Related Dementias: Genes, Proteins, Metabolites, What Does it … · 2020. 4. 7. · 729 Post-Mortem Analyses • Final Dataset: 1262 participants (Last Clinical Visit) • Demographic

The Search for the Cause and the Cure for Alzheimer’s Disease and

Related Dementias:

Genes, Proteins, Metabolites, What Does it All Mean?

Dr. Dayan GoodenoweFounder, Prodrome Sciences Inc.

1

“Plurality must never be posited without necessity”

William of Ockham, “Ockham’s Razor”

Complexity must be proven, not assumed

-----------------------------------------------------------------------

“Everything should be made as simple as possible, but not simpler”

Albert Einstein

Be aware of oversimplification

2

First things first…

Let’s talk about

death and dying

3

All Cause Mortality – USA 2012

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Cardiovascular

Cerebrovascular

Alzheimer's and Parkinson's

Cancer

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Cancer Cerebrovascular

AD and PDCardiovascular

Major Causes of Death – USA 2012

Age Range

Second things second…

Let’s talk about the basic

structure of our biology and

how do we use this

information to monitor

health and disease

7

DNA

mRNA

proteins

activated proteins

substrates products

(genome)

(proteome)

(metabolome)

Genotype

Genes, Proteins and Metabolites:

8

DNA

mRNA

proteins

activated proteins

substrates products

(genome)

(proteome)

(metabolome)

Genotype


Only 10-15% of AD cases can be linked to genetic causes

9

DNA

mRNA

proteins

activated proteins

substrates products

(genome)

(proteome)

(metabolome)

Phenotype

Environment

Environment10


DNA

mRNA

proteins

activated proteins

substrates products

(genome)

(proteome)

(metabolome)

Phenotype

Environment

Environment

Over 85% of AD cases can be linked to acquired changes due to environmental interactions

11


Trend of Age-specific Incidence Rate of CRC in Japan (1970-1999)

Males, Incidence/100,000

Colon Cancer Rates in Japan

20 Years Earlier

3X More Cases

12

All Cause Mortality – USA 2012

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Age (Years)

50-60 Death-Free Years

What is Happening

Here?

Disease-Mediated Mortality

Time

Healthy

At-Risk

Active Disease

Death

14

This is the Disease Prodrome

Curing Disease

Time

Healthy

At-Risk

Active Disease

Death

15

To Cure a Disease We Must Detect and Correct the Prodrome Before

it Becomes a Disease

• Part I – Clinical - What exactly is dementia?

• Part II – Post-mortem - What does the human brain tell us about dementia?

• Part III - Biochemistry – What are the key biochemical features of dementia?

• Part IV – Epidemiology – The prodromal features of dementia; dementia and mortality

• Part V – Therapeutics – Novel neuroprotective and neuroregenerative possibilities

• Part VI – What to do while we wait for the cure

OK, Now Let’s Talk About Dementia:16

1616

Part I:

What Exactly Is

Dementia?

17

Dementia = Decreased Cognition:18

1818

Prevalence increases dramatically after age 7519

1919

More Prevalent in Females (Occurs Earlier)

2020

ACh

AcCh

Pre-Synaptic Terminal

Post-Synaptic Terminal

ACh

ACh

ACh

AChACh

Acetylcholine Esterase

CHT

ChAT

The Neurochemistry of Thinking:21

21

Perry et al., 1978

Post Mortem (Cortex):

22

22

The Neurochemistry of Thinking:

22

PreSynaptic Terminalis

PostSynaptic Terminalis

ACh

ACh

ACh

AChACh

ACh

Drachman, 1977

Healthy Volunteers:

Scopolamine (muscarinicantagonist)

X X X

Short-term memory loss similar to AD

23

23


23

PreSynaptic Terminalis

PostSynaptic Terminalis

ACh

ACh

ACh

AChACh

ACh

Drachman, 1977

Healthy Volunteers:

Scopolamine (muscarinic antagonist)

+

Physostigmine

(ACE Inhibitor – Like Aricept)

X XAttenuation of memory loss

24

24


24

• Risk of dementia begins to significantly increase after age 75;

• More common in females than males

• Cumulative prevalence at age 95 is ~80%;

• Decreased cholinergic function is the primary, if not sole, proximate cause of impaired cognition;

• This fact has remained unchanged for over 35 years

• What is the cause of cholinergic dysfunction?

