
71 yo E4/3 2013 2015 (MEND 2 yr)

CVLT-II B 3%ile 84%ile (3SD)
Total Recog Hits <1%ile 50%ile
CVLT-II 54%ile 96%ile
Auditory delayed 13%ile 79%ile
memory
Reverse digit 24%ile 74%ile
span
Processing 93%ile 98%ile
speed*
Metabolism and Cognition Go Hand in Hand
66M ApoE4/3 2014 2015 (MEND 10

mos.)
Fasting insulin 32 8
Hs-CRP 9.9 3
Homocysteine 15 8
Vitamin D3 21 40
Symptoms Struggling Working full-time
MRI hippocampal 17%ile 75%ile
volume
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Improvement on ReCODE
55F ApoE4/4 2015 2016 (MEND 5

mos.)
Neurocognitive 16%ile 73%ile
index
Composite 1%ile 61%ile
memory
Verbal memory 3%ile 93%ile
speed
Executive 14%ile 58%ile
function
Cognitive 16%ile 61%ile
flexibility
Programmatics, not “pill-osophy”

Algorithm and ReCODE
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So how does one go about developing

an effective treatment for an incurable
disease?
2 fundamental approaches…
Canonical Alzheimer’s disease
ApoE4 AD
(p-, A, etc.)
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1/12/2017
The Chimp That Killed the Rhino

Evolution, Shortgevity, Alzheimer’s, and the God Gene

220,000
7 million years ago
6 million years ago
5 million years ago
4 million years ago
3 million years ago
2 million years ago
1 million years ago
years ago
ApoE3
ApoE4
ApoE2
80,000
years ago
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1/12/2017
ApoE4—new mechanism
ApoE4
Theendakara, V. et al. Neuroprotective Sirtuin

ratio reversed by ApoE4. Proc Natl Acad Sci U S
A 110, 18303-18308,
RelA
doi:10.1073/pnas.1314145110 (2013
ApoE4 Theendakara, V. et al. Direct Transcriptional Effects
of Apolipoprotein E. J Neurosci 36, 685-700,
doi:10.1523/JNEUROSCI.3562-15.2016 (2016). 28
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ApoE4-promoter interactions by ChIP-Seq
Glucose homeostasis & diabetes
Microtubule disassembly Synapse dysfunction
APOE4
Aging & SirT

Inflammation
Theendakara, V. et al.
Neuroprotective Sirtuin ratio
reversed by ApoE4. Proc Natl Acad
Sci U S A 110, 18303-18308,
doi:10.1073/pnas.1314145110
(2013
Neurotrophins and cell death
Theendakara, V. et al. Direct
Transcriptional Effects of Apolipoprotein
E. J Neurosci 36, 685-700,
doi:10.1523/JNEUROSCI.3562-15.2016
(2016).
Organisms produce amyloid in response to 3 major

metabolic and toxic perturbations
• Inflammation (e.g., NFkB activation), be it infectious (e.g.,
from biofilms) or sterile (e.g., AGE-modified proteins).
• The withdrawal of trophic support (e.g., nerve growth factor,
estradiol, testosterone, vitamin D, etc.).
• Exposure to toxins, such as divalent metals (e.g., mercury).
• These form the basis for types 1, 2, and 3 AD/MCI/SCI,
respectively.
• Combinations of these types are common, for example
glycotoxic (type 1.5), in which the advanced glycation
endproducts (AGEs) cause inflammation and the insulin
resistance leads to trophic withdrawal signaling.
• Other inputs such as sleep apnea, trauma, and vascular
insufficiency trigger amyloid via these same 3 major causes.
1. Bredesen, D.E. Reversal of cognitive decline: A novel therapeutic program. Aging Journal Vol. 6 N9, 1-11 (2014)
2. Bredesen, D. E. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. Aging (Albany NY) 7, 595-600 (2015)
3. Bredesen, D. E. Inhalational Alzheimer's disease: an unrecognized - and treatable - epidemic. Aging (Albany NY) 8, 304-313 (2016)
4. Bredesen, D. E. et al. Reversal of cognitive decline in Alzheimer's disease. Aging (Albany NY) 8, 1250-1258, doi:10.18632/aging.100981 (2016)
5. Theendakara, V. et al. Direct Transcriptional Effects of Apolipoprotein E. J Neurosci 36, 685-700, doi:10.1523/JNEUROSCI.3562-15.2016 (2016)
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Trophic, Anti-trophic,
Anti-AD Pro-AD
sAPP sAPP
A
CTF Jcasp
C31
Neurite Retraction
TAU Neurofibrillary
Tangle
A plaques
Mitochondria
Bredesen, D.E. Reversal of cognitive decline: A novel therapeutic program. Aging
Journal Vol. 6 N9, 1-11 (2014) 31
Kurakin, A. & Bredesen, D. E. Dynamic self-guiding analysis of Alzheimer's disease. Oncotarget 6, 14092-14122 (2015)
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Chronic illnesses as signaling imbalances

Osteoclastic
Osteoblastic
Osteoporosis:
<
Cytoblastic
Cytoclastic
Cancer:
>
Synaptoblastic
Synaptoclastic
Alzheimer’s: <
Journal Vol. 6 N9, 1-11 (2014)
Synaptic element interdependence
Bredesen, D. E. Neurodegeneration in Alzheimer's disease: caspases and synaptic

element interdependence. Mol Neurodegener 4, 27, doi:1750-1326-4-27 [pii]
10.1186/1750-1326-4-27 (2009).
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A roof with 36 holes…
The perfect Alzheimer’s drug would:

Reduce APP -cleavage, reduce -cleavage, increase -cleavage,
reduce caspase-6 cleavage, reduce caspase-3 cleavage, prevent
oligomerization, increase neprilysin, increase IDE, increase
microglial clearance of A, increase autophagy, increase BDNF,
increase NGF, increase netrin-1, increase ADNP, reduce
homocysteine, increase PP2A activity, reduce phospho-tau,
increase phagocytosis index, increase insulin sensitivity,
improve axoplasmic transport, enhance mitochondrial function
and biogenesis, reduce oxidative damage and optimize ROS
production, enhance cholinergic neurotransmission, increase
synaptoblastic signaling, reduce synaptoclastic signaling,
improve LTP, optimize estradiol, progesterone, E2:P ratio, free T3,
free T4, TSH, pregnenolone, testosterone, cortisol, DHEA, and
insulin, reduce inflammation, increase resolvins, enhance
detoxification, improve vascularization, increase cAMP, increase
glutathione, provide synaptic components, optimize all metals,
increase GABA, increase vitamin D signaling, increase SirT1,
reduce NFkB, increase telomere length, reduce glial scarring,
enhance repair, etc.
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The 21st-century physician
The ReCODE Protocol
• We have mapped the many molecular mechanisms of

cognitive decline and AD onto a treatment protocol.
• These include dozens of interventions, beginning with
DESS, hormonal optimization, nutrients, targeted herbs,
brain stimulation, drugs, etc.
• No one intervention closes all 36 holes.
• Approach: pull out all of the stops.
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ReCODE program
• Inflammation: resolution (resolvins), inhibition, removal
of source(s).
• Infections (chronic): Borrelia, other tick-borne, chronic
viruses, Stachybotrys, etc..
• Atrophic: optimization of hormones, homocysteine,
methylation, trophic support, antioxidants, GSH, et al.
• Toxins: metals including Cu:Zn ratio, Hg; mycotoxins.
• Metabolism including glycotoxicity (type 1.5).
• Regeneration, protection.
Central concepts
• “Alzheimer’s disease” is a pathologist’s diagnosis. This term
should not be followed by a period any more than fever
should be—Alzheimer’s disease due to what?
• What is referred to as “Alzheimer’s disease” is actually a
protective response to 3 major metabolic and toxic insults:
inflammation/infection, trophic withdrawal, and toxin
exposure.
• Evaluation of patients with cognitive decline reveals 5 major
types (and combinations of these types): type 1 (inflammatory
(“hot”)), 1.5 (glycotoxic (“sweet”)), 2 (atrophic (“cold”)), 3
(toxic (“vile”)), 4 (vascular (“pale”)), and 5 (traumatic
(“dazed”)).
• There are approximately 100 biochemical, genetic, functional,
and historical parameters that characterize each patient or
person at risk.
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Basic concepts of the protocol

• Identify all contributors to the imbalanced plasticity network (from 100,
e.g., copper:zinc ratio > 1.3, RBC Mg < 5.2, hs-CRP > 1.0, homocysteine
> 7, fasting insulin > 4.5, C4a > 2800, free T3 < 3.2, TSH > 2.0, Cyrex
Array 2 +, etc., etc., etc.). From these, we use a software algorithm to
construct a “why memory loss” table weighted for each type.
• Determine the degree of contribution to types 1 (inflammatory (“hot”)),
1.5 (glycotoxic (“sweet”)), 2 (atrophic (“cold”)), 3 (toxic (“vile”)), 4
(vascular (“pale”)), or 5 (traumatic (“dazed”)).
• For each abnormality identified, we want to go beyond simply
normalizing the test, we want to optimize the value.
• We want to address as many of the abnormalities as possible, not just
one, and the earlier in the process, the greater chance for success.
• For each treatment we include, the goal is to design the treatment so
that it will be as physiological and upstream as possible.
• The program is personalized.
Evaluation Step 1: Determine Subtype(s)
• Presymptomatic vs. SCI vs. MCI vs. AD.

