1. 36 GOALS OF BREDESEN SYSTEM
   1. decrease NET AB production
   2. increase AB degredation
   3. decrease AB oligeomerization
   4. increase BDNF
   5. Increase NGF
   6. increase G-CSF
   7. Increase ADNP
   8. decrease p-tau
   9. decrease phospho-tau
   10. decrease homocysteine
   11. build synapses
   12. decrease 4/2
   13. increase AB breakdown
   14. increase A:G ratio
   15. decrease inflammation
   16. inhibit NFkB
   17. increase GSH
   18. increase antioxidants
   19. decrease Fe (decreaseCu, ?increase Zn)
       1. target is Zn:fCu of 100:10-15)
   20. increase CBF
   21. increase Ach
   22. increase alpha7 signaling
   23. increase AB transport
   24. increase AB clearance
   25. decrease ApoE4 effect
   26. increase GABA
   27. Decrease NMDA
   28. Optimize Hormones
   29. Increase Vitamin D
   30. decrease pro-NGF
   31. decrease caspase-6
   32. decrease N-APP
   33. increase memory
   34. increase energy
   35. increase mitochondrial function
   36. increase mitochondrial protection
   37. Subtopic 37
2. 1 Energy
   1. ROS species
   2. SEE JEFF BLAND'S BOOK
   3. Ties to Obesity 6 Communication
3. 2 Defense
   1. AB as a ROS species
   2. Oxidative Stress / Mitochondria/apoptosis/Inflammation
      1. MTHFR
         1. oxidative damage/thiols/ rel to MTHFR
      2. Glutathione
         1. GSTP1*C
            1. this allelic variant leads to AB path and apotosis 2/2 to increased oxidative stress
      3. CoEnzyme Q 10
      4. Oxidized LDL
      5. Melatonin
         1. free radical scavenger
         2. ?? cAMP MOA protection??
         3. cholinergic system protection
         4. reduce neuroinflammation
            1. reduce overactivation of microglia
            2. attenuated NFK-B
            3. IL-1
            4. attenuated Reactive NO
            5. reduced IL-6 activiation
            6. reduced TNF-alpha
         5. antineuro-excitotoxic effects
         6. regulates circadian phasing
         7. SIDE EFFECTS OF MELATONIN
            1. fever (on first day)
            2. RLS
            3. pigmentation of arm/legs
            4. HA
            5. THROMBOSIS
            6. early GI upset
            7. Subtopic 7
      6. Curcumin
   3. MTHFR
      1. oxidative damage/thiols/ rel to MTHFR
   4. Glutathione
      1. GSTP1*C
         1. this allelic variant leads to AB path and apotosis 2/2 to increased oxidative stress
   5. CoEnzyme Q 10
   6. Oxidized LDL
   7. Melatonin
      1. free radical scavenger
      2. ?? cAMP MOA protection??
      3. cholinergic system protection
      4. reduce neuroinflammation
         1. reduce overactivation of microglia
         2. attenuated NFK-B
            1. IL-1
         3. attenuated Reactive NO
         4. reduced IL-6 activiation
         5. reduced TNF-alpha
      5. antineuro-excitotoxic effects
      6. regulates circadian phasing
      7. SIDE EFFECTS OF MELATONIN
         1. fever (on first day)
         2. RLS
         3. pigmentation of arm/legs
         4. HA
         5. THROMBOSIS
         6. early GI upset
         7. Subtopic 7
   8. Curcumin
4. 3 Structure
   1. synaptic reorganization v maintenance
   2. Dependence Receptors
   3. Extracellular Matrix
      1. collagen
      2. laminin
      3. heparin
      4. Netrin
      5. etc
   4. cell membrane
      1. DHA/EPA
      2. Centrophenoxamine
         1. best in combo with
         2. 500-2000mg/day
   5. DHA/EPA
   6. Centrophenoxamine
      1. best in combo with
      2. 500-2000mg/day
   7. Inflammation
      1. oxidized LDL
      2. role of antioxidant foods
         1. James Joseph work on antioxidants: blueberries and strawberries
   8. oxidized LDL
   9. role of antioxidant foods
      1. James Joseph work on antioxidants: blueberries and strawberries
   10. Blood Brain Barrier issues
       1. "leaky brain?"
