Alzheimer’s Disease

Alzheimer’s Disease

Alzheimer’s Disease

Genotype

vs

Phenotype

Alzheimer’s Disease

Aging Genomics Epigenetics

Cerebrovascular disorders Metabolic disorders Environmental factors

Medicina Genómica

Ambiente

Nutrición

Etiología

Tratamiento

Diagnóstico

Genómica

Transcriptómica

Proteómica

Metabolómica

Nutrigenética

Nutrigenómica

Farmacogenética

Farmacogenómica

Quimiogenómica

Toxicogenómica

Terapia Génica

Clonación

Programa EuroEspes de Medicina Genómica

Genotipo Perfil Genómico

Fenotipo SNC

Respuesta Farmacogenómica

Etnia Historia Familiar Genotipo de Enfermedad Genotipo Farmacogenético Genotipo Farmacogenómico Genotipo Nutrigenético Genotipo Nutrigenómico

Fenotipo de Enfermedad Edad y Sexo Edad de Comienzo Estadio y Severidad Patología Concomitante Correlación Genotipo-Fenotipo Condiciones Nutricionales

Genómica Funcional Transcriptómica Proteómica Metabolómica

Intervención Terapéutica

Genotipo-Metabolismo Farmacológico Farmacocinética Farmacodinámica

Modificación Fenotípica Bioquímica Neuroquímica Neuropsicología Humor Conducta Memoria y Aprendizaje Funcionamiento Neuroimagen Función cerebral Función cerebrovascular Perfil de Expresión Génica Transcriptómica Proteómica Metabolómica

Monogenic Disorder Polygenic/Complex Disorder

Gene Gene-1 Gene-2 Gene-3 Gene-4

Mutation Genetic Variation

Abnormal Protein Abnormal Protein Network

Inheritance Pattern Inheritance Pattern Mendelian Dominant Recessive X-Linked

Non-Mendelian Complex Susceptibility

Phenotypic Expression

100% Genetic Risk in Population Phenotypic Expression

Variable Genetic Risk Associated with Environmental Factors

Family Risk Family Risk 100% Mendelian Genetics Variable Depending upon Environmental Factors

and/or Associated Medical Conditions

5-10% 80-90%

Alzheimer’s Disease

Pathogenesis

Alzheimer’s Disease Macroscopic Neuropathology

Alzheimer’s Disease Microscopic Neuropathology

APP Mutations

APP Mutations Alzheimer’s disease

GP: N=1087 AD: N=368

Amyloid Plaque Formation in Alzheimer’s disease

Presenilin-1 (PSEN1) and 2 (PSEN2) Mutations

Presenilin-1 (PSEN1) Mutations in Alzheimer’s disease

MAPT Mutations

Alzheimer’s Disease Microscopic Neuropathology

D D

C

N APP

PEN-2

APH-1 APH-2 Nicastrin

γ-Secretase

β-Secretase

α-Secretase

Notch

C

N

GACE

TACE

C83 C99

p3 Aβ

Membrane

Cytosol

γ-Secretase Inhibitors

β-Secretase Inhibitors

α-Secretase Analogs Agonists

Internalization

Neuronal Damage

Externalization

Fibrillogenesis

Amyloid Deposition

Senile Plaques

Amyloid Angiopathy

Brain Damage

Cerebrovascular Damage

APP 21q21

PS1 14q24.3

PS2 1q31-q32

BACE 11q23.3

TACE 2p25

GACE ???