• Several different metabolic syndromes are called
“Alzheimer’s disease:”
• Type 1: Inflammatory (“Hot”)
• Type 2: Atrophic (“Cold”)
• (Type 1.5: Glycotoxic (“Sweet” combines 1 and 2))
• Type 3: Toxic (“Vile”)—a fundamentally different
problem.
• Type 4: Vascular (“Pale”)
• Type 5: Traumatic (“Dazed”)
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Characteristics of type 3 AD
• Age at symptom onset < 65.
• ApoE4-negative (usually).
• Negative family history (or only older).
• Low triglycerides and/or zinc.
• HPA dysfunction.
• Depression.
• Problems with math or organization or word finding.
• Exposure to toxins (mercury, mycotoxins, CIRS-related such
as Lyme, MARCoNS, surgical implants, others).
• Precipitation or exacerbation by stress.
• “Atypical Alzheimer’s,” often with frontal effects and imaging.
Characteristics of type 3 AD (cont’d)

• High C4a (>2800), TGF-beta-1 (>2380); low MSH (<35).
• HLA-DR/DQ with “dreaded” multiple biotoxin sensitive or
pathogen-specific (4-3-53, 11-3-52B, 12-3-52B, 14-5-52B).
• MARCoNS (multiple-antibiotic resistant coagulase-negative
Staphylococcus, deep nasopharyngeal culture)—biofilm
assessment.
• Visual contrast sensitivity abnormalities.
• Surprisingly, most do NOT have allergic symptoms.
• Most do not fulfill criteria for CIRS, yet have laboratory values
compatible with CIRS.
• Potential relationship to Lewy body disease.
• Most difficult type of AD to treat successfully.
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50 yo woman with depression post-hysterectomy

• Over the ensuing 4 years, developed word-finding difficulty,
disorientation, difficulty following recipes, difficulty driving.
• Declined markedly with stress, sleep deprivation, and viral illness.
• Neuropsych: poor semantic fluency, paucity of speech,
confabulation; frontal, temporal, and parietal deficits.
• FDG-PET: temporal and parietal > frontal reduced glucose
utilization, compatible with Alzheimer’s disease.
• Seen at university dementia center, started on antidepressant and
donepezil.
• ApoE3/3, negative family history, hs-CRP 0.2, C4a 5547, TGF-1
7037, VCS failed, anti-Lyme negative, anti-thyroglobulin antibodies
1:2000.
• Treated with MEND, intranasal VIP. Improvements in memory,
interaction, following directions, MoCA.
• Most difficult type of AD to treat successfully.
HLA-DR/DQ haplotypes in type 3 AD

Table 1. HLA‐DR/DQ haplotypes in patients with type 3 Alzheimer’s disease

Age at symptom Major symptoms HLA‐DR/DQ Comment
onset (years) Human Leucokyte
Antigen type
50 Dyscalculia, 10‐3‐52B ApoE3/3
executive 10‐5 (low MSH)
54 Executive, visual 11‐3‐52B ** ApoE3/3
7‐2‐53 *
72 Executive, 4‐3‐53 ** ApoE3/3
dyscalculia 15‐6‐51 * (Lyme)
65 Spatial > verbal 11‐3‐52B ** ApoE3/3
memory, attention, 13‐6‐52B *
irritability,
depression
54 Executive, 17‐2‐52A * ApoE4/4
visuospatial, 1‐5 (low MSH)
memory,
depression
59 Aphasia, executive, 12‐3‐52B ** ApoE2/3
dyscalculia, 15‐6‐51 * (Lyme)
depression
59 Headache, 4‐3‐53 ** ApoE ND
executive 15‐6‐51 * (Lyme)
66 Headache, 11‐3‐52B ** ApoE ND
executive, memory 13‐6‐52C *
*Pathogen‐specific HLA‐DR/DQ‐related sensitivity (mold or Lyme).
**Multiple‐biotoxin‐sensitive HLA‐DR/DQ association.
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• Inflammatory/infectious.
• Increase in hs-CRP and/or other inflammatory markers
(e.g., increases in IL-6, IL-8, TNF, etc.)
• Reduction in A/G ratio.
• Increase in M1/M2 ratio; reduction in MFI.
• ApoE4 is important risk factor.
• Presentation is typically amnestic.
• Hippocampal atrophy is common.
• Seek cause(s) of inflammation (e.g., gut leak, AGEs, diet,
poor oral hygiene, etc.)
• Atrophic (“cold”).
• Patients tend to be older than type 1.
• Typically amnestic presentation; patients often protest that
nothing is wrong.
• Reductions in trophic support (e.g., estradiol, progesterone,
testosterone, vitamin D, pregnenolone, thyroid, NGF, BDNF).
• ApoE4 is risk factor.
• Rapid reductions in support are most concerning (cf.
oophorectomy at <41 without HRT), c/w depR mismatch.
• Optimizing support may be complicated by receptor
response, HRT controversy, trophic factor delivery (intranasal
vs. peptides vs. indirect, etc.).
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Characteristics of type 1.5 AD

• Glycotoxic (“sweet”).
• Inflammatory part from AGEs (via RAGE, glyoxals, etc.)
and related.
• Atrophic part from insulin resistance (e.g., IRS1 S/T
phos.).
• Goetzl noted insulin resistance in 100% of the neural
exosomes from AD patients (measured via IRS1).
• ApoE4 is an important risk factor.
• Amnestic presentation is common.
• Paradox of insulin sensitization and trophic requirement.
66 yo man with “senior moments”

• Family history+ in both parents.
• ApoE3/4, amyloid PET markedly positive, FDG-PET
typical for AD, hippocampal volume reduced,
neuropsych testing MCI.
• Fasting insulin 32, HgbA1c 5.5, FBS 96.
• Homocysteine 15.1.
• Vitamin D 21.
• Testosterone 264, free T3 2.4, TSH 2.21.
• Responded metabolically, cognitively, and volumetrically
to MEND. Neurologist said he is now “normal.”
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Why Memory Loss? Files and ReCODE
EVALUATION: preliminary considerations

• Exclude non-AD pathophysiology? Or consider the lack of
successful Rx for FTD, LBD, PSP, and other neurodegenerative
conditions?
• Lewy body dementia? Visual hallucinations? “Show time?” Sleeping
late? Delusions? REM behavioral disturbance? Gait abnormality?
Parkinsonian features? (Also note mixed AD/LBD and PD dementia.)
• Vascular dementia? Mixed?
• CTE? Note combination of depression, aggression, and dementia.
• Frontotemporal lobar degeneration? Behavioral symptoms? Primary
progressive aphasia?
• Less common: progressive supranuclear paralysis (PSP), multi-
system atrophy (MSA), corticobasal degeneration (CBD), etc.
• Primarily amnestic or cortical? Aphasia, dyscalculia, visual agnosia,
prosopagnosia?
• Executive dysfunction?
• Depression?
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EVALUATION: documentation
• MRI with volumetrics
• FDG-PET scan
• Amyloid PET and/or Tau PET
• Quantitative neuropsychological tests (standard vs. on-
line)
• CSF? (reduced A42, increased tau and p-tau)
• Genetics—genome vs. exome vs. SNPs—especially
ApoE, PS1, PS2, APP, NALP1 (innate), CR1 (innate),
CD33 (clearance), TREM2 (inflammation), VDR (NHR),
klotho (anti-AD), MTHFR (methylation) (SNPs AD)
• Serum tests
EVALUATION: inflammation
• hs-CRP
• IL-6
• TNF-
• A/G ratio
• Infectious? HSV-1, P. gingivalis, other oral bacteria,
Borrelia, other spirochetes and tick-borne pathogens,
fungi (C. glabrata et al.)
• Many others optional
• Genetics—especially ApoE4, NALP1 (innate), CR1
(innate), TREM2 (inflammation)
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EVALUATION: glucose, insulin resistance

• Fasting insulin
• Fasting glucose
• Hemoglobin A1c
• Neural exosome IRS1 phosphorylation ratio
• History of pre-diabetes or diabetes?
• Simple carbohydrates in diet? Carb craving?
• Stress? Nighttime eating? Cushingoid?
EVALUATION: one-carbon metabolism

• Homocysteine and PP2A PTM (multiple mechanisms, e.g., ER stress,
tau phosphorylation, excitotoxicity)
• --Protein phosphatase 2A is the major enzyme that
dephosphorylates phospho-tau. It consists of 3 subunits, A, B, and
C.
• --Homocysteine causes a modification in the catalytic subunit (C) to
reduce binding to the regulatory subunit (B).
• --For comparison, ApoE4 also reduces PP2A activity but does so at
the transcriptional level (R. Rao et al.).
• Vitamin B12 (200-900??)
• Methylmalonic acid (variability)
• Folate
• Pyridoxine
• Genetics—especially MTHFR (677, 1298, etc.), MTRR, BHMT (betaine
homocysteine methyl transferase), CBS (cystathionine beta
synthase)
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EVALUATION: hormones
• Thyroid: basal body temperature, Thyroflex, fT3, fT4, rT3,
fT3:rT3 ratio, TSH.
• Estradiol, progesterone, E2:P ratio, testosterone (total
and free). Serum vs. salivary vs. urine. Blood spot? ZRT
Labs or Precision?
• DHEA, pregnenolone, cortisol.
• Metabolite ratios (optional).
• Vitamin D (25-hydroxycholecalciferol vs. calcitriol) and
the IOM.
• History of oophorectomy? Age?
• History of HRT? Bio-identical?
• History of anti-testosterone Rx?
EVALUATION: metal homeostasis

• Cu:Zn ratio (Brewer, Van Tiggelen)
• Serum copper, zinc, selenium.
• Ceruloplasmin; Cu – 3x ceruloplasmin <30.
• RBC magnesium.
• Calcium
• Potassium (risk factor)
• Heavy metals: Hg, Pb, Cd, As (metalloid)
• To provoke or not to provoke?
1. Brewer, G. J. & Kaur, S. Zinc deficiency and zinc therapy efficacy with reduction of serum free copper in Alzheimer's disease. International journal
of Alzheimer's disease 2013, 586365, doi:10.1155/2013/586365 (2013).
2. Van Tiggelen, C. J. M. Nutritional Aspects of Senile Dementia of the Alzheimer Type (SDAT). Journal of Orthomolecular Medicine 4, 205-210
(1989)
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EVALUATION: toxins (type 3 vs. all)

• Heavy metals, especially mercury.
• CIRS symptoms? Allergic—asthma, sinusitis, epistaxis,
rashes, chemical sensitivities, MCAD (mast cell
activation disorder), etc.
• HLA-DR/DQ.
• C4a (NJC-C4a).
• TGF-1, MSH, MMP9; optional: leptin, ADH, VEGF, VIP,
osmolality.
• MARCoNS culture.
• VCS (visual contrast sensitivity testing).
• RealTime Labs urinary mycotoxins.
EVALUATION: cytoprotection
• Glutathione
• Vitamin E < 13?
• Selenium
• Ascorbate
• Albumin < 4.5? A/G ratio < 1.8? Major carrier of A
peptide.
• Breath MS for ROS.
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EVALUATION: barrier leaks and the Smurf assay
• Cyrex Array 2: GI leak (trans-cellular or intercellular)

• Cyrex Array 20: blood-brain barrier leak
• Cyrex Array 3: gluten sensitivity
• Cyrex Array 4: other grain sensitivities
• Oral hygiene
• Nasopharyngeal MARCoNS, AD, and
the rhinencephalon
EVALUATION: alerts
• Visual hallucinations, delusions, REM behavioral
disturbance, constipation, anosmia, passing out,
autonomic disturbance (e.g., arrhythmia, postural
hypotension), newly sleeping late, resting tremor: alert
re synucleinopathy, LBD or PD or MSA.
• Kleptomania, loss of empathy, saying inappropriate
things, apathy, executive dysfunction, primary
progressive aphasia: alert re FTLD.
• Atrial fibrillation, hypertension, dyslipidemia, sudden
neurological changes, peripheral vascular disease: alert
re vascular dementia.
• Conjugate upgaze or downgaze paresis: alert re PSP.
• Rapid course over weeks or a few months: alert re CJD,
prion illnesses.
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The protocol works best for:
•Presymptomatics (cf. 7 million E4/4, 75 million E4).