Part I Summary:25

2525

Part II:

What Does the Brain

Tell Us About

Dementia?

Post-Mortem Analyses

26

26

Amyloid Plaques

Shrinkage

Tangles

Three main pathologies:27

2727

AD Pathology and Cholinergic Function

Perry et al., 1981

28

28

WOW! – More Plaques = Less Cholinergic Function – Is this the smoking gun?

28

• By age 95, 80% of persons have amyloid pathology;• In the elderly, plaques and tangles appear together

Braak and Braak, 1997

29

29

Amyloid Pathology and Aging:

29

Braak and Braak, 1997

30

30

Neurofibrillary Tangles and Aging:

• By age 80, everybody has tangles in their brain

30

AD Pathology and Cognition at Time of Death:

Bennett et al., 2005

31

31

• 55% of cognitively normal elderly meet the pathological criteria for AD diagnosis at death

31

Clearly, AD Pathology

is not Causing

Dementia

Let’s keep searching…

32

32

Post-Mortem Brain Analyses

Brain Regions Studied: Inferior Temporal Cortex; Medial Frontal Cortex; CerebellumBasic Pathology: Tangles, AmyloidLipids (LC-MS/MS; n=122): Ethanolamine Plasmalogens (PlsEtn; n=15); Phosphatidylethanolamines (PtdEtn; n=16); Phosphatidylcholines (PtdCho; n=31); Triglycerides (TAG; n=10); Glycerols (DAG/VAG; n=47); Cholesterol (Free, esterified, total)

Transcripts (RT-PCR; n=25): Peroxisomal (DHAPAT, ADAP-S, PEX5, PEX7, PEX11a,b); Methyltransferases (PEMT, COMT, PNMT); Mitochondrial Biogenesis (TFAM, NRF1, PGC1α, COX1); Cholinergic (ACHE, CHAT, CHT); Inflammation (GFAP, LysM, MBP, CRP); Membrane (FLOT); Other (Mt-1, Mt-2)

33

Gender n Age Cognitive StatusNCI / MCI / AD

BraakI+II / III / IV / V+VI

Cerad1 / 2 / 3 / 4

Female 51 90.0 ± 5.0 20 / 12 / 19 7 / 15 / 12 / 17 19 / 13 / 5 / 14

Male 49 86.9 ± 6.2 18 / 12 / 19 14 / 11 / 16 / 8 16 / 15 / 7 / 11

Total 100 88.5 ± 5.8 38 / 24 / 38 21 / 26 / 28 / 25 35 / 28 / 12 / 25

Ordered Regression of NCI/MCI/AD:

Model adjusted for age, education and sex

• Membrane DHA-Plasmalogen levels have the strongest association with cognition of all brain pathologies studied

• Flotillin is a biomarker of membrane lipid rafts (where β-secretase is located); CHT is the Choline High Affinity Transporter which is obligate for cholinergic neuron viability.

34

Variable OR (e^bStdX) p

DHA-PlsEtn 0.199 3.8e-05

Flotillin 2.95 8.0e-08

CHT 0.394 2.9e-02

Tangles 1.93 2.9e-02

Cognition Flotillin

ApoE ε4

Amyloid

Tangles CHTDHA-PlsEtn

• Membrane DHA-Plasmalogenlevels interact with Tangles and reduce the contribution of Tangles to Cognition

• APOE and Amyloid are not associated with cognition when tangle density is in model

35

Interaction Map of Brain Pathology and Cognition

Part II Summary

• When multiple variables are examined together, the key brain pathologies associated with decreased cognition are:• Decreased plasmalogens (membrane lipid);• Increased Flotillin (biomarker of lipid raft region of

membranes);• Decreased Choline High Affinity Transporter (biomarker of

cholinergic neurons);• Neurofibrillary Tangles.

