I nsulin Resistance and I nsulin Resistance and Alzheimer s - - PowerPoint PPT Presentation

I nsulin Resistance and I nsulin Resistance and Alzheimer Alzheimer’ ’s Disease: s Disease: A Novel Therapeutic Target A Novel Therapeutic Target

Suzanne Craft Suzanne Craft

Geriatric Research, Education, and Clinical Center Geriatric Research, Education, and Clinical Center VA Puget Sound VA Puget Sound Professor of Psychiatry and Behavioral Sciences Professor of Psychiatry and Behavioral Sciences University of Washington School of Medicine University of Washington School of Medicine

Overview Overview

• Insulin plays a role in cognition and normal

Insulin plays a role in cognition and normal brain function brain function

• Dysregulation of insulin increases risk for AD

Dysregulation of insulin increases risk for AD and other neurodegenerative diseases and other neurodegenerative diseases

• Potential mechanisms of increased risk:

Potential mechanisms of increased risk: Effects on inflammation and Effects on inflammation and β β-

• amyloid

amyloid

• Therapeutic applications: Effects of treating

Therapeutic applications: Effects of treating insulin resistance and insulin resistance and normalzing normalzing CNS insulin CNS insulin

I nsulin and the Brain I nsulin and the Brain

• I nsulin crosses BBB via

I nsulin crosses BBB via saturable saturable receptor receptor-

• mediated

mediated trancytosis trancytosis (Banks et al, 97)

(Banks et al, 97)

• I nsulin receptors have synaptic localization in

I nsulin receptors have synaptic localization in hippocampus and throughout cortex hippocampus and throughout cortex (

( Apelt Apelt et al, 2001) et al, 2001)

• I ncreases glucose utilization in specific brain

I ncreases glucose utilization in specific brain regions regions (Bingham et al, 2002)

(Bingham et al, 2002)

• I ncreases levels of dopamine, acetylcholine,

I ncreases levels of dopamine, acetylcholine, norepinephrine norepinephrine (

( Figlewicz Figlewicz et al, 1993) et al, 1993)

• Modulates membrane potentials, membrane

Modulates membrane potentials, membrane expression of NMDA receptors, and neuronal expression of NMDA receptors, and neuronal firing/ LTP in hippocampus and EC firing/ LTP in hippocampus and EC (

( Skeberdis Skeberdis et al, 2001) et al, 2001)

• Enhances memory at

Enhances memory at optimal

• ptimal dose

dose

Chronic Effects of I nsulin: Chronic Effects of I nsulin: Too Much of a Good Thing Too Much of a Good Thing

• Insulin typically secreted and cleared quickly

Insulin typically secreted and cleared quickly

• High, chronic elevations problematic

High, chronic elevations problematic

• Reduced brain insulin uptake

Reduced brain insulin uptake

(Schwartz et al, 1990; Stein et al, 1987) (Schwartz et al, 1990; Stein et al, 1987)

• Reduced neurotransmitter levels

Reduced neurotransmitter levels

• Reduced glucose utilization (periphery

Reduced glucose utilization (periphery and CNS?) and CNS?)

• Memory impairment

Memory impairment

I nsulin Resistance and I nsulin Resistance and Alzheimer Alzheimer’ ’s Disease s Disease

• Insulin resistance/hyperinsulinemia increase risk
• f AD and memory impairment (Ott et al, 1999; Peila et al,

2002; Luchsinger et al, 2004)

• Risk increases with age (Ryan et al, 2001)
• Insulin resistance a particular risk factor for AD

patients without the APOE-e4 allele (Kuusisto et al, 97;

Liotsa et al, 02; Craft et al, 03)

• Insulin may modulate risk in part through effects
• n Aβ42

Modulates Aβ42 levels in vitro Enhances release, regulates degradation by IDE (Gasparini et

al, 2001; Qiu et al, 2001; Zhao et al, 2004)

Does I nsulin Affect CNS Does I nsulin Affect CNS Levels of A Levels of Aβ β? ?