   11. Synaptic structural components
       1. DHA
       2. Citicholine
       3. Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses.
   12. DHA
   13. Citicholine
   14. Look for references on CDP-choline (which is DHA + Citicholine) which makes Phosphatidylcholine
5. Floating Topic
   1. ATMs
      1. Antecedents
         1. early oophorectomy
         2. metabolic syndrome
         3. head trauma
            1. chronic traumatic encephalopathy
            2. tau related pathology (known)
         4. chronic traumatic encephalopathy
            1. tau related pathology (known)
         5. inflammatory processes
         6. Most cases are familial w these polymorphisms
         7. hyperhomocysteinemia
         8. gene variation in Amyloid Precursor Proteins
            1. chromosome 21
         9. Genome Wide Meta-analysis
         10. Presenilin
             1. PSEN1
             2. chromosome 14
             3. PSEN2
             4. chromosome 1
         11. APOE*E4 allele
             1. chromosome 19
             2. associated with earlier age of onset (of late onset)
             3. increase risk 3-8x depending on if hetero or homozygous
             4. APOE*E2 seems to reduce risk
             5. APOE*E3 seems neutral
             6. most common70-80% of pop
         12. Genetics
             1. Most cases are familial w these polymorphisms
             2. gene variation in Amyloid Precursor Proteins
             3. chromosome 21
             4. Genome Wide Meta-analysis
             5. Presenilin
             6. PSEN1
             7. chromosome 14
             8. PSEN2
             9. chromosome 1
             10. APOE*E4 allele
             11. chromosome 19
             12. associated with earlier age of onset (of late onset)
             13. increase risk 3-8x depending on if hetero or homozygous
             14. APOE*E2 seems to reduce risk
             15. APOE*E3 seems neutral
             16. most common70-80% of pop
             17. BIN1
             18. APP related A673T
             19. protective against AD by REDUCING Beta-cleavage of APP
             20. Bredesen sites this in REversal Cog Decline article
             21. CLU
             22. CR1
             23. PICALM
             24. IGAP found 11 genes
             25. HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4
             26. part of the GWAS collaboration
             27. TRYOBP
             28. master regulatory gene rel microglial dys/function
             29. examples of computated network theory (slide 11/15 of Icahn school PICS!)
             30. TREM2
             31. rare mutation 3x AD risk
             32. protective TREML2
             33. Tau Pathology
             34. APOE
             35. TREM
             36. chromosome 3
             37. GLIS3
             38. also implicated in diabetes
             39. CD33
             40. regulates microglia to clear BAP from the brain
             41. HFE
             42. CETP gene regulation see 6 communication
             43. Iron/Cholesterol/HFE gene
         13. BIN1
         14. APP related A673T
             1. protective against AD by REDUCING Beta-cleavage of APP
             2. Bredesen sites this in REversal Cog Decline article
         15. CLU
         16. PICALM
         17. CR1
         18. IGAP found 11 genes
             1. HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4
             2. part of the GWAS collaboration
         19. TRYOBP
             1. master regulatory gene rel microglial dys/function
             2. examples of computated network theory (slide 11/15 of Icahn school PICS!)