• APOE e4 genotype is NOT directly associated with decreased cognition (associated with increased amyloid)

• Brain Amyloid is NOT directly associated decreased cognition (associated with increased tangles)

Which of these associations are CAUSING decreased cognition?!

36

Part III:

Biochemistry

37

Plasmalogens are a special class of membrane phospholipid

38

The fatty acid sidechains

mediate fluidity

38

Neurotransmitter Release: 39

3939

Plasmalogens and membrane fusion40

PlsEtn (18:0/20:4)

PlsEtn (16:0/18:1)

PtdEtn (16:0/18:1)

PtdEtn (18:0/20:4)

Glaser and Gross, 1995

40

Plasmalogens:

Amyloid Pathology

4141

Amyloid Plaques are Comprised of Aβ Protein

Fragments

α-Secretase = Healthy APP Processing

β-Secretase = Pathologic APP Processing

42

4242

The Biochemistry of Amyloid Plaque Formation

α-Secretase is Located in Phospholipid-Rich Membranes(remember DHA-Plasmalogen)

β-Secretase is Located in Cholesterol-Rich Membranes(remember Flotillin)

43

4343

The Membrane Location of Amyloid Plaque Formation

Membrane Modification and Amyloid 44

• Increasing Membrane DHA-Plasmalogen Increases α-Secretase Levels and activity

4444

DHA-Plasmalogenprecursor

Increasing Membrane DHA-Plasmalogen Levels:

• Reduces Aβ42 Levels

• Neutralizes Effect of Cholesterol

45

4545

Membrane Modification and Amyloid

-.6

-.5

-.4

-.3

-.2

-.1

0.1

.2.3

Non E4 E4

-.6

-.5

-.4

-.3

-.2

-.1

0.1

.2.3

Female Male

-.6

-.5

-.4

-.3

-.2

-.1

0.1

.2.3

Female Male

Variable Coef p

ApoE ε2ε3/ε3ε3 Reference

ApoE ε3ε4/ε4ε4 0.417 1.3e-03

DHA-PlsEtn (=mean +1SD) -0.295 3.7e-02

Age 0.028 6.5e-01

Female Reference

Male 0.044 5.1e-01

E4

Non E4 DHA-PlsEtn( >Mean + 1SD)

DHA-PlsEtn( < Mean + 1SD)

DHA-PlsEtn (>Mean + 1SD)

DHA-PlsEtn( < Mean + 1SD)

Human Brain Membrane Composition, APOE, and AmyloidA

myl

oid

Outcome: Brain Amyloid

High membrane DHA-PlsEtncounteracts the association between ε4 and amyloid

46

(Metabolites) (Genes) (Proteins)

Plasmalogens:

Age and Gender

47

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

30-39 40-49 50-59 60-69 70-79 80-89 >90

Me

an

He

igh

t R

ati

o

Ohio_CTL_F

Ohio_CTL_M

SDCL_CTL_F

SDCL_CTL_M

48

Blood Plasmalogens and Age

Part III Summary

• Low brain plasmalogen levels are associated with lower cognition:• Low membrane plasmalogens = reduced membrane

fusion

• High brain plasmalogen levels are associated with lower brain amyloid:• Increasing membrane plasmalogens reduces amyloid

production

• Serum plasmalogen levels decline with age.