Nicastrin Chr.1

PARK1 4p21

NOTCH 19p13.2-p13.1

PEN-2 Chr.19

APH-1 Chr.1/5

APOE 19q13.2

ACE 17q23

TAU 17q21.1

CASP3 4q35

UB 17p12-p11.1

IDE 10q23-q25

A2M 12p13.3-p12.3

PSMC1 19p13.3

PSMC2 7q22.1-q22.3

HSPD1 2q33.1

LRP1 12q13.1-q13.3

PRNP 20pter-p12

CTSB 8p22

Genomic Integration

Protein Synthesis Protein Misfolding

Ubiquitin 26S Proteasome

Conformational Change

Aggregation

Protofibrils Oligomers Aggregates Chaperones

Aβ Vaccination Immunization

Aβ Aggregation Inhibitors

β-Breakers

CHO Regulators Neuroprotective Agents Antioxidants Anti-inflammatory Drugs

Gene Therapy

RNAi

Vasoactive Agents

Brain Amyloidogenesis and Potential Therapeutic Interventions

R. Cacabelos, Pharmacogenomics 2004; 5(8):1049-1105

Terapia Actual Anti-Alzheimer

EA

Galantamine

Inhibidores del Acetilcolinesterasa

Rivastigmine Tacrine Donepezil

Antagonistas de NMDA

Memantine

LTP Restauradores

Reguladores de Serotonina

Terapias en Desarrollo Clínico

Antiinflamatorios

PPR-α agonist: Roglitazone

Patología de Tau

Metabolismo de Lípidos

Estimulantes Colinérgicos

NGF

Agentes Neurotrópicos

Antioxidantes

Patología de Aβ

Antihistamínicos

Vitamin B6

Reguladores Hormonales

Enfermedad de Alzheimer

Inmunoterapia Inmunización Activa

Inmunización Pasiva

Alzheimer’s Disease

Immunotherapy

Vacuna EuroEspes EB-101

Ratón APP/PS1

Vacuna EuroEspes EB-101

Diseño Bimodal Vacuna Preventiva/Profiláctica Vacuna Terapéutica

Animales Transgénicos Doble Mutación: APP + PSEN1

Liposomas Inmunógeno/Ag: AB1-42 Factor Neurotrófico S1P (Sphingosine-1-Phosphate)

Vacuna EuroEspes EB-101

Liposomes 1,2-Dioleoyl-sn-Glycero-3-Phosphocholine (DOPC) 1-Palmitoyl-2-oeloyl-sn-glycero-3-phosphatidylglycerol, Sodium salt (POPG) Cholesterol (CHO) +/- D-Erythro-Sphingosine-1-Phosphate (S1P)

Immunogen

Amyloid-Beta 1-42

EB-101

Vacuna EuroEspes EB-101

APPswe/PS1dE9 double-transgenic mice (B6C3F1/J)

Expression of Chimeric mouse/human Amyloid Precursor Protein (Mo/HuAPP695swe) and human presenilin 1 (PS1-dE6) mutans

Preventive Protocol (pre-onset) Age: 7 weeks EB101: 9 inj 100 uL x 7 months End: 11 months

Therapeutic Protocol (post-onset) Age: 35 weeks EB101: 9 inj 100 uL x 7 months End: 18 months

Vacuna EuroEspes EB-101

Vacuna EuroEspes EB-101

Pre-Symptomatic

Onset Mild

Severe

0 5 10 15 20

Preventive Vaccination 2-11 months

Therapeutic Vaccination 10-18 months

Vacuna EuroEspes EB-101

Analytical Process Antibody titers EB-101 Prophylactic Effects EB-101 Therapeutic Effects AD Neuropathological Markers Immune Response Behavioral changes

Vacunación Preventiva Placas de β-amiloide

Vacuna

Liposomas

PBS

Vacuna EuroEspes EB-101

Vacuna

Liposomas

PBS

Ovillos neurofibrilares

Vacuna EuroEspes EB-101

Vacunación Preventiva

Vacuna Liposomas PBS

CD45 – linf B

GFAP - astroglia

CD3 – linf T

Vacuna EuroEspes EB-101

Vacunación Preventiva

Aβ/NFT

CD45/NFT

GFAP/NFT

Relación entre biomarcadores

Vacuna EuroEspes EB-101

Vacunación Preventiva

Placas de β-amiloide

PBS

Vacuna

Liposomas

Vacuna EuroEspes EB-101

Vacunación Terapéutica

Ovillos neurofibrilares

Vacuna

Liposomas

PBS

Vacuna EuroEspes EB-101

Vacunación Terapéutica

Vacuna Liposomas Control

GFAP - astroglia

CD45 – linf B

CD3 – linf T

Vacuna EuroEspes EB-101

Vacunación Terapéutica

Reducción de Proceso Amiloidogénico

Vacuna EuroEspes EB-101

Vacunación Preventiva+Terapéutica

DRUGS Metabolism Disease

PHA

RM

AC

OG

ENO

MIC

S

PHA

RM

AC

OG

ENET

ICS

Cacabelos (2005)