         20. TREM2
             1. rare mutation 3x AD risk
             2. protective TREML2
         21. Tau Pathology
             1. APOE
             2. TREM
             3. chromosome 3
             4. GLIS3
             5. also implicated in diabetes
         22. HFE
         23. CD33
             1. regulates microglia to clear BAP from the brain
      2. Mediators
         1. aging
      3. Triggers
         1. aging
   2. Sleep
      1. fantastic article with MOAs on sleep and amyloid
   3. Stress
   4. Relationships
   5. Nutrition
      1. foods that damage
         1. "stripped carbs"
            1. processed foods
         2. high fat diets
         3. ?Dairy
            1. D-galactose causing memory impairment
            2. fermented dairy is likely better
            3. 65% of worldwide pop might be lactose intolerant
      2. foods that heal
         1. GAP diet
         2. Paleo diet
            1. see the
         3. Lower Glycemic Index foods
      3. "stripped carbs"
         1. processed foods
      4. high fat diets
      5. ?Dairy
         1. D-galactose causing memory impairment
            1. fermented dairy is likely better
         2. 65% of worldwide pop might be lactose intolerant
      6. GAP diet
      7. Paleo diet
         1. see the
      8. Lower Glycemic Index foods
   6. Movement
6. 4 Biotransformation Detox
   1. AB is a metal binding peptide
   2. ApoE
      1. risk factor to not be able to detox mercury
      2. another article
   3. risk factor to not be able to detox mercury
   4. another article
   5. Iron/cholesterol/HFE gene
   6. Glutathione
      1. GSTT1 deletion
      2. glutathione rel to ApoE4
   7. GSTT1 deletion
   8. glutathione rel to ApoE4
   9. Heavy Metals
      1. induce a neurotoxic autoimmune response
         1. Amy Myers summit interview Dhatis Karrahzian
            1. he OPPOSES chelation for this reason
   10. induce a neurotoxic autoimmune response
       1. Amy Myers summit interview Dhatis Karrahzian
          1. he OPPOSES chelation for this reason
7. 5 Absorption
   1. BOOK BRAIN MAKER
   2. Subtopic 2
   3. see JAGS 2015
8. 6 Communication
   1. AB is a lysosomatrophic detergent
   2. Trophic factors
      1. defintion of TROPHIC factors = a general pro-survival action exerted on target cells by different classes of extracellular messengers (eg NGF, BDNF)
      2. LIST OF RESULTS OF TROPHIC FACTORS + APP "Synaptic element interdependence" (source is Bredesen Brain Health Fla PPT slide 41)
         1. downregulation C31, BCTF, sAPPB, AB
         2. downreg Thr668 phos
         3. upreg AICD, KAI1
         4. Upreg APP-Fe65
         5. upreg APP-Dab
         6. Subtopic 6
   3. anti-trophic factors
      1. LIST OF RESULTS OF APP +AB "Synaptic element interdependence" (source is Bredesen Brain Health Fla PPT slide 41)
         1. upreg C31
         2. downreg APP-Fe65
         3. down reg Dab
         4. downreg APPalpha
         5. upreg sAPPbeta
         6. upreg Thr668 phos
   4. Dependence Receptors
   5. Stress elevated glucocorticoid levels
      1. effect mood, memory, and hippocampal volumes
      2. both increased and decreased corticosteroids are associated with cognitive dysfunction.
         1. D Bredesen Aging Brain
   6. effect mood, memory, and hippocampal volumes
   7. both increased and decreased corticosteroids are associated with cognitive dysfunction.
      1. D Bredesen Aging Brain
   8. Optimal cognitive function requires appropriate concentrations of thyroid hormone, pregnenolone, cortisol, and melatonin, among others, and, whereas decreased thyroid hormone or pregnenolone is associated with reduced cognitive function,
   9. From D Brednesen the AGing Brain
      1. Optimal cognitive function requires appropriate concentrations of thyroid hormone, pregnenolone, cortisol, and melatonin, among others, and, whereas decreased thyroid hormone or pregnenolone is associated with reduced cognitive function,
   10. Leptin
       1. low plasma leptin rel to AD
       2. Subtopic 2
   11. Neurotransmitters
       1. see DKHARRAZIAN
       2. Joel Robertson
       3. Ach, glutamate, GABA
   12. Obesity
       1. is a primary cause of Insulin Resistance
       2. midlife central obesity is biggest risk factor for AD
       3. Free fatty acids are a MECHANISTIC link bet obesity and IR
          1. normally insulin INHIBITS adipocyte hormone-sensitive lipase activity
             1. it therefore DECREASES the amount of FFA released from adipose tissue
          2. NORMALIZING FFA levels results in a 50% increase in insulin sensitivity in obese adults
       4. Obesity-assoc FFA elevations may affect AD pathogensis
          1. FFA inhibits IDE (metallprotease that plays a key role in clearance of AB AND is essential for normal insulin signaling to occur
          2. FFAs stimulate teh assembly of amyloid AND tau filaments (in vitro)
          3. FFAs induce inflammation
             1. particularly thru interactions with TNF-A
             2. TNF-A is OVEREXRPRESSED IN ADIPOSE of obese, IR
             3. neutralization of TNF-A increases insulin sensitivity and DECREASES plasma FFA level
          4. TNF-A
             1. role in AD pathogen?