•SCI (subjective cognitive impairment).
•MCI, especially if aMCI and identifiable contributors.
•Early AD, especially if not already on donepezil or memantine.
•People with cognitive changes who are otherwise healthy.
•Non-type 3 SCI, MCI, or early AD.
•Atrophy limited to hippocampus.
•Age < 75.
The protocol works least well for:
•Advanced Alzheimer’s disease (except for behavior).

•Long-term, progressive symptoms (but note EC).
•Age > 75.
•Type 3 when beyond early MCI.
•On multiple medications, especially donepezil and memantine.
•Poorly compliant person/team (including family, MD).
•Those who are slow, with diffuse synaptic loss.
•**Beware candidates for congophilic angiopathy (esp. E4/4 males).**
32
1/12/2017
Basic concepts of the protocol

• A key component of the program is that it is iterative.
• Drugs are the dessert, not the entrée.
• The earlier you treat, the greater your chance for
complete reversal.
• As the metabolic parameters go, so goes the cognition.
• The prionic loop effect creates a threshold, so you do
not usually need to do every step.
Closing the complexity gap (/chasm)
33
1/12/2017
Closing the complexity gap
• Neural exosomes.
• Dense dynamic personalized data clouds
(Institute for Systems Biology).
• Microbiomes (gut, rhinosinal, oral).
• Combining plasticity training with biochemical
optimization (Posit Science).
Summary
• What is referred to as “Alzheimer’s disease” is the result of a protective response to
3 major metabolic and toxic perturbations: inflammation (be it infectious or sterile),
trophic withdrawal (trophic factors, hormones, vitamins, etc.), and specific toxins
(divalent metals, mycotoxins, et al.).
• There are 3 major subtypes of Alzheimer’s disease (and combinations of these 3

subtypes), and these are readily disclosed by metabolic and genetic profiling.
• Cognitive decline in early Alzheimer’s disease and its forerunners, MCI (mild
cognitive impairment) and SCI (subjective cognitive impairment), is reversible, and
improvement sustainable, using a programmatic approach rather than a
monotherapy (Bredesen, Aging 2014; Bredesen et al., Aging 2016).
• Not surprisingly, the earlier that treatment is initiated, the greater chance for
improvement: in the first 125 patients, over 50% saw improvement using our
protocol, including nearly all who were in the early stages.
• We can reduce the global burden of dementia markedly, and increase the global
cognitive ability, through metabolic profiling, prevention and early reversal, and
personalized, programmatic approaches to cognitive (and overall) health. This could
be a highly efficient use of practitioner time and healthcare finances.
34
1/12/2017
A new dawn
SirT1-NFkB mutual inhibition
35
1/12/2017
ApoE4: ApoE3:
RelA dominant SirT1 dominant
71
ApoE4 and plasticity ratio
150 sAPPsAPP sAPPA

150
100
100
% APP
% APP
*
50 50 *
* * *
0 0
P
4∆
3
4
P
4∆
oE
oE
AP
oE
oE
AP
oE
oE
Ap
Ap
Ap
Ap
Ap
Ap
P+
P+
P+
P+
P+
P+
AP
AP
AP
AP
AP
AP
36
1/12/2017
Prolegomenon and Summary
EVALUATION: other risk factors

• Sleep apnea
• History of head trauma
• History of loss of consciousness
• Presence of dental amalgams
• History of hypertension
• Consumption of seed oils
• Neuroactive medications (especially with anti-
cholinergic activity), direct or indirect: e.g.,
benzodiazepines, statins, proton pump inhibitors,
antipsychotics, antihistamines, anesthetics, EtOH, illicit
drugs, etc.
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1/12/2017
EVALUATION: other risk factors (2)

• Poor oral hygiene? Root canal history?
• Sinusitis
• Metabolic syndrome
• History of alcohol withdrawal symptoms
• History of vascular disease
• Exposure to mitochondrial toxins (e.g., antibiotics,
statins, ApoE4, griseofulvin, AZT, acetaminophen,
NSAIDS, cocaine, methamphetamine, L-DOPA, EtOH)
• Renal, hepatic, or pulmonary disease?
• BMI > 25?
EVALUATION: other risk factors (3)

• Sleep < 7 hours/night?
• Seropositive for HSV-1?
• Headaches?
• Mold exposure?
• History of meningitis?
• History of cancer?
• Gluten sensitivity or other food sensitivity?
38
1/12/2017
The readout: plasticity ratio (cf. HDL:LDL)
AD has programmatic components:

EMT (epithelial-mesenchymal transition)
39
1/12/2017
Alzheimer’s and the EMT

AD: Type IV Organized (E) Unicellular (M) AD
EMT?
Metabolism Oxphos Glycolysis Glycolysis
Inflammation Low High High
SirT1/NFkB SirT1 dominant NFkB dominant NFkB dominant
ROS Low High High
Cytoskeleton Intact Breakdown Breakdown
Insulin signaling Sensitive Resistant Resistant
Secretory Low High ??
Intercellular Present Lost Lost (synapses)

junctions
ApoE4-mediated RelA nuclear translocation

SHSY5Y-extract; IP: Rel-A
80 WB: RelA
110 PARP
50
80 50
RelA WB: ApoE
50
30
50
ApoE 40
30 GAPDH
30
Subcellular fraction Cy Nuc Cy Nuc Cy Nuc
ApoE - E3 E4 ApoE - E3 E4
SirT1
Ladder input (-)Ab ApoE Ab
40
1/12/2017
Is amyloid a “memory” component of the innate immune

response?
• Increasing implication of amyloid- as part of the inflammatory

response (e.g., relationship to NFkB).
• In particular, as part of the innate immune system response
(DAMP (damage/danger-associated molecular pattern)?).
• Amyloid noted for very long half-life.
• Hippocampus plastic, yet amyloid remains.
• Amyloid often present for years prior to symptoms.
• Dynamic nature suggests polymerization and depolymerization.
• Suggests model as on-site maintenance—essentially a
“memory” component of the innate immune response,
analogous to the more elegant memory mechanisms of the
adaptive immune response.
SUMMARY
•The problem and the need.

•The success to date.
•Scientific background, resulting model, and implications.
•Details of evaluation.
•Details of treatment.
•Troubleshooting.
•Issues and concerns.

•Questions and discussion.
•Future directions.
41
1/12/2017
55 y.o. attorney with 4-yr history of severe memory loss
• Left stove on multiple times when leaving home.

• Recorded conversations since she could not remember.
• Carried iPad to note everything.
• Unable to practice or to learn new information.
• Lost mid-sentence; had a talk with her children.
• Iterative Rx returned her to normal over 10 mos.
• Back at work, learning new areas of law, and learned
Spanish.
• iPad optional
The fifth P: Progressive
42
1/12/2017
Julie G and ApoE4.info
Any accurate theory of AD should explain:
•The AD11 mouse.

•The 7 paradox.
•Lack of successful therapeutic development to date.
•The remarkable diversity of risk factors for AD; relation to ASCVD.

•The high prevalence of AD in the elderly.
•The mechanism(s) by which ApoE4 increases risk for AD.
•The physiological role(s) of A peptides.
•The anatomic pattern of spread of AD pathology.

•The association of plastic brain regions with AD pathology.
•Why some people (and transgenic mice) collect large amounts of A peptide
without displaying symptoms of AD.
•The relationship between A and tau pathology.
43
1/12/2017
Frame of reference and points of view
•Taking a seemingly insoluble problem and making it

soluble by changing the coordinate system or frame of
reference.
Back to basics: cellular dependence
•Rita Levi-Montalcini, the 1986 Nobel Prize, and the trophic

factor hypothesis.
• It has been generally assumed that trophic factor withdrawal is associated with
the loss of a positive survival signal, such as that associated with the
phosphorylation of Akt.
• However, data accumulated over the past 20 years argue that there is a
complementary cell death signal mediated by specific receptors, dubbed
dependence receptors, activated by trophic ligand withdrawal but blocked by
ligand binding (Rabizadeh et al., Science 1993; Mehlen et al., Nature 1998).
44
1/12/2017
Levi-Montalcini and the classic view

Trophic factor
receptor
Trophic
factor
The old view: passive death

Trophic factor
receptor
No trophic
ligand
45
1/12/2017
The Dependence Receptor Concept

Dependence
Receptor
Trophic No ligand
ligand (or anti-trophic ligand)
Programmed
Cell
death
Diversity of Dependence Receptors

DCC
UNC5Hs Integrins
p75NTR   RET
MIDAS
Cadherin
motif
domain
D412 D707
(D1185) ZU-5
Chopper
D1290
D1017
Hirschprung’s Disease (megacolon)
Immunoglobin-like domain
Thrombospondin type I-like domain
Fibronectin-like domain
Death domain
Cysteine-rich domain
Medullary Carcinoma Tyrosine kinase domain
46
1/12/2017
An engineer’s view of the neuron
Integration
Analog  digital
Electrical (chemical) input
Via membrane conductance
Σ = Electrical input  electrical output
47
1/12/2017
Integration over anatomical vs.

biochemical space
Cholesterol Metabolism
Reelin
(ApoE, ABCA1, etc.)
Vitamin D Neurotransmitters
(Ach, glutamate, GABA, etc.)
Hormones,
(Thyroid, Estrogen,
Progesterone)
ECM (collagen, laminin,
Trophic Factors netrin, heparin, etc.)
(NGF, BDNF, N1, etc.)

biochemical space
Reelin
(ApoE, ABCA1, etc.)
(ACh, glutamate, GABA, etc.)
Hormones,
(Thyroid, Estrogen,
Progesterone, etc.)
Integration
Analog  digital (slow) output
Receptor signaling input
Via nuclei and cytoplasm
Σ = Chemical milieu input  morphogenetic output
48
1/12/2017
The big problem with neurodegenerative disease

Healthy Advanced
Brain Alzheimer’s PET Scans:
Alzheimer’s Disease
Histopathology
97
The Status Quo:

Alzheimer’s is a disease of toxicity
• Focus is on the chemical & physical Physicochemical effect or

effects of A peptide: signaling imbalance?
– Lysosomatropic detergent
Healthy Advanced
– Metal-binding peptide Brain Alzheimer’s
– Reactive oxygen species

– Many other theories
• Approach reinforced by 50,000+
papers…all of which fail to answer
key questions
• Why do healthy brains produce
Aß peptide?
• Recent results from transgenic mice
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1/12/2017
Why do neurons degenerate?