• Will insulin administration raise A

Will insulin administration raise Aβ β42 levels in 42 levels in CSF, consistent with CSF, consistent with in vitro in vitro effects of insulin effects of insulin

• n A
• n Aβ

β release & degradation? release & degradation?

• Will effects differ according to age?

Will effects differ according to age?

• Will results be related to changes in

Will results be related to changes in biomarkers associated with inflammation? biomarkers associated with inflammation?

Methods Methods

IV IV

90 90 min min 105 105 min min

Insulin/dextrose or saline infusion Insulin/dextrose or saline infusion

Cognitive Cognitive testing testing Plasma glucose Plasma glucose measured every measured every 5 5-

• 10 min

10 min LP for CSF LP for CSF collection collection

Saline Saline I nsulin I nsulin ( 85 µU/ml )

)

Dextrose Dextrose ( 95 mg/dl ) Fasted Subjects (n=16, mean age = 68.7) Fasted Subjects (n=16, mean age = 68.7)

Separate days, counterbalanced order

Effects of I nsulin on CSF A Effects of I nsulin on CSF Aß ß42 Levels in 42 Levels in Normal Older Adults: Results Normal Older Adults: Results

• 30
• 10

10 30 30 50 70 50 60 70 80 90

Age

% Change in CSF Aβ42 Levels ( pg / ml ) r = .64, p < .008 r = .64, p < .008 r = .85 r = .85 p < .008 p < .008

< 70 yrs ≥ 70 yrs

Insulin Insulin-

• induced change in A

induced change in Aβ β42 42 is correlated with age is correlated with age

Watson GS, et al. Watson GS, et al. Neurology 2003;60(12):1899-903

Results Results Cytokines Cytokines

3.5 0.5 1 1.5 2 2.5 3

Insulin Saline

CSF IL-1β (pg / ml)

Saline Insulin

0.6 1.2 1.8

CSF IL-6 (pg / ml) 5 CSF IL-1α (pg / ml)

Saline

1 2 3 4

Insulin 1 2 3

Insulin Saline

CSF TNFα (pg / ml)

*p-values < .0001-.002 Fishel et al. Neurology, 2005

Results Results CSF F2 CSF F2-

• I soP

I soP

CSF F2-Isoprostane levels increase in response to insulin

* p < .01

F2-IsoP (pg / ml) Insulin

30 30 10 10 20 20 40 40 50 50

Saline

Results Results

Insulin-induced change in CSF Aβ42 is correlated with F2-Isoprostane levels for the OLDER normal adults normal adults

OLDER

ALL : r = .15, p = ns

• 400
• 200

200 400 600 800

• 20

20 40 60

Insulin - Saline CSF Aβ42 Levels ( pg / ml ) Insulin - Saline CSF F2-IsoP Levels ( pg / ml )

OLD : r = .87, p = .005

Does insulin have similar role Does insulin have similar role in in A Aβ β regulation in periphery? regulation in periphery?

• A

Aβ β cleared in liver and other peripheral sites cleared in liver and other peripheral sites

( (Ghiso Ghiso et al 04) et al 04)

• Plasma A

Plasma Aβ β elevated for some AD patients, declines elevated for some AD patients, declines with progression with progression (

(Mayeux Mayeux et al. 03; et al. 03; Ertekin Ertekin-

• Taner

Taner et al. 04) et al. 04)

• A

Aβ β transported between periphery and brain transported between periphery and brain

( (Mackic Mackic et al. 02; et al. 02; DeMattos DeMattos et al. 02) et al. 02)

• IGF

IGF-

• 1 and insulin increase levels of carrier proteins

1 and insulin increase levels of carrier proteins that bind A that bind Aβ β and regulate its transport and regulate its transport

( (Carro Carro et al. 02) et al. 02)

• High plasma A

High plasma Aβ β may obstruct clearance from or may obstruct clearance from or increase transport into brain increase transport into brain

Dose Dose-

• response effects of

response effects of intravenous insulin on plasma A intravenous insulin on plasma Aβ β42 42