49

Part IV:

Epidemiology

50

50

Epidemiologically, there is only ONE (1)

variable that matters to you or me:

Time to Dementia

The goal is to make this as long as possible

Risk factors accelerate this time;

Protective factors slow this time

51

Rush University Longitudinal Study on Aging

LastClinical

Visit

T0T-1T-2T-3T-4T-5

T+1 T+2 T+3 T+4

T>5

T+5 T>5

Participants Still Living (n=896)

Yearly Clinical Visits

Participants Deceased SinceLast Visit (n=862)

8782 Serum Sample Analyses

729 Post-Mortem Analyses

• Final Dataset: 1262 participants (Last Clinical Visit)• Demographic data: Age, Sex• Genetic Data: APOE genotype• Metabolomic Data: HDL/LDL, Triglycerides, Glucose, Plasmalogens;• Clinical Data: Diagnosis of Dementia, Cognitive Status

52

Prodrome Analysis

Mortality Analysis(Later…)

Rush University Longitudinal Study on AgingVariable Values

n, Visit 1 (Female | Male) 1262 (959 | 303)

n, Visit 2 (Female | Male) 1262 (959 | 303)

n, Deceased post visit 2 (Female | Male) 557 (399 | 158)

Education, Mean ± SD 15.4 ± 3.5

APOE Genotype: ε2ε3 | ε3ε3 | ε3ε4,ε4ε4 180 | 800 | 282

Visit 1 Age, Mean ± SD 81.3 ± 7.4

Visit 2 Age, Mean ± SD 85.0 ± 7.6

ΔAge (V2-V1) 3.7 ± 1.5

Visit 1 Diagnosis: NCI | MCI | AD 899 | 304 | 59

Visit 2 Diagnosis: NCI | MCI | AD 774 | 302 | 186

Visit 1 Dementia: No | Yes 1185 | 77

Visit 2 Dementia: No | Yes 1036 | 226

Visit 1 Global Cognition, Mean ± SD 0.092 ± 0.628

Visit 2 Global Cognition, Mean ± SD -0.199 ± 0.915

ΔGlobal Cognition (V2-V1) -0.291 ± 0.566

Visit 1 Plasmalogens, Mean ± SD -0.065 ± 0.178

Visit 2 Plasmalogens, Mean ± SD -0.098 ± 0.193

ΔPlasmalogens (V2-V1) -0.032 ± 0.177

Age to death from visit 2, Mean ± SD 1.6 ± 1.5

53

Probability of Dementia at a

Given Point in Time

(Last Clinical Visit)

54

Cross-Sectional AnalysesDementia

(OR)

Visit 2

Plasmalogens

(at visit)

0.520

(4.0e-12)

APOE: ε3ε3

ε2ε3

ε3ε4,ε4ε4

Reference

0.756

(2.6e-01)

2.309

(4.9e-06)

Age (SD=7.6y)

(at visit)

2.094

(5.8e-15)

Education 0.967

(6.8e-01)

Sex: Female

Male

Reference

1.071

(7.1e-01)

Odds ratios expressed per SD

55

0

20

040

060

0

Fre

qu

en

cy

-1 -.5 0 .5 1PBV2

13.6%

7.7%

4.3%

2.3%

22.7%

35.2%

50.1%

Prevalence of Dementia per Standard Deviation (SD) Plasmalogen

1 Plasmalogen SD ~= 7.5 Years of Age

Total Population(Mean ± 95% CI)

Probability of Dementia (Age and Plasmalogens)

56

Probability of a Non-

Demented Person Becoming

Demented in the Future

(Initial Visit versus Last

Clinical Visit Analysis)

57

ΔDementia

OR (p)

Plasmalogens

(V1)

0.571

(3.7e-06)

ΔPlasmalogens

(V2-V1)

0.594

(3.5e-06)

APOE: ε3ε3

ε2ε3

ε3ε4,ε4ε4

Reference

0.739

(3.1e-01)

2.029

(1.4e-03)

Age (SD=7.4y)

(V1)

2.033

(2.7e-10)

ΔAge

(V2-V1)

1.806

(2.5e-07)

Education 0.974

(7.8e-01)

Sex: Female

Male

Reference

1.027

(9.1e-01)