A New View of Alzheimer’s Disease
Proliferation Migration Integration
Cancer: imbalance in proliferation/survival vs. turnover

Tumor
Suppressor
Oncogenes Genes
Cancer
CANCER
50
1/12/2017
Alzheimer’s disease: imbalance in plasticity

Synaptic Synaptic
Reorganization Maintenance
Alzheimer’s
ALZHEIMER’S Disease
APP—candidate mediator of plasticity balance
51
1/12/2017
Amyloid Precursor Protein (APP)
-secretase -secretase
cleavage cleavage
26D6
NH2 COOH
-secretase
cleavage
A “D664A”
CT15 antibody
KKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
664 antibody
“C31”
The Mouse That Remembered to Roar:

Alzheimer’s Electrophysiology Normalized by Blocking C31
Galvan et al., PNAS 2006
52
1/12/2017
Control mice in Morris water maze
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1/12/2017
“Mouzheimer’s”
Mouzheimer’s no more
54
1/12/2017
Is APP involved in physiological plasticity?
Normal mouse (trial #8)
55
1/12/2017
“Sheldon Cooper mouse”
Modeling human disorders in Drosophila
56
1/12/2017
Alzflymer’s
Alzflymer’s
Alzflymer’s
Left: Off Right: On
57
1/12/2017
Activity Assay
400
*
Total Activity: 24 hours
350
APP,BACE/GS
300
250
200
150
100
50
0
DR- DR+ AL- AL+
Response to treatment with d-amphetamine
Before D-amphetamine treatment On D-amphetamine 24hr off D-amphetamine

(1.0 mg/ml)
1800
1800
1600 3000
1600
1400 1400 2500
1200 1200
2000
1000 1000
800 800 1500
600 600
1000
400 400
500
200 200
0 1 2
0 1 2
0 1 2
DR- DR+ DR- DR+ DR- DR+
APP,BACE/GS
58
1/12/2017
A Drosophila Hyperactivity Disorder (ADHD)

•Males >> Females.
•Exacerbated markedly by high CHO:protein diet.
•Reduced with aging.
•Associated with sleep/nocturnal dysrhythmic pattern.
•Reversibly responsive to d-amphetamine.
•“Paradoxical response” to d-amphetamine.
Research to Clinical Development:

Bench to Bedside
Alzheimer’s Drug Development Network

Varghese John, Ph.D., and Dale E. Bredesen, M.D.
PK/PD ADME-TOX
Research & Clinical
Screening Chronic Analoging Regulatory
Target ID Development
Efficacy “Candidate”
Team Team Team Team Team Phase 1,

Johnson Olivier: Alpha Patricia Barbara Mahta IND etc.
Clare Lisa: Assays Karen Davos Remy
Ram & Compound Olivia Stelios
Alexander Libraries Alex Clinical
Sonia (FDA & CNS Sylvia Consult.
Darci focused) IAS CEREB
Mike
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1/12/2017
F03: Multiple Mechanisms Against Alzheimer’s
• Reduces A
• Increases sAPP F03
• Blocks ApoE4 effect
• Improves LTP
• Blocks neuronal programmed cell death
• Excellent blood-brain barrier penetration
• High therapeutic index
• Markedly outperforms memantine and donepezil in Tg Mo
F03 restores novel object recognition completely
60
1/12/2017
Conclusions from the research bench

• APP is an integrating dependence receptor.
• APP is a mediator of both neurite outgrowth and neurite
retraction, depending on its incoming signals.
• APP functions as a molecular switch, with prionic loop
feedback (i.e., anti-homeostatic).
• Connectomic studies reveal many different inputs to the
plasticity balance mediated by APP, linking
epidemiological studies with molecular studies.
• APP downstream signaling links to phospho-tau and
other characteristics of AD, such as WAVE-1.
• ApoE4 functions by a novel mechanism (and by multiple
mechanisms) to alter cellular programming.
Combining the research and clinical findings offers

a novel look at what AD actually represents
• What is referred to as “Alzheimer’s disease” is actually a
protective response to 3 major metabolic and toxic insults
and combinations thereof.
• For many people, “Alzheimer’s disease” is not a disease—it is
a programmatic downsizing of the neural plasticity network.
• “AD” is not a mysterious, untreatable brain disease—it is a
reversible, metabolic/toxic, usually systemic illness with a
relatively large window for treatment.
• With respect to treatment of AD, drugs are the dessert, not the
entrée (and salad is the salad).
• The role of toxic exposures in AD has been under-recognized.
• For optimal responses, monotherapeutics should be replaced
by programmatics.
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1/12/2017
20th-century evaluation of cognitive decline
• Neurological exam—often negative.

• Behavioral assessment—doesn’t reveal etiology or
suggest therapy.
• Quantitative neuropsychological examination—causes
stress and takes several hours.
• MRI without volumetrics—usually negative or showing
mild atrophy.
• Labs—basic chemistries, usually unrevealing.
• The vast majority of critical parameters is left
unevaluated.
Playing chess with the devil
62
1/12/2017
Goals and arrows in the quiver

Nutrition: Ketoflex 12/3
• Nutrition—arguably the single most powerful of all of the protocol elements.
• Almost no one with cognitive decline presents with an optimal diet.
• Nutrition as outlined by a neuroscientist…(with thanks to Dr. L and JG).
• Avoid the “Berfuda Triangle” (simple carbohydrates, saturated fats, and low
fiber).
• Convert from CHO-based to good-fats-based; sensitize insulin receptor (cf.
neural exosomes for IRS1 phos.), optimize nutrients, plant-based, induce
autophagy (12/3), mild ketosis.
• Majority of calories from non-starchy vegetables (best local, organic) and good
fats. Include cooked and raw vegetables, dark green, rainbow, and crucifers.
• Include detoxifying vegetables such as cilantro, cruciferous vegetables,
Jerusalem artichoke.
• Low glycemic fruits (no fruit juice!) such as berries; no pineapple or high
glycemic fruits.
• Fats such as avocado, coconut oil, MCT oil (8 vs. 12 C)
MEND: Goals and arrows in the quiver

• Nutrition (cont’d).
• “Meat is a condiment.” If used at all, it should be as grass-fed beef
or pastured poultry.
• If fish: wild caught, SMASH fish (salmon, mackerel, anchovies,
sardines, herring). Avoid fish with high Hg (long-lived, large mouth).
• Mild ketosis (0.5-2mM -OH-butyrate target per JG).
• Pastured eggs.
• Avoid gluten, dairy, and other sensitive items.
• Dirty dozen vs. clean 15.
• Heal gut (bone broth or colostrum, not L-glutamine), then pro-biotics
and pre-biotics.
• Compare Gundry (esp. re lectins), Fuhrman, Hyman, Perlmutter.
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1/12/2017
Sleep is critical
• “When does MCI improve?”—conversation with expert.
• Exclude sleep apnea!
• Good sleep hygiene (dark, no EMF, wind down, quiet, etc.).
• Timing as close to 8 hours/night as possible; preferably begin
before midnight (best with natural light).
• May precede with “meditation on steroids.”
• Melatonin physiological dose.
• Tryptophan if ruminations.
• No food for at least 3 hours prior to bedtime.
• If continued problems, obtain expert evaluation—stress?
Hormonal? Hygiene? Etc.
MEND: Goals and arrows in the quiver
• Exercise: both aerobic and strength, total 5x/wk for 45-

60’.
• Stress: (1) Issue for all, but especially type 3; (2)
Meditation, Neural Agility; (3) Breathing; (4) Cortisol, rT3;
(5) Adrenal fatigue; (6) Joy, music, and lifestyle.
• Remove contributors! PPI, statins, neuroactive
medications, simple CHO, etc.
• When to use HBOT?
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1/12/2017
MEND: Arrows in the quiver (2)

• Hormone optimization with bio-identical where indicated: (1) Pregnenolone; (2)
fT3, fT4, rT3, TSH; (3) E2, P, E2:P, bio-identical HRT; (4) Test.; (5) Insulin; (6)
Cortisol; DHEA; (7) Vitamin D + K2.
• Herbs (e.g., Ashwagandha to increase receptor-mediated clearance of amyloid-
; Bacopa monnieri (multiple mechanisms), Hericium, Rhodiola, Gotu kola,
Shankhpushpi, etc.).
• Optimize metal metabolism: (1) Cu:Zn ratio; (2) RBC Mg; (3) K; (4) Hg, Pb, Cd,
As; (5) Se; (6) Li.
• (Mg, Zn, Cu:Zn ratio, Se, Mn, Fe, Hg, etc.).
• Provide synaptic components: citicoline and omega-3.
• Goal: homocysteine < 7. Me-B12 (and adenosyl), Me-folate, P5P, TMG.
• Goal: 25-OH-D3 50-80ng/ml, with vit K2 (100mcg).
• Barriers: oral, gut, nasal, cutaneous, ocular, blood-brain, respiratory, etc.
• Goal: (1) FINS < 5, HgbA1c < 5.6, FBS < 90. Insulin and CHO; (2) Combination to
optimize; (3) May need insulin-inducing drug ultimately.
MEND: Arrows in the quiver (3)

• Brain training controversy; over-training.
• Anti-inflammation vs. resolution of inflammation vs.
hypo-inflammation. ISIS (WAR) vs. (mal-)adaptive
• DHA and other omega-3 vs. CAA vs. protected omega-3.
• Detox protocols. Sauna, Castille soap, l-GSH, etc.
• Intranasal trophic support. Pros/cons SNIFF.
• When are stem cells appropriate?
• Anti-microbials? Anti-biofilms? MARCoNS?
• When are drugs helpful? Include monoclonals? F03?
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1/12/2017
Protocol Linchpins
• Hormonal optimization: (1) Pregnenolone; (2) fT3, fT4, rT3,
TSH; (3) E2, P, E2:P, bio-identical HRT; (4) Test.; (5) Insulin; (6)
Cortisol; DHEA; (7) Vitamin D + K2.
• Critical herbs: (1) Bacopa monnieri; (2) Withania somnifera;
(3) Turmeric (curcumin source); (4) Hericium erinaceus; (5)
Rhodiola; (6) Others (mint, sage, cilantro, etc.).
• Barriers: (1) GI; (2) BBB; (3) Oral; (4) Nasal/sinus; (5)
Integument (skin, nails, hair).
• Antioxidants: Se, C, E (mixed), GSH, lipoic acid, SOD, MT, etc.
• Trophic factors: (1) NGF—ALCAR, Hericium; (2) BDNF—
exercise; (3) VIP—intranasal; (4) Insulin, IGF.
Protocol Linchpins
• Key modulators: (1) Coconut oil or MCT; (2) Curcumin;
(3) Resveratrol; (4) Citicoline; (5) Omega-3; (6)
Nicotinamide riboside; (7) D-ribose; (8) Ubiquinol.
• Resolvins (SPM Active).
• GI health: (1) Evaluate (Cyrex 2); (2) Heal (bone broth, or
colostrum, or L-glutamine); (3) Repopulate (pro-biotics);
(4) Support (pre-biotics); (5) Cherish (avoid sugar,
gluten); (6) Assist (digestive enzymes, S. boulardi,
betaine-HCl).
• Toxins: (1) Type 3; (2) Heavy metals; (3) CIRS,
mycotoxins, and Lyme (Borrelia); (4) Cu:Zn ratio.
• Brain exercise (Brain HQ, Lumosity, Dakim, etc.)
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1/12/2017
Practical matters
• Toxins: (1) Metals; (2) Mycotoxins; (3) Others
colostrum, or L-glutamine); (3) Repopulate (pro-biotics); (4)
Support (pre-biotics); (5) Cherish (avoid sugar, gluten); (6)
Assist (digestive enzymes, S. boulardi, betaine-HCl).
• Stress: Neural Agility?
• A few words on sleep: (1) Cleansing; (2) Rule out sleep apnea;
(3) Melatonin, tryptophan, 5HT, others; (4) Timing; (5) Noise,
EMF, light.
• Infections and Alzheimer’s: HSV-1, P. gingivalis, Candida,
others.
• Brain training options (Posit, Lumosity, Dakim, et al.) and
issues (efficacy, exhaustion, timing, environment)
Characteristics of success
• Diligence with program.