• 100

100

• 50

50 50 50 100 100 150 150 200 200

% change in plasma Aβ42 AD AD Normal Normal

• 0.33

0.33 1 1 1.67 1.67 *p=0.009 *p=0.009

Infusion Rate Infusion Rate ( (µ µU/kg/min) U/kg/min)

Reger Reger et al. et al. in press in press

Model of Peripheral I nsulin Resistance & Model of Peripheral I nsulin Resistance & Hyperinsulinemia Hyperinsulinemia Effects on A Effects on Aβ β Regulation Regulation

Therapeutic I mplications Therapeutic I mplications

• Raising plasma insulin invoked age

Raising plasma insulin invoked age-

• related

related increases in CSF A increases in CSF Aβ β42 & inflammatory markers for 42 & inflammatory markers for normal adults, raised plasma A normal adults, raised plasma Aβ β for AD patients for AD patients

• Mechanisms through which insulin resistance

Mechanisms through which insulin resistance increases risk of AD with age? increases risk of AD with age?

• Treatment of insulin resistance that lowers insulin

Treatment of insulin resistance that lowers insulin and improves its effectiveness may be of and improves its effectiveness may be of therapeutic benefit therapeutic benefit

• PPAR

PPARγ γ agonists ( agonists (TZDs TZDs) promising because they ) promising because they increase peripheral insulin sensitivity, reduce increase peripheral insulin sensitivity, reduce peripheral insulin and inflammation peripheral insulin and inflammation

Rosiglitazone Rosiglitazone Treatment Affects Brain A Treatment Affects Brain Aβ β42, 42, I DE Levels & Memory in AD Mouse Model I DE Levels & Memory in AD Mouse Model

9 month old male TG2576 mice treated for 4 mos with 4mg / kg rosiglitazone or placebo

Pedersen et al. Exp Pedersen et al. Exp Neurol Neurol, , in press in press 400 400 800 800 1200 1200 1600 1600 2000 2000

Untreated Untreated Rosi Rosi

Brain A Brain Aβ β42 levels 42 levels

( ( pmol/g pmol/g ) )

400 400 800 800 1200 1200 1600 1600 2000 2000

Untreated Untreated Rosi Rosi Brain A Brain Aβ β42 levels 42 levels ( ( pmol/g pmol/g ) )

Rosiglitazone Rosiglitazone Treatment Affects Brain A Treatment Affects Brain Aβ β42, 42, I DE Levels & Memory in AD Mouse Model I DE Levels & Memory in AD Mouse Model

9 month old male TG2576 mice treated for 4 mos with 4mg / kg rosiglitazone or placebo

400 400 800 800 1200 1200 1600 1600 2000 2000

Untreated Untreated Rosi Rosi Brain A Brain Aβ β42 levels 42 levels ( ( pmol/g pmol/g ) )

TG TG TG+R TG+R WT WT

Hippocampal IDE mRNA Hippocampal IDE mRNA

TG TG TG+R TG+R WT WT

Hippocampal IDE mRNA Hippocampal IDE mRNA

Pedersen et al. Exp Pedersen et al. Exp Neurol Neurol, , in press in press

Rosiglitazone Rosiglitazone Treatment Affects Brain A Treatment Affects Brain Aβ β42, 42, I DE Levels & Memory in AD Mouse Model I DE Levels & Memory in AD Mouse Model

9 month old male TG2576 mice treated for 4 mos with 4mg / kg rosiglitazone or placebo

400 400 800 800 1200 1200 1600 1600 2000 2000

Untreated Untreated Rosi Rosi Brain A Brain Aβ β42 levels 42 levels ( ( pmol/g pmol/g ) )

Day 1 Day 1 Day 2 Day 2 Day 3 Day 3 0.0 0.0 0.5 0.5 1.0 1.0 1.5 1.5 2.0 2.0 2.5 2.5 3.0 3.0