58

Probability of a non-demented person becoming demented in 3.7 years


Probability of a non-demented person becoming demented in 3.7 years

59

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

30-39 40-49 50-59 60-69 70-79 80-89 >90

Me

an

He

igh

t R

ati

o

Ohio_CTL_F

Ohio_CTL_M

SDCL_CTL_F

SDCL_CTL_M

Dementia in elderly persons who have normal plasmalogens

60

Although the population average decreases over time, this decrease does not occur in everyone - the top 10% of the elderly have levels similar to young persons

What is the incidence of dementia in elderly persons that do not have an age-associated decrease in plasmalogens?

Longitudinal - Time to Dementia Analyses

VariableAll

(n)No Dementia Dementia

All

(n) No Dementia Dementia

Female 859 859 0 859 696 163

Male 275 275 0 275 221 54

Plasmalogens

>1SD (high)123 123 0 123 117 6

Plasmalogens

rest1011 1011 0 1011 800 211

ApoE e2e3 708 708 0 708 586 122

ApoE e3e3 158 158 0 158 134 24

ApoE e3e4/e4e4 268 268 0 268 197 71

61

Baseline At Event

123 / 1234 = ~ Top 10%

1231011

Cases of Dementia in the 6-Year Follow-up

VariableEvents

Observed

Events

Expectedp

Plasmalogens

(1SD)6 29.7

ApoE ε3ε3 122 139.2

1.20e-04ApoE ε2ε3 24 32

ApoE ε3ε4, ε4ε4 71 45.8

• There should have been 30 cases – there were only 6

• Incidence of dementia was 80% lower in high Plasmalogen subjects versus the general population

62

63

Longitudinal - Time to Dementia Analyses

1. High plasmalogen levels slow the time to dementia2. The APOE e4 genotype accelerates the time to dementia

1

2

Longitudinal Analyses

- Mortality -

64

Rush University Longitudinal Study on Aging

LastClinical

Visit

T0T-1T-2T-3T-4T-5

T+1 T+2 T+3 T+4

T>5

T+5 T>5

Participants Still Living (n=896)

Yearly Clinical Visits

Participants Deceased SinceLast Visit (n=862)

8782 Serum Sample Analyses

729 Post-Mortem Analyses

65

Mortality Analysis

Odds of Dying 1.6 Years after Last Clinical VisitDeath, OR (p) Death, OR (p) Death, OR (p)

Plasmalogens (V1) 0.444 (2.6e-20) 0.432 (1.3e-21) 0.424 (5.2e-23)

ΔPlasmalogens 0.538 (2.6e-13) 0.530 (3.7e-14) 0.514 (1.7e-15)

Global Cognition (V1) 0.691 (7.0e-06) N/A N/A

ΔGlobal Cognition (V2-V1) 0.617 (1.1e-08) N/A N/A

Diagnosis (V2): NCI

MCI

ADN/A

Reference

2.152 (1.7e-06)

3.520 (3.0e-09)N/A

Dementia (V2): No

YesN/A N/A

Reference

2.460 (1.6e-06)

APOE: ε3ε3

ε2ε3

ε3ε4,ε4ε4

Reference

1.234 (3.0e-01)

1.100 (5.8e-01)

Reference

1.210 (3.4e-01)

1.143 (4.3e-01)

Reference

1.073 (7.2e-01)

1.199 (2.7e-01)

Age (V1) 1.948 (1.6e-16) 2.061 (1.2e-19) 2.178 (2.4e-23)

ΔAge (V2-V1) 1.069 (3.5e-01) 1.110 (1.3e-01) 1.109 (1.3e-01)

Education 1.034 (6.6e-01) 0.958 (5.3e-01) 0.949 (4.4e-01)

Sex: Female

Male

Reference

1.898 (5.7e-05)

Reference

1.899 (4.7e-05)

Reference

1.885 (4.9e-05)