• Attention to detail.
• Improvement in lab values.
• Supportive spouse or significant other.
• Follow-up.
• Repeated optimization.
• Helpful physician.
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1/12/2017
Characteristics of reduced success
• Lack of diligence with program.

• Lack of attention to detail.
• Lack of improvement in lab values.
• Delay in starting program until late in the illness.
• Lack of follow-up.
• Assuming the first phase is the final plan.
• Unhelpful physician.
Objections and concerns
• But I don’t want to give up ice cream.

• But I don’t want to give up chocolate.
• But I love pizza.
• But I can’t eat dinner until late at night.
• I have sugar cravings.
• My husband isn’t that much better than I am.
• Coconut oil is saturated fat—isn’t that bad?
• I can’t get more than 5 hours of sleep per night.
• I don’t have time to exercise.
• The program is too complicated.
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1/12/2017
Objections and concerns (2)
• I can’t reduce stress in my life.

• But I love meat.
• But I have a sweet tooth.
• I’d rather wait to do the program until I’m more
affected—I’m not that bad now.
• Isn’t celiac disease rare?
• None of the program components sounds like a cure.
• Can’t you just give me a pill?
• But there is nothing better than junk food!
• But my doctor told me that everyone knows
Alzheimer’s is untreatable.
Window on the mind: neural exosomes
69
1/12/2017
Enhancements on the way
• Neural exosomes (e.g., Nanosomix).

• Neurovision retinal imaging.
• NeuroTrack and mesial temporal lobe.
• Intranasal trophic peptides (beyond VIP, insulin, ADNP).
• Non-intranasal trophic peptides (e.g., IV Cerebrolysin).
• Novel PET tracers (beyond tau-binding).
• Stem cell improvements.
• Improved understanding of CIRS-type 3 AD connection, and CIRS-
LBD connection.
• Enhanced detoxification protocols.
• Continued optimization of critical nutritional components.
• Role of nitric oxide.
Key takeaways :
• Cognitive decline from early Alzheimer’s disease and its
precursors, MCI and SCI, can be reversed, and improvement
sustained.
• This requires science, diligence, and attention to detail; of
course there is no guarantee, but results are unequaled.
• Metabolic status and cognitive status go hand in hand.
• The first thing for people/patients to do is to take a deep
breath, relax, and abandon all feelings of hopelessness and
despair.
• The next thing to do is to get serious about following the
program. A health coach may be very helpful.
• The third thing to do is to recognize that it will take time (3-12
months) and optimization to make a real difference.
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1/12/2017
Therapeutic Convergence
t->
Rx (20th century) Dx (20th century)
71
1/12/2017
t->
Dx (21st century)
Rx (21st century)
t->
Dx (21st century)
Rx (21st century)
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1/12/2017
t->
Dx (21st century)
Rx (21st century)
Memory…
Inflammation Trophic Factors
Diet Vitamin D3
Stress Sleep
Reduced Mitochondrial Function
Mitochondrial Function Hormones
And many other things… And many other things…
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1/12/2017
Forgettory…
Diet Vitamin D3
Stress Sleep
And many other things…
What is wrong with clinical trials for Alzheimer’s disease?

((Everything…)
y g )
CLINICAL TRIALS Current Future
Goal Less decline Improve (optimally back to normal) and

sustain
Therapeutic space sampled Small Large
Focus FDA-centric; Pharma-centric; NIH- Patient-centric

centric
Trials Many patients, high cost, long trials, to Short, few patients, rapidly iterative,
identify small effect seek large effect
Rx Mono Rx Systems of Rx
Analysis 1 variable Multi-variable
When Rx AD Early MCI and ASx
Goal of Rx Incremental, financial Disruptive; minimize pt. cost
Trial length Long (e.g., 18 mos.) Short (e.g., 2-3 mos.), iterative
Trial cost High Low
Data gathering on patients Extensive, lengthy Focus on key points
Rx paradigm One size fits all Personalized

Evaluation Dx Causes of problem
Rx space sampled Small Large
Target Pharma, FDA Patients
Strategy Inside the box (and a tiny box, at that) Outside the box
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1/12/2017
The ReCODE Protocol
• We have mapped the many molecular mechanisms of

cognitive decline and AD onto a treatment protocol.
• These include dozens of interventions, beginning with DESS,
hormonal optimization, nutrients, targeted herbs, brain
stimulation, drugs, etc.
• No one intervention closes all 36 holes.
• Approach: pull out all of the stops.
• Practical issues:
• Nutrition: Ketoflex 12/3: anti-inflammatory, no simple
carbohydrates, heal GI leak and BBB leak, change metabolism
to fat from CHO, nutrient dense, 12hr/3hr fast, low glycemic
index, good fats, color, veg. first (cf. Fuhrman, Hyman, Katz).
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1/12/2017
MEND 3.0 Protocol Linchpins

• Exercise: need both CV and weights, >30’, 5x/wk.
EMF, light.
• Stress: (1) Issue for all, but especially type 3; (2) Meditation,
Neural Agility; (3) Breathing; (4) Cortisol, rT3; (5) Adrenal
fatigue; (6) Joy and lifestyle.
• Homocysteine: (1) Target <7; (2) Me-B12, Me-THF, P5P, TMG.
• Insulin and CHO: (1) FINS, FBS, HgbA1c; (2) Combination to
optimize; (3) May need insulin-inducing drug ultimately.
• Metal optimization: (1) Cu:Zn ratio; (2) RBC Mg; (3) K; (4) Hg,
Pb, Cd, As.
MEND 3.0 Protocol Linchpins (3)

• Key modulators: (1) Coconut oil; (2) Curcumin; (3)
Resveratrol; (4) Citicoline; (5) Omega-3; (6) Nicotinamide
riboside; (7) D-ribose; (8) Ubiquinol.
• Resolvins (SPM Active).
colostrum, or L-glutamine); (3) Repopulate (pro-biotics);
(4) Support (pre-biotics); (5) Cherish (avoid sugar,
gluten); (6) Assist (digestive enzymes, S. boulardi,
betaine-HCl).
• Toxins: (1) Type 3; (2) Heavy metals; (3) CIRS,
mycotoxins, and Lyme (Borrelia); (4) Cu:Zn ratio.
• Brain exercise (Posit, Lumosity, Dakim, etc.)
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MEND: Practical matters

• Toxins: (1) Metals; (2) Mycotoxins; (3) Others
colostrum, or L-glutamine); (3) Repopulate (pro-biotics); (4)
Support (pre-biotics); (5) Cherish (avoid sugar, gluten); (6)
Assist (digestive enzymes, S. boulardi, betaine-HCl).
• Stress: Neural Agility?
EMF, light.
• Infections and Alzheimer’s: HSV-1, P. gingivalis, Candida,
others.
• Brain training options (Posit, Lumosity, Dakim, et al.) and
issues (efficacy, exhaustion, timing, environment)
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APP- Selective BACE Inhibitors (ASBIs)

APP-selective (ASBI)
 Novel inhibitors that interact with the catalytic site of BACE & bind
to the ectodomain of APP.
 Inhibitors are effective in sAPP A42 in cells transfected with APPwt

but not APPsw.
 Exhibit selectivity for APP over NRG1 and PSGL1.
Strategy for AD and MCI Rx
All molecular
mechanisms Evaluation Why memory
(36) loss?
System 1.0:
comprehensive,
personalized
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The first systems therapeutics clinical trial
• Systems Therapeutics (and U.S. case)

• F03
• Synaptik (multiple network-specific components)
• Computer-based assessment and memory training
• Sleep enhancement
• Exercise-induced BDNF increase
• AD-specific diet
Medicine Synaptik Nutrition Cognitive Physical Sleep Aid

Guidance Exercise Exercise
First clinical trial proposed for 2011.
“Game of Throwns” (243/244)

Semagacesta Rosiglitazone
Dimebon x2
t
R.I.P. R.I.P.
Bapineuzumab
AN-1792 Alzhemed Flurizan Rember
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Metabolism, cognition, and the phagocytosis index
66M ApoE4/3 2014 2015 (MEND 10

mos.)
Fasting insulin 32 8
Hs-CRP 9.9 3
Homocysteine 15 8
Vitamin D3 21 40
Symptoms Struggling Working full-time
MRI hippocampal 17%ile 75%ile
volume
Proof of Improvement on MEND
71 yo E4/3 2013 2015 (MEND 2 yr)

CVLT-II B 3%ile 84%ile (3SD)
Total Recog Hits <1%ile 50%ile
CVLT-II 54%ile 96%ile
Auditory delayed 13%ile 79%ile
memory
Reverse digit 24%ile 74%ile
span
speed*
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Improvement on MEND
55F ApoE4/4 2015 2016 (MEND 5

mos.)
Neurocognitive 16%ile 73%ile
index
Composite 1%ile 61%ile
memory
Verbal memory 3%ile 93%ile
speed
Executive 14%ile 58%ile
function
Cognitive 16%ile 61%ile
flexibility

• Recorded conversations since she could not
remember.
Spanish.
• iPad optional
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Synaptoblastic:synaptoclastic imbalance
Trophic, Anti-trophic,
Anti-AD Pro-AD
sAPP sAPP
A
CTF Jcasp
C31
Neurite Retraction
TAU Neurofibrillary
Tangle
A plaques
Mitochondria
Journal Vol. 6 N9, 1-11 (2014) 166
83
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Everyone here is helping to effect change:
“Never doubt the ability of a small group of

committed individuals to change the world.
Indeed, it is the only thing that ever has.”
--- Margaret Mead
East Meets West
84
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Effecting change:

--- Margaret Mead
85
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Patient History and Diagnosis Status

System
Evaluation 1.0 Pilot
JB; 67F 3/3 2yr memory ; MCI Normal x 2 yrs;
FH+ working
DB; 70M 4/3 12yr memory ; MCI “Clearly
PET+, NPs+ improved;”
working
DT; 70M 4/3 4yr memory ; Early AD Improved;
M,NPs+ MemTrax +
RM; 75M 3/3 1yr memory  SCI Improved;
working
KH; 75F C677T 1yr memory  MCI Improved
CF; 55F 3/3 4yr memory  MCI Normal x occ.