             2. increased in CSF of ADs and MCIs
             3. inhibits AB transport from brain to periphery
             4. THUS, TNF-A elevations associated with obesity, IR an hyperinsulinemia may result in increased brain accumulation of AB
   13. Sex Hormones
       1. Testosterone
       2. Progesterone
       3. Estrogen
       4. DHEA
          1. Kalish understanding
       5. Adrenal/Cortisol
          1. Stress considerations
             1. "Glucocorticoid Cascade hypothesis" (AKA: "Neurotoxicity Hypothesis")
             2. assoc bet cumulative exposure to high glucocort and hippocampal atrophy
             3. theory is that the prolonged exposure causes decreased neuronal resistance to insults
             4. Subtopic 2
       6. Cholesterol dysregulation
          1. CETP gene variant
             1. disruption of HDL regulation
       7. think about Iron/cholesterol/HFE gene in 4 Biotransformation
   14. Insulin and the Brain
       1. easily crosses BBB via receptors
          1. insulin receptors are in
             1. astrocytes
             2. neuronal synapses
             3. CONCENTRATED IN OLFACTORY BULB, CEREBRAL CORTEX, HIPPOC, HYPOTHAL, AMYGDALA, and SEPTUM
       2. likely memory related mechanisms
          1. modulation of synaptic struc/fxn, LTP and CNS levels of NTs such as Ach and NorEpi that are known to influence cognitive
       3. GLUT 4 and GLUT 8 transporters
       4. Functions in the brain that are DIRECTLY disrupted in insulin resistant conditions
          1. Peripheral hyperinsulinemia a/w insulin resistance reduces insulin transport across BBB
             1. lowers insulin levels and activity in the brain
          2. Reduced brain insulin is a/w
             1. increased tau phosphorylation (in mouse)
             2. AB levles (in mouse)
          3. IV Insulin infusion
             1. raised plasma AB42 in AD patients (but not normal adults)
             2. this increase in AB42 was exaggerated in OBESE/high BMI
             3. Insulin may interfere w AB degradation via its regulation of metalloprotease insulin degrading enzyme
             4. this might be important as mechanisms regulating clearance of AB might be esp important in LOAD
9. 7 Transport
   1. DKHARRAZHIAN CONCEPTS
   2. Blood Pressure changes and cortical atrophy
   3. Dyslipidemia
      1. midLIFE high TC a/w increase risk AD and dementia
      2. NO rel bet TC and VaD observed
      3. DLD role in Insulin Resistance syndrome
         1. Insulin is a primary regulator of lipid metabolism
            1. insulin STIMULATES lipogenesis
            2. REDUCES lipolysis
         2. in adipocytes, IR leads to accelerated lipolysis and INCREASED FFA leves
            1. EXCESS FFA influx into liver inhibits Insulin suppression of hepatic VLDL secretion
            2. the hepatic VLDL process is essential for preventing post-prandial hyperlipidemia
            3. acute inhibitory effects of insulin on lipid production are essential for rapid hepatic adaptation to metabolic shifts bet fasting and refeeding in order to maintain plasma lipids within an optimal physiolofic range
         3. THUS, IR adults have higher and more prolonged post-prandial excursions of VLDL and other deleterious lipids
         4. LIPOPROTEIN MEDIATION
            1. y
            2. there seems to be a relationship with postprandial lipid levels assoc with increased risk of AD and amyloid clearance
            3. ApoE and ApoJ mediate AB transport bet brain and periphery
            4. binding of AB to ApoE reduces efflux
            5. whereas binding of AB42 to ApoJ increases LRP2-mediated efflux (out of brain)
            6. THE LIPIDATION STATUS OF APOE AFFECTS ITS INTERACTION WITH AB