Genetic Polymorphisms

Pharmacokinetics Absortion Distribution Metabolism Excretion

Pharmacodynamics Receptors Ion channels Enzymes Proteins

Pathogenic mechanisms Transcriptomics Proteomics Metabolomics

Safety Efficacy

30-90% variability

Pathogenic Genes

Drug Metabolism

Drug Transporters

Pleiotropic Genes

Drug Action

Disease PGx Outcome

Phenotype-A Phenotype-B

Genotype Surrogate markers

Biomarkers

Treatment

Pathogenic genes

Pleiotropic genes

Mechanism of Action

Drug Metabolism

Drug Transporters

Transcriptomics

Proteomics

Metabolomics Disease/Phenotype Modification

Genomics

Substrates Inducers

Inhibitors

Influence of APOE genotypes on Alzheimer’s disease-related phenotypes

APOE

Beta-Amyloid Deposition

Lymphocyte Apoptosis

CSF Tau NFT

Cytokine - Histamine Levels

ApoE Levels

Arterial Atherosclerosis

Brain Function EEG/FNI

Brain Function Cognition

Senile Plaques Amyloid Angiopathy

CHO/ApoE Receptors

Cholesterol HDL/LDL/VLDL/TG

Plasma & CSF BAP

Brain Perfusion CV Hemodynamics Brain Atrophy

Liver Function GOT/GPT/GGT

Cardiovascular Function

APOE Genotype DistributionAPOE Distribution in Hypertension, Diabetes and Dementia

Cacabelos et al., EuroEspes Biomedical Research Center, 2000

Control

Hypertension

Diabetes

Dementia

0% 20% 40% 60% 80% 100%

APOE-2/2APOE-2/3APOE-2/4APOE-3/3APOE-3/4APOE-4/4

Cacabelos, Psychogeriatrics (2000)

APOE Genotypes in CNS Disorders

C ANX DEP PSY STR AD PAR ADHD MIG EPI VD VE MS CVI BT CNN MR PTBS0%

20%

40%

60%

80%

100%

APOE-2/2APOE-2/3APOE-2/4APOE-3/3APOE-3/4APOE-4/4

APOE-2/2 0,32 0 0,24 0,62 0 0 0 0 0,46 0 0 0,26 0 0 0 0 0 1,89APOE-2/3 7,3 7,72 7,64 13,58 4,48 7,79 12,33 9,52 6,91 9,86 7,07 6,05 23,81 7,97 0 8 8,7 11,86APOE-2/4 1,27 1,05 1,67 1,23 2,98 1,3 1,37 0 1,84 0 1,52 1,58 0 0,73 9,09 0 1,74 0APOE-3/3 71,11 74,74 74,22 63,58 74,63 54,55 65,75 76,19 66,82 66,2 48,99 70,79 61,9 73,19 81,82 68 64,34 67,8APOE-3/4 18,41 15,09 15,27 20,37 17,91 30,3 17,81 14,29 22,13 23,94 35,85 18,68 14,29 15,94 9,09 24 24,35 16,96APOE-4/4 1,59 1,4 0,96 0,62 0 6,06 2,74 0 1,84 0 6,57 2,64 0 2,17 0 0 0,87 1,69

p<0.

001

p<0.