Working
RM2; 72M 3/3 7yr memory  MCI Improved;
working
DL; 55M 4/3 2yr memory  SCI Normal; working
SB; 63F 4/3 FH dementia SCI ASx, normal PET
MR; 60F 4/3 4yr rapid decline; Late AD Decline

MoCA 6, PiB+
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Effecting change:
The opaque, impenetrable Alzheimer’s pane is

shattering, and we are peering into the engine
driving cognitive decline.
Hippocrates comes to Silicon Valley
• The need for large datasets.

• Extensive networks, not single targets.
• Programmatics, not pills.
• Personalized programs, not one-size-fits-all.
• Previously impossible disease subtyping.
• Predictive power, thus preventive power.
• Complex algorithms.
• New trends toward “patient” knowledge and empowerment.
• Result: dramatic reduction in chronic illness, cost of
healthcare.
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Characteristics of success
• Diligence with program.

• Attention to detail.
• Improvement in lab values.
• Supportive spouse or significant other.
• Follow-up.
• Repeated optimization.
• Helpful physician.
Characteristics of reduced success
• Lack of diligence with program.

• Lack of attention to detail.
• Lack of improvement in lab values.
• Delay in starting program until late in the illness.
• Lack of follow-up.
• Assuming the first phase is the final plan.
• Unhelpful physician.
88
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What this program is not:
• A program of supplements.
• A simple lifestyle program.
• A substitute for your physician.
• The standard, ineffective approach of Aricept and
Namenda (which is not to say that these should be
discontinued—there are concerns about
discontinuation).
What this program is:
• A medical information program based on 25 years of

basic science research.
• A foundation on which to build.
• A novel approach called MEND, the first one showing
success in reversing cognitive decline (as published in
2014).
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From the Alzheimer’s Association:
• “Myth 8: There are treatments available to stop the

progression of Alzheimer's disease
• Reality: At this time, there is no treatment to cure, delay or stop
the progression of Alzheimer's disease. FDA-approved drugs
temporarily slow worsening of symptoms for about 6 to 12 months,
on average, for about half of the individuals who take them.”
Key takeaways from these 4 days:

• Cognitive decline from early Alzheimer’s disease and its
precursors, MCI and SCI, can be reversed, and improvement
sustained.
• This requires science, diligence, and attention to detail; of
course there is no guarantee, but results are unequaled.
• Metabolic status and cognitive status go hand in hand.
• The first thing to do is to take a deep breath, relax, and
abandon all feelings of hopelessness and despair.
• The next thing to do is to get serious about following the
program.
• The third thing to do is to recognize that it will take time (3-12
months) and optimization to make a real difference.
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Is Alzheimer’s disease incurable?
• •Show success of MEND—Julie G and slides

• •Small amount of scientific background--OK
• •Key point is that AD is, up to a point, a metabolic
disease with many different contributors.
• •Key contributors: insulin resistance, inflammation,
homocysteine, hypovitaminosis D, hormonal
imbalance, etc.
• •These combine to cause problems, and therefore,
need to address as many as possible.
• What it is, and what it is not.

neurodegeneration).
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neurodegeneration).

neurodegeneration).
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Just stop for a moment, and think:
What would a world with dementia rates

slashed look like?
Goal: reduce dementia costs in California by 50% ($10B/yr)
• Program on prevention and early reversal (C-PPD).

• 2S-4A = “Too Smart For Alzheimer’s” = State program to
reduce dementia.
• Elements of the program:
• Public service announcements.
• Support for testing everyone over 45.
• High ROI given current dementia costs.
• Many interested individuals may be helpful.
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Thanks for your support of Alzheimer’s

disease research and therapy
Veronica Galvan (UTSA) Karen Poksay
Shahrooz Rabizadeh (Nantworks) Ram Rao
Darci Kane Alexei Kurakin
Brittany Philpot Clare Peters-Libeu
Patricia Spilman
Matthew Hart (UTSA) Varghese John
David Madden
Alex Matalis
Olivia Gorostiza Qiang Zhang
Olivier Descamps Veena Theendakara
Michael Mitsumori Jesus Campagna
Collaborators: Krys Bankiewicz, Pankaj Kapahi, Patrick Mehlen, Ed
Koo, Allan Butterfield
Thanks for support: State of California, NINDS, NIA, Douglas and Ellen
Rosenberg Foundation, NCI, ABI, ISOA, Drown Foundation, Hoag
Fdn., Bechtel Fdn., Hillblom Fdn.
t->
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t->
Dx (21st century)
Rx (21st century)
t->
Dx (21st century)
Rx (21st century)
95
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t->
Dx (21st century)
Rx (21st century)
70 y.o. man with accelerating memory loss due to Alzheimer’s disease
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Spanish.
• iPad optional

Spanish.
• iPad optional
97
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The current dogma

98
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A critical goal of research is to

challenge the dogma


--- Margaret Mead
99
1/12/2017
5,000,000
Californians
Many questions to answer

•How late in the course is this therapeutic approach effective?
•How long can the therapeutic benefit be sustained?
•Are there AD subtypes for which this approach is more (or less)
effective?
•Is this program effective in familial AD?
•Would an analogous approach be effective for Parkinson’s, Lewy
body disease (LBD), frontotemporal lobar degeneration (FTLD),
progressive supranuclear palsy (PSP), ALS, and other
neurodegenerative diseases?
•Might this program serve as a platform on which to test new drugs for
AD that would fail as monotherapeutics?
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November 15‐18, 2015
Summary—and E4 info site
•Patients who were struggling at work, or having to terminate their

employment, were able to return to work or continue their work.
•Improvement has been sustained, with the longest ongoing treatment
being two and one-half years.
•None of the patients was able to follow the entire protocol, but a
threshold effect suggests that following at least a significant part of it
may be sufficient.
•The therapeutic program, dubbed MEND, is personalized, and
designed to address the many contributors to the plasticity network
that are imbalanced in AD, as well as serving as a platform for novel
drug candidate testing.
•Continued iteration, both for each patient and for the system as a
whole, is optimal.
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((Everything…)
y g )

sustain

centric
Trial cost High Low

A roof with 36 holes…
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Frame of reference
•Taking a seemingly insoluble problem and making it

soluble by changing the coordinate system or frame of
reference.
•The AD11 mouse.



•Mono-explanations: AO, p-, inflam, ROS, metal binding, lysosomatrophic
detergent, channels, Ab-PrP, pro-NGF, p75NTR, TNF, NO, glutamate, PirB,
i li t
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The big problem with neurodegenerative disease

Healthy Advanced
Brain Alzheimer’s PET Scans:
Alzheimer’s Disease
Histopathology
207
Back to basics: cellular dependence
•Rita Levi-Montalcini, the 1986 Nobel Prize, and the trophic

factor hypothesis.
• It has been generally assumed that trophic factor withdrawal is associated with
the loss of a positive survival signal, such as that associated with the
phosphorylation of Akt.
• However, data accumulated over the past 20 years argue that there is a
complementary cell death signal mediated by specific receptors, dubbed
dependence receptors, activated by trophic ligand withdrawal but blocked by
ligand binding (Rabizadeh et al., Science 1993; Mehlen et al., Nature 1998).
104
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Levi-Montalcini and the classic view

Trophic factor
receptor
Trophic
factor
The old view: passive death

Trophic factor
receptor
No trophic
ligand
105
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The Dependence Receptor Concept

Dependence
Receptor
Trophic No ligand
ligand (or anti-trophic ligand)
Programmed
Cell
death

DCC
UNC5Hs Integrins
p75NTR   RET
MIDAS
Cadherin
motif
domain
D412 D707
(D1185) ZU-5
Chopper
D1290
D1017
Hirschprung’s Disease (megacolon)
Death domain
Medullary Carcinoma Tyrosine kinase domain
106
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Integration
Analog  digital
Electrical (chemical) input
Via membrane conductance
Σ = Electrical input  electrical output
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biochemical space
Reelin
(ApoE, ABCA1, etc.)
(Ach, glutamate, GABA, etc.)
Hormones,
(Thyroid, Estrogen,
Progesterone)

biochemical space
Reelin
(ApoE, ABCA1, etc.)
(ACh, glutamate, GABA, etc.)
Hormones,
(Thyroid, Estrogen,
Progesterone, etc.)
Integration
Analog  digital (slow) output
Receptor signaling input
Via nuclei and cytoplasm
Σ = Chemical milieu input  morphogenetic output
108
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Normal mouse (trial #8)
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“Sheldon Cooper mouse”
F03: Multiple Mechanisms Against Alzheimer’s
• Reduces A
• Increases sAPP F03
• Blocks ApoE4 effect
• Improves LTP
• Blocks neuronal programmed cell death
• Excellent blood-brain barrier penetration
• High therapeutic index
• Markedly outperforms memantine and donepezil in Tg Mo
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F03 restores novel object recognition completely
APP- Selective BACE Inhibitors (ASBIs)

APP-selective (ASBI)
 Novel inhibitors that interact with the catalytic site of BACE & bind
to the ectodomain of APP.
 Inhibitors are effective in sAPP A42 in cells transfected with APPwt

but not APPsw.
 Exhibit selectivity for APP over NRG1 and PSGL1.
111
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ApoE4: ApoE3:
223
The EMT (epithelial-mesenchymal

transition)
112
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Alzheimer’s and the EMT