            7. highly lipidated ApoE increases AB brain efflux thereby reducing AB deposition
            8. POORLY LIPIDATED ApoE increases amyloid burden
            9. the lipidation status of peripheral AB may also affect its clearance
            10. OBSTRUCTING AB clearance in the peripheral "sink" may increase brain accumulation
            11. it is controversial what is the specific mediators of peripheral AB clearance (?ApoE, ApoJ)
            12. SOLUBLE LRP (Lipoprotein Receptor Related Protein)
            13. may be a key mediator of peripheral AB clearance
            14. LRP N terminal cleavage by B-secretase releases sLRP into plasma where it bind to AB
            15. AD patients had a 30% decrease in sLRP and a 280% INCREASE IN PROPORTION OF OXIDIZED sLRP (which has a lower affinity for AB)
            16. and large increases in the % of free plasma AB40 and AB42
            17. notably only a SMALL FRACTION OF plasma AB was BOUND to ApoE or ApoJ
            18. Subtopic 3
            19. THUS, investigation of sLRP and its modulators may provide important evidence for this promising therapeutic target.
            20. Insulin MODULATES LRP EXPRESSION AND TRANSLOCATION to the plasma membrane with it may more readily encounter B-secretase adn produce sLRP
      4. HTN and Vascular Dysfunction
         1. Insulin directly affects vasoreactivity and hemodynamic functions the story of "IMPAIRMENT OF FUNCTIONAL HYPEREMIA"
            1. capillary recruitment
            2. vasodilation
            3. Insulin normally increases NO-mediated vasodilation and regulates vascoconstriction via endothelin-1
            4. CONVERSELY- IR decreases NO and increases endothelin 1 activity favoring vasoconstriction and reducing capillary recruitment
            5. in turn, endothelial dysfunction reduces insluin transport ultimately reducing capillary recruitment and microvascular blood flow
            6. regional blood floow
            7. in brain, vasoconstriction and reduced capillary recrutiment may interfere with functions of the neurovascular nit, the coordinated interaction of astrocyte, neuron, and endothelium which couples neural activity with increased blood flow (ie "FUNCTIONAL HYPEREMIA)
            8. in turn, endothelial dysfunction reduces insluin transport ultimately reducing capillary recruitment and microvascular blood flow
            9. this exacerbates glucose and lipid abnormalities and establishes a Negative FEEDBACK LOOP bet progressive endothelial dysfunction and increasing IR
         2. 50% of HTN patients are IR and manifest ENDOTHELIAL DYSFUNCTION due to above mentioned
            1. HTN impairs "functional hyperemia"
            2. this impairment is induced by dysregulation of vasoactive mediators such as NO and endothelin 1, OXIDATIVE STRESS, by structural alteration of the vessels and inadequate cerebral autoregulation
            3. all these have been linked BACK to IR
10. Unincorporated
    1. Mechanistic Theories/Drivers
       1. BAP and tau as prions
          1. Bresden EBO
    2. BAP and tau as prions
       1. Bresden EBO
    3. Depression
       1. Genomind
    4. Genomind
    5. ADHD
    6. ElectroMag Radiation Toxicity
    7. snRNA aggregates linked to pathology
    8. Apolipoprotein J - clusterins
       1. soak up amyloid
    9. Bexarotene
       1. takes fluid off brain via upregulation/production of apoE
    10. takes fluid off brain via upregulation/production of apoE
    11. - Healthy Brain Initiative 2013-2018C
    12. - Cori Bargmann - Rockefeller Univ
    13. - Paige Cramer - inducible pluripotent stem cells (programmed for success)
    14. Calcium Regulatory Pathways
        1. see also Jay Lombard