001

ANX: p<0.001 v s AD, VDDEP: p<0.001 v s AD, VDPSY: p<0.005 v s AD; p<0.001 v s VD: p<0.04 v s VEAD: p<0.03 v s MIG; p<0.001 v s VE; p<0.03 v s PTBSMIG: p<0.002 v s VDVD: p<0.001 v s VE; p<0.008 v s PTBSVE: p<0.05 v s MS

C: 315ANX: 285DEP: 419PSY: 162STR: 67AD: 231PAR: 73ADHD: 42MIG: 217EPI: 71VD: 198VE: 380MS: 21CVI: 138BT: 11CNN: 25MR: 115PTBS: 59

Cacabelos et al (2010)

Control GDS-3 GDS-4 GDS-5 GDS-6 GDS-7

APOE-2/2 APOE-2/3 APOE-2/4 APOE-3/3 APOE-3/4 APOE-4/4

R. Cacabelos (2005)

Right Occipital B-DTO-Hb Variation

Time (sec/10)

0 10 20 30 40 50 60 70 80 90 100 110

Hb

(mm

ol*m

m)

-0,08

-0,06

-0,04

-0,02

0,00

DHbTHbOHb

Left Occipital S-DTO-Hb Variation

Time (sec/10)

-100 0 100 200 300 400 500 600 700

Hb

(mm

ol*m

m)

-0,2

-0,1

0,0

0,1

0,2

0,3

0,4

DHbTHbOHb

AD-APOE-3/3

Right Occipital B-DTO-Hb Variation

Time (sec/10)

0 10 20 30 40 50 60 70 80 90 100 110

Hb

(mm

ol*m

m)

-0,06

-0,05

-0,04

-0,03

-0,02

-0,01

0,00

DHbTHbOHb

Right Occipital S-DTO-Hb Variation

Time (sec/10)

-100 0 100 200 300 400 500 600 700

Hb

(mm

ol*m

m)

-0,12

-0,10

-0,08

-0,06

-0,04

-0,02

0,00

0,02

DHbTHbOHb

AD-APOE-4/4

Basal Conditions

Visual Stimulation

APOE-Related Brain Optical Topography Changes

Cacabelos et al (2008)

APOE-Related DTO-Hb Species

APOE-2/2 APOE-2/3 APOE-2/4 APOE-3/3 APOE-3/4 APOE-4/4

0

0,5

-0,5

-1

-1,5

mmol*mm BDHb SDHb BTHb STHb BOHb SOHb

1 2 3 4 5 6

7 8 9 10 11 12 13 14

(1)p<0.009 BDHb-2/3 vs BDHb-4/4(2)p<0.02 SDHb-2/3 vs SDHb-4/4(3)p<0.03 BTHb-2/3 vs BTHb-4/4(4)p<0.03 STHb-2/3 vs STHb-4/4(5)p<0.05 BOHb-2/3 vs BOHb-3/3(6)p<0.03 SOHb-2/3 vs SOHb-4/4(7)p<0.03 SDHb-3/3 vs SDHb-4/4(8)p<0.03 BTHb-3/3 vs STHb-3/3

(9)p<0.001 STHb-3/3 vs STHb-4/4(10)p<0.05 BOHb-3/3 vs SOHb-3/3(11)p<0.007 SOHb-3/3 vs SOHb-4/4(12)p<0.02 BDHb-3/4 vs BDHb-4/4(13)p<0.02 STHb-3/4 vs STHb-4/4(14)p<0.01 SOHb-3/4 vs SOHb-4/4

APOE-3/3 APOE-4/4 APOE-3/3

Basal Stimulation Recovery

APOE-2/3

APOE-2/4

APOE-3/3

APOE-3/4

APOE-4/4

Op

tica

l Bra

in T

op

ogr

aph

y

AP

OE

Ge

no

typ

e-R

ela

ted

C

ort

ical

DO

T H

em

ogl

ob

in C

on

sum

pti

on

R. Cacabelos, Expert Rev Mol Diag (2009)

R. Cacabelos, Expert Rev Mol Diag (2009)

CYP2D6-Related Therapeutic Response in Alzheimer's DiseaseCognitive Performance in Extensive (EM), Intermediate (IM),