*

WT TG+R TG

TG TG TG+R TG+R WT WT

Hippocampal IDE mRNA Hippocampal IDE mRNA

Working Memory Errors Working Memory Errors

Pedersen et al. Exp Pedersen et al. Exp Neurol Neurol, , in press in press

Effects of Effects of Rosiglitazone Rosiglitazone on Cognition in

• n Cognition in

Patients with Early AD or Patients with Early AD or Amnestic Amnestic MCI MCI

Subjects Subjects

• Amnestic

Amnestic MCI or early AD MCI or early AD (Petersen et al. 2003 or

(Petersen et al. 2003 or NINCDS/ADRDA criteria) NINCDS/ADRDA criteria), CDR = 0.5 or 1.0, MMSE > 15

, CDR = 0.5 or 1.0, MMSE > 15

• No diabetes or other relevant medical conditions

No diabetes or other relevant medical conditions

• No meds with known CNS effects other than

No meds with known CNS effects other than ChEI ChEI

Cognitive Testing Cognitive Testing

Treatment Treatment Initiated Initiated

Wk 32 Wk 32 Washout Washout Wk 8 Wk 8 Wk 16 Wk 16 Wk 0 Wk 0 Wk 24 Wk 24

Double Double-

• blind

blind Randomized (2:1) Randomized (2:1)

Rosiglitazone Rosiglitazone (n= 20) (n= 20) Placebo (n= 10) Placebo (n= 10)

Watson et al. Watson et al. Am J Geriatr Psychiatry Am J Geriatr Psychiatry 2005 2005

Sample Sample Demographics Cognitive Cognitive Battery Battery Demographics

• General Cognition

General Cognition Mini Mental State Exam Mini Mental State Exam

• Memory

Memory Buschke Buschke Reminding Test Reminding Test Story Recall Story Recall

• Attention

Attention Stroop Stroop Interference Test Interference Test Trail Trail-

• Making Test

Making Test

• Language

Language Semantic Fluency Semantic Fluency Picture Naming Picture Naming Narrative Writing Narrative Writing

Rosi (n = 20) Placebo (n = 10)

Age years 72.8 (6.6) 73.3 (6.0) AD/MCI 14/6 7/3 Sex (F/M) 6/14 3/7 MMSE 22.7 (4.5) 23.3 (5.4) BMI 24.2 (2.7) 24.4 (4.2) ChEI + 25% 20%

Results Results Delayed Verbal Memory

Delayed Verbal Memory

p = 0.04 p = 0.04 p = 0.001 p = 0.001

Total Words Recalled Total Words Recalled

placebo rosiglitazone 5 5 6 6 7 7

Month 2 Month 2 Month 4 Month 4 Month 6 Month 6

Watson GS, et al. Watson GS, et al. Am J Geriatr Psychiatry Am J Geriatr Psychiatry (In press). (In press).

Results Results

• Plasma insulin levels lower after 6

Plasma insulin levels lower after 6 months for months for rosi rosi-

• treated group (p=.0026)

treated group (p=.0026)

• Improvement in memory, selective

Improvement in memory, selective attention, and verbal fluency related to attention, and verbal fluency related to metabolic treatment response metabolic treatment response – – indexed indexed by reduced insulin levels by reduced insulin levels

• No relationship between treatment

No relationship between treatment response and stage of disease response and stage of disease

Rosiglitazione Rosiglitazione XR Study AVA100193 XR Study AVA100193

Risner Risner et al., et al., Pharmacogenomics Pharmacogenomics J, 2006 J, 2006

• Population:

Population:

– – Mild to moderate Alzheimer Mild to moderate Alzheimer’ ’s Disease (MMSE 16 s Disease (MMSE 16 – – 26) 26) – – Treatment na Treatment naï ïve, receiving no AD pharmacotherapies ve, receiving no AD pharmacotherapies

• Primary Objectives

Primary Objectives:

: – – Cognitive function: Cognitive function: ADAS ADAS-

• cog

cog – – Clinical response: Clinical response: CI BI C+ CI BI C+

• Secondary Objectives:

Secondary Objectives:

– – Other Cognitive/ Functional assessments: Other Cognitive/ Functional assessments: NPI , MMSE NPI , MMSE – – Safety, tolerability: Safety, tolerability: AEs, AEs, hematology hematology, etc , etc – – I nsulin sensitivity, glycemic control: I nsulin sensitivity, glycemic control: insulin, glucose, etc insulin, glucose, etc – – Pharmacogenetics: Pharmacogenetics: interaction by APOE genotype interaction by APOE genotype

GlaxoSmithKline AVA100193 GlaxoSmithKline AVA100193

24 24-

• week, DB, PBO

week, DB, PBO-

• controlled, dose

controlled, dose-

• ranging

ranging study to investigate rosiglitazone in AD study to investigate rosiglitazone in AD

• 2 wk 0

2 wk 4 wk 8 wk 12 wk 16 wk 24 26 wk V1 V2 V3 V4 V5 V6 V7 V8 V9

Screening Screening End of Treatment End of Treatment Randomization Randomization Follow Follow-

• up

up Placebo n = 125 2 mg RSG n = 125 4 mg RSG n = 125 8 mg RSG n = 125 4 mg RSG

Risner Risner et al. et al. Pharmacogenomics Pharmacogenomics J J, 2006 , 2006

GSK GSK Rosiglitazone Rosiglitazone Trial : AVA100193 Trial : AVA100193

Demographics Demographics

Placebo Placebo (N=122) (N=122) RSG 2mg RSG 2mg (N=127) (N=127) RSG 4mg RSG 4mg (N=130) (N=130) RSG 8mg RSG 8mg (N=132) (N=132) Gender: Gender: Female Female Male Male 77 (63%) 77 (63%) 45 (37%) 45 (37%) 71 (56%) 71 (56%) 56 (44%) 56 (44%) 73 (56%) 73 (56%) 57 (44%) 57 (44%) 87 (66%) 87 (66%) 45 (34%) 45 (34%) Age: Age: Mean (SD) Mean (SD) Min Min-

• Max

Max 71.8 (8.2) 71.8 (8.2) 50 50 -

• 85

85 70.9 (8.5) 70.9 (8.5) 50 50 -

• 85

85 69.7 (9.0) 69.7 (9.0) 50 50 -

• 85

85 70.5 (8.5) 70.5 (8.5) 51 51 -

• 85

85 BMI: BMI: Mean (SD) Mean (SD) 25.67 (3.8) 25.67 (3.8) 25.51 (4.0) 25.51 (4.0) 25.88 (3.4) 25.88 (3.4) 25.82 (3.9) 25.82 (3.9) MMSE : MMSE : Mean Mean 20.8 (3.44) 20.8 (3.44) 21.3 (3.07) 21.3 (3.07) 21.6 (2.87) 21.6 (2.87) 21.4 (3.20) 21.4 (3.20)

Analysis Summary : Analysis Summary : Change from Baseline in ADAS Change from Baseline in ADAS-

• Cog at

Cog at Week 24 (LOCF) Week 24 (LOCF)

Treatment Treatment N N Least Squares Least Squares Mean (SE) Mean (SE) Treatment Comparison Treatment Comparison (RSG vs. Placebo) (RSG vs. Placebo)

Difference Difference p p-

• value

value

Placebo Placebo 122 122

• 0.4 (0.55)

0.4 (0.55) RSG 2 mg RSG 2 mg 126 126

• 0.2 (0.54)

0.2 (0.54) 0.25 0.25 0.74 0.74 4 mg 4 mg 129 129

• 0.9 (0.54)

0.9 (0.54)

• 0.46

0.46 0.52 0.52 8 mg 8 mg 131 131

• 0.7 (0.53)

0.7 (0.53)

• 0.27

0.27 0.71 0.71

ADAS ADAS-

• cog assesses various cognitive abilities such as memory, orienta

cog assesses various cognitive abilities such as memory, orientation in tion in time and place, etc. Scores range from 0 to 70; higher scores i time and place, etc. Scores range from 0 to 70; higher scores indicate greater ndicate greater dysfunction while negative change indicates improvement dysfunction while negative change indicates improvement