AD: Type IV Organized (E) Unicellular (M) AD
EMT?
Metabolism Oxphos Glycolysis Glycolysis
Inflammation Low High High
SirT1/NFkB SirT1 dominant NFkB dominant NFkB dominant
ROS Low High High
Cytoskeleton Intact Breakdown Breakdown
Insulin signaling Sensitive Resistant Resistant
Secretory Low High ??
Intercellular Present Lost Lost (synapses)

junctions

((Everything…)
y g )

sustain

centric
Trial cost High Low

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Window on the mind: neural exosomes
Strategy for AD and MCI Rx
All molecular
mechanisms Evaluation Why memory
(36) loss?
System 1.0:
comprehensive,
personalized
114
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36 mechanisms
Goal
 A production
(net)
A degradation
 A oligomer‐
ization
BDNF
NGF
G‐CSF
ADNP
p‐tau
homocysteine
Build synapses
4/2
 Abreakdown
A/G ratio
inflammation
Inhibit NFkB
GSH
antioxidants
Fe (Cu Zn?)
Target is Zn:fCu of
100:10‐15.
CBF
ACh
7 signaling
 A transport
 A clearance
ApoE4 effect
GABA
NMDA
Optimize
hormones
vitamin D
pro‐NGF
caspase‐6
N‐APP
memory
Energy
Mitochondrial
function
Mitochondrial
protection
Summary--Conceptual
•Our findings suggest that AD is fundamentally related to a plasticity

balance, analogous to oncogene:tumor suppressor gene balance.
•In this model, AD results from a synaptoblastic:synaptoclastic
imbalance that is metabolically induced, mediated by dependence
receptors (including APP), and amplified by prionic loops.
•Therefore, one translational approach involves correcting this
imbalance by targeting APP signaling directly.
•However, an optimal approach would include impacting multiple
network components, as physiologically and as far upstream as
possible.
•We have had initial success both pre-clinically and clinically with this
approach, but much more proof is needed, as well as optimization of
each network component therapeutic.
115
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Summary--Conceptual
•Our findings suggest that AD is fundamentally related to a plasticity

balance, analogous to oncogene:tumor suppressor gene balance.
•In this model, AD results from a synaptoblastic:synaptoclastic
imbalance that is metabolically induced, mediated by dependence
receptors (including APP), and amplified by prionic loops.
•Therefore, one translational approach involves correcting this
imbalance by targeting APP signaling directly.
•However, an optimal approach would include impacting multiple
network components, as physiologically and as far upstream as
possible.
•We have had initial success both pre-clinically and clinically with this
approach, but much more proof is needed, as well as optimization of
each network component therapeutic.
116
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The ApoE4-interacting
promoters identify
genes mediating the
very processes
associated with AD. APOE
4
These results thus offer
new insight into the
mechanism by which
ApoE4 confers risk for Aging & SirT
Inflammation
the development of
Alzheimer’s disease, as
well as novel targets for Neuronal cell death
AD therapeutics.
promoters identify
genes mediating the
very processes
4
mechanism by which
Inflammation
the development of
AD therapeutics.
118
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promoters identify
genes mediating the
very processes
4
mechanism by which
Inflammation
the development of
AD therapeutics.
119
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Memory…
Diet Vitamin D3
Stress Sleep
Forgettory…
Diet Vitamin D3
Stress Sleep
120
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The readout: plasticity ratio (cf. HDL:LDL)

• F03

First clinical trial is set for 2014.
121
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Apolipoprotein E (ApoE): The God Gene?

•A small set of genes is associated with the appearance of
hominids 5-7 million years ago.
•Prominent among these are pro-inflammatory genes.
•ApoE has 3 alleles: ApoE2, 3, and 4. ApoE4 is primordial.
•ApoE3 did not appear until 220,000 years ago, and ApoE2
not until 80,000 years ago.
•ApoE4 pro-inflammatory effect allowed us to come down
from the trees, roam the savannah, eat raw meat, fight.
•Antagonistic pleiotropy, longevity, ApoE4.
The Mouse That Remembered to Roar:

Alzheimer’s Electrophysiology Normalized by Blocking C31
Galvan et al., PNAS 2006
122
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Control mice in Morris water maze
123
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“Mouzheimer’s”
Mouzheimer’s no more
124
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Is APP involved in physiological plasticity?
“Sirtuinversion”
Normal AD
A172-extract
SirT2 SirT2
40 40
SirT1 SirT1
110 110
SirT6 SirT6
40
40
ApoE  E3 E4 ApoE 2/4 2/3 3/4 3/4 2/4 2/4 2/4 3/3 3/4
Theendakara et al., PNAS 2013
125
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The Status Quo:

Alzheimer’s is a disease of toxicity
• Focus is on the chemical & physical Physicochemical effect or

effects of A peptide: signaling imbalance?
– Lysosomatropic detergent
Healthy Advanced
– Metal-binding peptide Brain Alzheimer’s
– Reactive oxygen species

– Many other theories
• Approach reinforced by 50,000+
papers…all of which fail to answer
key questions
• Why do healthy brains produce
Aß peptide?
• Recent results from transgenic mice
Patient History and Diagnosis Status

System
Evaluation 1.0 Pilot
JB; 67F 3/3 2yr memory ; MCI Normal x 2 yrs;
FH+ working
DB; 70M 4/3 12yr memory ; MCI “Clearly
PET+, NPs+ improved;”
working
DT; 70M 4/3 4yr memory ; Early AD Improved;
M,NPs+ MemTrax +
RM; 75M 3/3 1yr memory  SCI Improved;
working
KH; 75F C677T 1yr memory  MCI Improved
CF; 55F 3/3 4yr memory  MCI Normal x occ.

Working
RM2; 72M 3/3 7yr memory  MCI Improved;
working
DL; 55M 4/3 2yr memory  SCI Normal; working
SB; 63F 4/3 FH dementia SCI ASx, normal PET
MR; 60F 4/3 4yr rapid decline; Late AD Decline

MoCA 6, PiB+
126
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A Roof with 36 holes…
253
70 y.o. man with accelerating memory loss due to Alzheimer’s disease
127
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Better patches for the holes…
255
Optimal solution for each hole…
256
128
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•The AD11 mouse.



• “I’ve gone over…to the bright side.”
•After it was clear that cardiovascular disease

and AD have similar epidemiology, I had a duh-
huh moment…
129
1/12/2017
Lineage-specific mutations mapped onto a schematic of the APOE protein (A) and primate
phylogeny (B).
McIntosh AM, Bennett C, Dickson D, Anestis SF, et al. (2012) The Apolipoprotein E (APOE) Gene Appears Functionally
Monomorphic in Chimpanzees (Pan troglodytes). PLoS ONE 7(10): e47760. doi:10.1371/journal.pone.0047760
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047760

sustain

centric
Trial cost High Low


130
1/12/2017


220,000
7 million years ago
6 million years ago
5 million years ago
4 million years ago
3 million years ago
2 million years ago
1 million years ago
years ago
ApoE3
ApoE4
ApoE2
80,000
years ago
131
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ApoE4: ApoE3:
263
East Meets West
132
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Modeling human disorders in Drosophila
Alzflymer’s
Alzflymer’s
133
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Alzflymer’s
Left: Off Right: On
Activity Assay
400
*
350
APP,BACE/GS
300
250
200
150
100
50
0
DR- DR+ AL- AL+
134
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Response to treatment with d-amphetamine
Before D-amphetamine treatment On D-amphetamine 24hr off D-amphetamine

(1.0 mg/ml)
1800
1800
1600 3000
1600
1400 1400 2500
1200 1200
2000
1000 1000
800 800 1500
600 600
1000
400 400
500
200 200
0 1 2
0 1 2
0 1 2
DR- DR+ DR- DR+ DR- DR+
APP,BACE/GS
A Drosophila Hyperactivity Disorder (ADHD)

•Males >> Females.
•Exacerbated markedly by high CHO:protein diet.
•Reduced with aging.
•Associated with sleep/nocturnal dysrhythmic pattern.
•Reversibly responsive to d-amphetamine.
•“Paradoxical response” to d-amphetamine.
135
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Memory…
Diet Vitamin D3
Stress Sleep
Forgettory…
Diet Vitamin D3
Stress Sleep
136
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Leaky gut and calories (Dr. P. Kapahi)
Leaky gut and calories (Dr. P. Kapahi)
137
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The Chimp That Ate the Rhino

220,000
7 million years ago
6 million years ago
5 million years ago
4 million years ago
3 million years ago
2 million years ago
1 million years ago
years ago
ApoE3
ApoE4
ApoE2
80,000
years ago
138
1/12/2017
Research to Clinical Development:

Bench to Bedside
Alzheimer’s Drug Development Network

Varghese John, Ph.D., and Dale E. Bredesen, M.D.
PK/PD ADME-TOX
Research & Clinical
Screening Chronic Analoging Regulatory
Target ID Development
Efficacy “Candidate”
Team Team Team Team Team Phase 1,

Johnson Olivier: Alpha Patricia Barbara Mahta IND etc.
Clare Lisa: Assays Karen Davos Remy
Ram & Compound Olivia Stelios
Alexander Libraries Alex Clinical
Sonia (FDA & CNS Sylvia Consult.
Darci focused) IAS CEREB
Mike
Screening for Novel Therapeutics
139
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Drugs: maybe the dessert; not the entrée
Placeholder for taking down 3-4 holes and showing what they are.
140
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“Forgettory” in D664A mice
New insights: “Field of Seems”
•It seems that, although neurodegenerative pathologically,

Alzheimer’s disease is largely driven metabolically, which may
bode well for successful intervention.
•It seems that the origin of prions may reside in biological signal
amplification, and that such amplification loops may underlie the
neurodegenerative process.
•It seems that “aggregation” may arise from amplification of

signal, and “misfolding” may result from alternative structures.
•It seems that many chronic illnesses, such as AD, ASCVD,

osteoporosis, and cancer, may result from chronic imbalances in
physiological signaling, amplified by anti-homeostatic signaling
(i.e., molecular switches such as APP).
141
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New insights: “Field of Seems” (2)
•It seems that Alzheimer’s disease features a network imbalance

that impacts plasticity, arguing for multiple targets that should be
engaged simultaneously.
•It seems that our current clinical trials—monotherapeutic, one-

size-fits-all, expensive, and lengthy—may be appropriately
complemented by trials that are polytheraputic, multi-modal,
personalized, and rapid.
•It seems that it may be advantageous to combine western,

mechanistic approaches with eastern, combinatorial approaches
to therapy.
OK, how about those 36 holes?
•Homocysteine
•Vitamin B12
•Vitamin D
•Sleep! (Timing, melatonin, autophagy, opening clearance, sleep apnea)

•Copper/Zinc ratio
•Diet!
•CRP, A/G ratio
•Estradiol, testosterone, pregnenolone, progesterone, cortisol (and kittens)

•Free T3, free T4, TSH, RT3
•Hemoglobin A1c, fasting insulin, GTT insulin (ketones)

•23&Me; ApoE4; PiB scan, Neurotrack, MemTrax, MoCA
•Exercise and BDNF
142
1/12/2017
Summary
143
1/12/2017
Systems Therapeutics,
President Obama, and
the End of Alzheimer’s
Disease
Dale E. Bredesen, M.D.
Women at the epicenter

of the epidemic
•65% of patients
•60% of caregivers
•More common than breast cancer
144
1/12/2017
OK, let’s talk about those 36 holes…

• F03

First clinical trial is set for 2013
Developing treatment and prevention for AD:

like playing chess with the devil.
145
1/12/2017
ApoE4 and plasticity ratio
150 sAPPsAPP sAPPA

150
100
100
% APP
% APP
*
50 50 *
* * *
0 0
P
4∆
3
4
P
4∆
oE
oE
AP
oE
oE
AP
oE
oE
Ap
Ap
Ap
Ap
Ap
Ap
P+
P+
P+
P+
P+
P+
AP
AP
AP
AP
AP
AP
State of Confusion
146
1/12/2017
CFN case (have testimonials??)
Phenoprinting
147
1/12/2017

148
1/12/2017
Alzheimer’s Disease: The facts and figures
There are 5.4 million people with Alzheimer’s in the U.S.;

this number will exceed 13 million by 2050.
Every 68 seconds someone is diagnosed with AD.

AD costs the U.S. over $180 billion annually.
No truly effective Rx has been developed for AD.
While many diseases are on the decline, AD is on the rise.