Poor (PM) and Ultra-rapid Metabolizers (UM)

EM-0 EM-1 EM-3 EM-6 EM-9EM-12 IM-0 IM-1 IM-3 IM-6 IM-9 IM-12 PM-0 PM-1 PM-3 PM-6 PM-9PM-12UM-0 UM-1 UM-3 UM-6 UM-9UM-120

5

10

15

20

25

30

35

XSD

X 21,58 21,57 21,53 21,54 22,66 23,78 21,4 21,67 22,2 22,1 22,5 22,71 20,74 20,65 20,24 19,04 18,57 18,07 22,65 23,02 22,49 21,73 21,34 21,28SD 9,02 7,46 6,99 5,17 8,09 5,81 6,28 5,58 6,2 6,48 6,39 5,07 6,72 6,52 6,11 5,39 5,52 5,86 6,76 5,67 4,62 5,68 4,99 7,75

ExtensiveMetabolizers

IntermediateMetabolizers

PoorMetabolizers

Ultra-rapidMetabolizers

MMSE Score

Cacabelos et al (2007)

Interaction of CYP2D6 and APOE in the Pharmacogenetics of Alzheimer's DiseaseInfluence of APOE Genotypes on CYP2D6-Related Extensive (EM), Intermediate (IM) and Poor Metabolizers (PM)

10 11 13 16 19 12 20 21 23 26 29 22 30 31 33 36 39 32 40 41 43 46 49 42 50 51 53 56 59 52 70 71 73 76 79 72 80 81 83 86 89 82 90 91 93 96 99 920

10

20

30

40

MeanSD

10:*1/*1-3/3-BL11:*1/*1-3/3-1M13:*1/*1-3/3-3M16:*1/*1-3/3-6M19:*1/*1-3/3-9M12:*1/*1-3/3-12M

*1/*1-3/3

10:*1/*1-3/4-BL11:*1/*1-3/4-1M13:*1/*1-3/4-3M16:*1/*1-3/4-6M19:*1/*1-3/4-9M12:*1/*1-3/4-12M

10:*1/*1-4/4-BL11:*1/*1-4/4-1M13:*1/*1-4/4-3M16:*1/*1-4/4-6M19:*1/*1-4/4-9M12:*1/*1-4/4-12M

10:*1/*4-3/3-BL11:*1/*4-3/3-1M13:*1/*4-3/3-3M16:*1/*4-3/3-6M19:*1/*4-3/3-9M12:*1/*4-3/3-12M

10:*1/*4-3/4-BL11:*1/*4-3/4-1M13:*1/*4-3/4-3M16:*1/*4-3/4-6M19:*1/*4-3/4-9M12:*1/*4-3/4-12M

10:*4/*4-3/3-BL11:*4/*4-3/3-1M13:*4/*4-3/3-3M16:*4/*4-3/3-6M19:*4/*4-3/3-9M12:*4/*4-3/3-12M

10:*4/*4-3/4-BL11:*4/*4-3/4-1M13:*4/*4-3/4-3M16:*4/*4-3/4-6M19:*4/*4-3/4-9M12:*4/*4-3/4-12M

10:*4/*4-4/4-BL11:*4/*4-4/4-1M13:*4/*4-4/4-3M16:*4/*4-4/4-6M19:*4/*4-4/4-9M12:*4/*4-4/4-12M

*1/*1-3/4 *1/*1-4/4 *1/*4-3/3 *1/*4-3/4 *4/*4-3/3 *4/*4-3/4 *4/*4-4/4

Extensiv e Metabolizers Intermediate Metabolizers Poor Metabolizers

MMSE Scor (mean)

Cacabelos (2007)

Farmacogenómica

Fármacos a la Carta

Food Drug

Nutrigenomics Pharmacogenomics

Outcome

Efficacy Safety

Personalized Nutrition

Personalized Therapeutics

Immunotherapy

World Guide for Drug Use and Pharmacogenomics