Analysis Summary : Analysis Summary : Change from Baseline in ADAS Change from Baseline in ADAS-

• Cog at

Cog at Week 24 by Treatment & APOE4 Carriage Week 24 by Treatment & APOE4 Carriage

APOE4 APOE4 Carriage Carriage Treatment (n) Treatment (n) LS Mean LS Mean (SE) (SE) p p-

• values

values for for Trt Trt Difference* Difference* p p– –value for value for Interaction Interaction No No Placebo (n =43) Placebo (n =43) RSG 2 mg (n=49) RSG 2 mg (n=49) 4 mg (n=45) 4 mg (n=45) 8 mg (n=42) 8 mg (n=42) 1.10 (0.96) 1.10 (0.96)

• 1.35 (0.90)

1.35 (0.90)

• 1.21 (0.90)

1.21 (0.90)

• 1.84 (0.95)

1.84 (0.95) 0.048 0.048 0.067 0.067 0.024 0.024 Yes Yes Placebo (n=35) Placebo (n=35) RSG 2 mg (n=36) RSG 2 mg (n=36) 4 mg (n=34) 4 mg (n=34) 8 mg (n=36) 8 mg (n=36)

• 1.10 (1.04)

1.10 (1.04) 2.46 (1.03) 2.46 (1.03) 0.39 (1.05) 0.39 (1.05) 0.39 (1.03) 0.39 (1.03) 0.012 0.012 0.29 0.29 0.29 0.29

0.014 0.014

Mean Change from Baseline in ADAS Mean Change from Baseline in ADAS-

• Cog

Cog for APOE4 for APOE4-

• Subjects Only

Subjects Only

• 2.5

2.5

Clinical improvement

Clinical decline

RSG 8 mg (p= 0.01) RSG 2 mg (p= 0.04) RSG 4 mg (p= 0.04)

• 2

2

• 1.5

1.5

• 1

1

• 0.5

0.5 0.5 0.5 1 1 1.5 1.5 PLACEBO 2 2 2.5 2.5

Baseline Week 8 Week 16 Week 24

I ntranasal I nsulin & the CNS I ntranasal I nsulin & the CNS

Intranasal insulin administration: Intranasal insulin administration:

• Increases CSF insulin and improves memory within 30

Increases CSF insulin and improves memory within 30-

• min in young, healthy adults without changing plasma

min in young, healthy adults without changing plasma glucose or insulin glucose or insulin (Born et al. 02; Benedict et al. 04)

(Born et al. 02; Benedict et al. 04)

• Can intranasal insulin administration

Can intranasal insulin administration “ “normalize normalize” ” reduced CNS insulin that characterizes some patients reduced CNS insulin that characterizes some patients with AD, and thereby improve memory? with AD, and thereby improve memory?

• Insulin

Insulin-

• like peptide signal measurable in rat

like peptide signal measurable in rat hippocampus, amygdala, frontal cortex 30 min after hippocampus, amygdala, frontal cortex 30 min after intranasal administration intranasal administration (Thorne et al. 04)

(Thorne et al. 04)

I ntranasal Pathways to the Brain I ntranasal Pathways to the Brain in Humans in Humans

• Bulk flow along

Bulk flow along rostral rostral (olfactory) or caudal (olfactory) or caudal (trigeminal) (trigeminal) perivascular perivascular channels; agents reach channels; agents reach brain in minutes brain in minutes

(Thorne et al. 01) (Thorne et al. 01)

• Axonal transport

Axonal transport through olfactory through olfactory neurons, which require neurons, which require hours to reach brain hours to reach brain

Study 1 Study 1 Methods Methods

Procedure Procedure

Blood draw Saline 20 IU Ins 40 IU Ins Blood draw 12 12-

• hour

hour fast fast Intranasal Intranasal Administration Administration 8:00 8:00 8:15 8:15 8:45 8:45 Cognitive Cognitive Testing Testing