66


Probability of Dying after Last Clinical Visit

67

Multiply by 2.5X if

demented

Part IV Summary:

• A low blood plasmalogen level is predictive of non-demented persons becoming demented in the near future;

• A high blood plasmalogen level is protective against dementia: the incidence of dementia in persons with high blood plasmalogens is 80% lower than in persons with average or low blood plasmalogens;

• Higher age, presence of dementia, low plasmalogens, and male sex all increased risk of dying

• There is no increased risk of mortality associated with the APOE e4 genotype – cognitive impairment drives the mortality risk

68

Part V:

APOE e4 Specific

Data

69

69

Patient Summary

70

Female

n (%)

Male

n (%)

n 674 (78.2%) 188 (21.8%)

NCI 441 (65.4%) 127 (67.6%)

MCI 135 (20.0%) 37 (19.7%)

AD 65 (9.6%) 16 (8.5%)

Undefined 33 (4.9%) 8 (4.3%)

ApoE ε2ε3 86 (12.8%) 31 (16.5%)

ApoE ε3ε3 434 (64.4%) 115 (61.2%)

ApoE ε3ε4/ε4ε4 154 (22.8%) 42 (22.3%)

Age (Average) 84.7 ± 7.4 84.8 ± 7.0

Age (Range) 58-104 65-100

Education 15.6 ± 3.2 16.2 ± 3.7*

Gcog -0.025 ± 0.80 -0.032 ± 0.77

Triglycerides (TG) 136.7 ± 69.4 122.0 ± 54.1*

Total Cholesterol (TC) 191.7 ± 38.8 160.9 ± 35.3*

HDL-C 63.7 ± 18.1 52.2 ± 15.0*

LDL-C 100.9 ± 33.4 84.3 ± 29.1*

HDL-C/TC 0.338 ± 0.091 0.331 ± 0.087

PtdEtn 16:0/22:6 (PE226) 1.56 ± 0.87 1.05 ± 0.63*

PlsEtn 16:0/22:4 (PL224) 0.84 ± 0.35 0.75 ± 0.30*

PlsEtn 18:0/20:5 (PL205) 1.32 ± 1.30 0.99 ± 0.85*

PlsEtn 16:0/22:6 (PL226) 3.45 ± 1.49 2.85 ± 1.11*

PL205/PE226 0.66 ± 0.51 0.74 ± 0.52*

PL226/PE226 1.86 ± 0.94 2.27 ± 1.09*

PL205/PL224 1.96 ± 2.67 1.54 ± 1.62*

PL226/PL224 4.57 ± 2.51 4.17 ± 1.98*

PL205/PL226 0.36 ± 0.23 0.33 ± 0.17

71

APOE, PlsEtn and Cognition

72

APOE, PlsEtn and AD Incidence

APOE, PlsEtn and Serum Lipids

73

-0.50

-0.40

-0.30

-0.20

-0.10

0.00

0.10

0.20

0.30

e2 e3 e4 Pls1 Pls2 Pls3 MGx1 MGx2 MGx3

PBV

50

55

60

65

70


HDL

100

110

120

130

140

150

160

170


TAG

160

165

170

175

180

185

190

195

200


TC

80

85

90

95

100

105

110

115


LDL

0.30

0.31

0.32

0.33

0.34

0.35

0.36

0.37

0.38


HDL/TC

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

e2

e3

e4

Pls

1

Pls

3

MG

x1

MG

x2

MG

x3

Pls

2

Part V Summary - A:

• ApoE genotype and PlsEtn metabotype exhibit no association with each other (PBV was constant across ApoEgenotypes)

• ApoE genotypes and PlsEtn metabotypes exhibit similar associations with cognition and percent AD cases

• Both ApoE genotype and PlsEtn metabotype affected each other’s associations with cognition and odds of AD. For example, the percentage of AD cases increased from 6·8% in Pls2:ε3 subjects to 16·9% in Pls2:ε4 and to 20·7% in Pls3:ε3 subjects and decreased to 1·4% in Pls2:ε2 and to 2·6% in Pls1:ε3 subjects