DCC
UNC5Hs Integrins
p75NTR   RET
MIDAS
Cadherin
motif
domain Patched
D412 D707
(D1185) ZU-5
Chopper D1392
D1290
D1017
AR Immunoglobin-like domain
D146 DNA-binding site Thrombospondin type I-like domain
PolyQ repeat Hormone-

binding Death domain

site Cysteine-rich domain
Tyrosine kinase domain
149
1/12/2017

DCC
p75NTR
(D1185)
Chopper
D1290
Colon Cancer
Death domain
Tyrosine kinase domain
Apolipoprotein E (ApoE): The God Gene?

•A small set of genes is associated with the appearance of
hominids 5-7 million years ago.
•Prominent among these are pro-inflammatory genes.
•ApoE has 3 alleles: ApoE2, 3, and 4. ApoE4 is primordial.
•ApoE3 did not appear until 220,000 years ago, and ApoE2
not until 80,000 years ago.
•ApoE4 pro-inflammatory effect allowed us to come down
from the trees, roam the savannah, eat raw meat, fight.
•Antagonistic pleiotropy, longevity, ApoE4.
150
1/12/2017
The Key: Memory Maintenance and AD Prevention
•Network of abnormalities (36 mechanisms)

•Systems Therapeutics
•Supplement combination
•Specific herb combination
•Sleep optimization
•Additional systems components
•Systems Therapeutics
•F03
•20 additional components
•Computer-based assessment and memory training
•Sleep enhancement
•Exercise-induced BDNF increase
•AD-specific diet
151
1/12/2017
Alzheimer’s Drug Discovery Network (ADDN)

Includes:
• Disease models: B254, B21, J20, J9, I5, M631L

•Assays: AlphaLisa, APPneo, sAPP, sAPP, p-tau, A42, etc.
•Network of scientists and consultants with expertise in medicinal chemistry,
neuroscience, neurology, screening, animal models, behavioral science, pre-
clinical development, clinical trials
•Intellectual property regarding novel therapeutics for AD
•25 years of experience with programmed cell death and neurodegeneration; 20

years of experience with drug development for AD
•Pipeline for additional drug development and optimization
Alzheimer’s Drug Discovery Network

(ADDN) Includes:
Disease models B254, B21, J20, J9, I5, M631L

Assays: AlphaLisa, APPneo, sAPPa, sAPPb, p-tau, Ab42, etc.
Network of scientists and consultants with expertise in
medicinal chemistry, neuroscience, neurology, screening, animal models,
behavioral science, pre-clinical development, clinical trials
Pipeline for additional therapeutic development and optimization
25 years of experience with programmed cell death and

neurodegeneration; 20 years of experience with drug development for AD
152
1/12/2017
Alzheimer’s Drug Discovery Network

(ADDN) Includes:
Disease models B254, B21, J20, J9, I5, M631L

Assays: AlphaLISA, APPneo, sAPP, sAPP, p-tau, A42, etc.
Network of scientists and consultants with expertise in
medicinal chemistry, neuroscience, neurology, screening, animal models,
behavioral science, pre-clinical development, clinical trials
Pipeline for additional therapeutic development and optimization
25 years of experience with programmed cell death and

neurodegeneration; 20 years of experience with drug development for AD
ASBI (APP‐specific BACE inhibitors)
“Inactive” complex
Mechanism of ASBI inhibitors of BACE-

APP cleavage
153
1/12/2017
Alzheimer’s Disease (AD) Therapeutic

Landscape
  Ab production
APPROVED
  A aggregation
 Donepezil (Aricept)
  A clearance
 Rivastigmine (Exelon)
  Tau aggregation/phosph
 Galantamine (Razadyne)
 Cholinergic drugs
 Tacrine (Cognex)
 Others
 Memantine (Namenda)
PHASE 3 PHASE 2 PHASE 1

 Solanezumab  ELND005  PBT2  AL-108  GSK933776
 NIC5-15  PF04360365  AF102B
 MABT5102A
 Bapineuzmab  Valproate  Bryostatin-1  Nicotinamide
 Talsaclidine
 EHT-0202  NP12  ACC001  UB311
 Alzemed   Antioxidant
 BMS708163  Lithium  AN1792  R1450  Begacestat
 Semagacestat  Statins  ABT089  NGF  CAD106
 V950  PF3084014
 AZD3480  SB742457
 Flurizan  Dimebon  E2012
 Huperzine-A  PRX03140  CTS21166
 Rosiglitazone  EGCg  EVP6124  PUFA  MK0752
 MEM3454  TTP448
 Phenserine  CHF5074
 PF-04447943
 Clinical Trial in AD terminated
Cognitive protection and optimization
•Need for prevention of dementia.
•Increased recognition and assessment of early

changes.
•Major concern of aging individuals.
•Increased understanding of underlying

mechanisms.
154
1/12/2017
Cognitive protection and optimization: competition
•Brainstrong, Neuro Optimizer, Memoractiv, Ginkgo

Smart, Procera AVH, etc.
•Most have one or a few components.
•All fail to address critical mechanisms of cognitive

decline.
•Assumption that antioxidants are always helpful,

ignoring recent data.
Origination of Synaptik
•Goal: to address all 36 mechanisms underlying age-
associated cognitive decline.
•Two indications:
•Prevention.
•With AD and MCI drugs, for optimization of drug effects.
•GRAS components.
•Cost effective.
•IP filed.
•Freedom to operate evaluated.

•Trial for 2012.
155
A
% APP
% APP
100
150
0
50
100
150
0
50
AP
P AP
P
AP
P+ AP
Ap P+
oE Ap
3
*
oE
3
AP
P+ AP
Ap P+
p
oE Ap
4
*
oE
4
*
AP
HN33; sAPP
P+ AP
Ap P+
oE Ap
HN33; sAPPsAPP
4∆ oE
*
4∆
*
B
% APP
% APP
Galangin
50
100
150
50
100
150
AP AP
P P
AP AP
P+ P+
Ap Ap
oE oE
3 3
*
AP AP
P+ P+
Ap Ap
oE oE
4
*
4
*
AP AP
P+
Ap P+
oE Ap
HEK293T; sAPP
4∆ oE
*
4∆
HEK293T; sAPPA
156
1/12/2017
1/12/2017
CMPD 14
ASBI and BACE inhibitors
Plate with phenotype cells
Add one clinical
compound per well
Select compound
that inhibits phenotype
& further evaluate protein target
For compound
Mig
Using a panel of analogs of target class
identify subtype that inhibits phenotype Intg. Cerogenes
AD
157
1/12/2017
Rationale for comprehensive therapeutic trial
•New pathogenetic insights: depR-based, prionic, molec. switch

•Compare HIV results
•Modest results from many mono-therapeutics
•No precedent for comprehensive therapy for AD
•Analogy to cancer, osteoporosis, atherosclerosis
•Failure of therapeutic trials to date

•Prevention, early Rx, later Rx
uAlkCMfTASQ
-DE_zCSZhWY
UaQPtykWpgk&feature=related
158
1/12/2017
159
1/12/2017
Prionic loops and anti-prions
APP + A  2A + sAPP + Jcasp + C31
Novel prions and anti-prions
APP + A  2A + sAPP + Jcasp + C31

(“4 Horsemen”)
APP + Netrin-1  sAPP + CTF

(“Alpha Couple”)
160
1/12/2017
Dependence Receptors as Molecular Switches
CLASSICAL SIGNAL TRANSDUCTION

Presence Anti-Apoptotic
of Ligand Signal
Absence of
k1 Complex
Trophic Ligand • Altered structure
ADD
NEGATIVE SIGNAL TRANSDUCTION
(may be multimeric)
L k-1 •  Caspase cleavage (AR)
Dependence • Anti-apoptotic signaling
Receptor Ligand
(p75NTR, AR, etc.)
Anti-Apoptotic
Signal
(NFB for p75NTR?)
Active caspase
(or possibly other protease)
k2
CP1
?
Mitochondria?
ADD CP2 Nuclei?
Other intermediates?
Pro-Apoptopic
Signal
Pro-caspase
(or possibly other pro-protease)
161
1/12/2017
“Switching drug:” F03 in vivo

APP species (% Control)
160
Control
140
120
100
80
60
40
20
0
sAPPalpha raw Abeta 42 MG APPneo
162
1/12/2017
Optimizing Your Brain

Dale Bredesen, MD
163

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1/12/2017

Dale E. Bredesen, M.D.

“There is nothing that will prevent, reverse, or

“Everyone knows someone who is a cancer

Women at the epicenter

Alzheimer’s Disease (AD) Therapeutic Landscape

PHASE 3 PHASE 2 PHASE 1

 Clinical Trial in AD terminated

“Game of Throwns” (243/244)

R.I.P. R.I.P. R.I.P.

Alzheimer’s: A Sad State of Affairs

•PATIENTS often do not seek medical care because they have

•PRIMARY CARE PROVIDERS often do not refer, since they

•SPECIALISTS often put the patients through hours of

20th century evaluation of cognitive decline

• “MRI of the brain and blood for CBC, metabolic panel,

Classical medicine: breaking through to AD cure?

67 y.o. woman with 2-yr history of progressive cognitive decline

• Mother died with dementia, onset age 62.

70 y.o. man with 12-yr history of accelerating memory loss

• ApoE4 positive (heterozygote)

Proof of Improvement on ReCODE

71 yo E4/3 2013 2015 (MEND 2 yr)

Metabolism and Cognition Go Hand in Hand

66M ApoE4/3 2014 2015 (MEND 10

55F ApoE4/4 2015 2016 (MEND 5

Programmatics, not “pill-osophy”

So how does one go about developing

Canonical Alzheimer’s disease

The Chimp That Killed the Rhino

The Chimp That Killed the Rhino

6 million years ago

5 million years ago

4 million years ago

3 million years ago

2 million years ago

1 million years ago

Theendakara, V. et al. Neuroprotective Sirtuin

ApoE4-promoter interactions by ChIP-Seq

Glucose homeostasis & diabetes

Microtubule disassembly Synapse dysfunction

Aging & SirT

Organisms produce amyloid in response to 3 major

Chronic illnesses as signaling imbalances

Synaptic element interdependence

Bredesen, D. E. Neurodegeneration in Alzheimer's disease: caspases and synaptic

A roof with 36 holes…

The perfect Alzheimer’s drug would:

The 21st-century physician

The ReCODE Protocol

• We have mapped the many molecular mechanisms of

Basic concepts of the protocol

Evaluation Step 1: Determine Subtype(s)

• Presymptomatic vs. SCI vs. MCI vs. AD.

Characteristics of type 3 AD (cont’d)

50 yo woman with depression post-hysterectomy

HLA-DR/DQ haplotypes in type 3 AD

Characteristics of type 1.5 AD

66 yo man with “senior moments”

•Beware candidates for congophilic angiopathy (esp. E4/4 males).