74

75

APOE, PlsEtn and HDL-MCE

Part V Summary – HDL-MCE

• Of the serum lipids investigated, only the HDL-C/TC ratio was observed to have a residual effect on cognition after correcting for ApoE and PBV

• ApoE and PBV were observed to have similar, but independent associations with HDL-C/TC ratio

• PBV has no effect on the HDL-C/TC ratio in ApoE e4 carriers;

• All roads lead to mechanisms that affect membrane composition:• ApoE e4 – indirectly via reduced HDL-C/TC• Plasmalogens – indirectly via increased HDL-C/TC and

directly (plasmalogens are actual membrane components)

76

Part VI:Novel Therapeutic Strategies

in Development

77

MPTP Treatment Depletes Serum Plasmalogensand Striatal Membrane Transporters

Striatal DAT Striatal VMAT2Serum PlsEtn

79

Plasmalogen precursor

Extent of demyelination vs duration of cuprizone treatment

80

Cuprizone administeredRegular diet control

Cuprizone + 25mg/kg cocktail Loss of myelin due to 6 wk cuprizonetreatment

Normal myelination in control animals(no cuprizone or cocktail)

Plasmalogenprecursors prevent demyelination (6 wkcuprizone+cocktail)

Effect of plasmalogen precursors on cuprizone-induced demyelination in mice at 6 weeks:

81

Plasmalogen Administration Improves Memory

82

Plasmalogen Clinical Trials

83

Plasmalogen Clinical Trials

84

Upcoming Phase I Clinical Trial in AD

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Public-Private Collaboration:

• University of Pennsylvania;• Will recruit, perform cognitive testing, administer Prodrome’s plasmalogen precursor

• Alzheimer’s Association (USA);• Will provide 100% of the funding (including drug manufacture);

• Prodrome Sciences Inc.• Will manufacture the plasmalogen bioprecursor

• Manufacturing scheduled to begin 2018.• Enrollment to begin in Q3 2018

• Will evaluate the utility of using Prodrome’s plasmalogen precursor for the treatment of cognitive impairment.

Part VI Summary:

• Plasmalogens can be restored and/or augmented using natural human bioprecursors – Medical Food;

• Plasmalogen bioprecursors are neuroprotective in animal models of neurodegeneration;

• Plasmalogen extracts have shown positive results in two small clinical trials;

• Synthetic plasmalogen bioprecursors are scheduled to enter robust human trials in 2018/19 to evaluate their potential utility in treating and preventing dementia.

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Part VII:What to do while we are

waiting for the cure?

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Eliminate the Bad:

• 21% of US AD cases are due to physical inactivity

• 12% due to diabetes + hypertension

• 11% due to smoking

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http://www.google.ca/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://blogforalzheimers.com/2011/12/27/exercise-can-help-prevent-alzheimers-disease-alzheimers-articles-information-and-resources/&ei=eF7uVOifLYWNyATp3IGwDQ&bvm=bv.86956481,d.aWw&psig=AFQjCNGdaRhxwFChJ5UsabAmo-xGuqfPOg&ust=1424994032448425

Add the Good…

• Mediterranean and DASH diets proven to slow cognitive decline in the elderly (Tangney et al., 2014)

• Physical activity reduces risk of MCI or AD diagnosis in the next 3.5 years by 50% (Covell et al., 2015)

• Aerobic and strength training increases cognition in dementia (Bossers et al., 2015)

• Be proactive – Dementia is not normal aging – it is unhealthy aging

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http://www.google.ca/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.aplaceformom.com/blog/10-16-14-food-from-greece/&ei=Q2TuVKzqOpKqyATus4C4Dw&psig=AFQjCNGdaRhxwFChJ5UsabAmo-xGuqfPOg&ust=1424994032448425

Thank You

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Documents

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