Study 1 Study 1 Methods Methods

Subjects Subjects

Normal Normal Controls Controls AD AD ε ε4 4-

• ε

ε4+ 4+ Mean ( Mean (sd sd) ) N N Age ( yrs ) Age ( yrs ) BMI ( kg/m BMI ( kg/m2

2 )

) ( max=144 ) ( max=144 ) DRS DRS Education Education 14 14 77 (6) 77 (6) 25 (3) 25 (3) 127 (10) 127 (10) 14 (2) 14 (2) 35 35 75 (6) 75 (6) 26 (3) 26 (3) 140 (4) 140 (4) 15 (2) 15 (2) 12 12 77 (5) 77 (5) 25 (3) 25 (3) 125 (11) 125 (11) 15 (2) 15 (2)

Study 1 Study 1 Results Results

Total Story Recall Total Story Recall

* *

130 110 Percent Change 90 70 20 IU Ins 40 IU Ins 50 30 10

• 10

Normal AD/e4+ AD/e4-

Reger Reger et al. et al. Neurobio Neurobio Aging 2006 Aging 2006

Study 2 Study 2 Methods Methods

AD AD ε ε4 4-

• ε

ε4+ 4+ Mean ( Mean (sd sd) ) N N Age ( yrs ) Age ( yrs ) BMI ( kg/m BMI ( kg/m2

2 )

) ( max=144 ) ( max=144 ) DRS DRS Education Education 11 11 76 (4) 76 (4) 26 (3) 26 (3) 131 (9) 131 (9) 14 (3) 14 (3) 23 23 77 (8) 77 (8) 26 (5) 26 (5) 130 (13) 130 (13) 15 (3) 15 (3)

Subjects

Study 2 Study 2 Results Results

Total Story Recall Total Story Recall 20 20 25 25 30 30 35 35 40 40 10 10 20 20 40 40 60 60 Recall Score Recall Score E4- E4+ Insulin Dose (IU) Insulin Dose (IU)

* * * * * * * p< 0.05 * p< 0.05

Summary Summary

• Insulin has numerous actions in CNS that affect

Insulin has numerous actions in CNS that affect cognition cognition

• Hyperinsulinemia

Hyperinsulinemia / insulin resistance increases / insulin resistance increases inflammation and CSF A inflammation and CSF Aβ β42 42

• These conditions may be potent AD risk factors,

These conditions may be potent AD risk factors, particularly for patients particularly for patients without without APOE APOE ε ε4 4-

• Treatment with PPAR

Treatment with PPARγ γ agonist agonist rosiglitazone rosiglitazone & & intranasal insulin intranasal insulin enhance cognition in AD / enhance cognition in AD / amnestic amnestic MCI MCI – – may represent novel therapeutic may represent novel therapeutic strategies for this subgroup of patients strategies for this subgroup of patients

Collaborators Collaborators

Steven Kahn, MB, Steven Kahn, MB, ChB ChB James Leverenz, MD James Leverenz, MD Thomas Montine, MD, PhD Thomas Montine, MD, PhD Ward Pedersen, PhD Ward Pedersen, PhD Elaine Peskind, MD Elaine Peskind, MD Stephen Plymate, MD Stephen Plymate, MD Murray Raskind, MD Sanjay Asthana, MD Sanjay Asthana, MD John Breitner, MD, MPH John Breitner, MD, MPH David Cook, PhD David Cook, PhD Mark Fishel, MD Mark Fishel, MD Pattie Green, PhD Pattie Green, PhD William Frey, II, PhD William Frey, II, PhD Murray Raskind, MD

This work was funded by the Department of Veterans Affairs, This work was funded by the Department of Veterans Affairs, NIA R01 AG10880, ISOA, and GlaxoSmithKline. NIA R01 AG10880, ISOA, and GlaxoSmithKline.

I nsulin and Neurodegenerative I nsulin and Neurodegenerative Disease Research Team Disease Research Team

Maggie Gillet Maggie Gillet Karen Hyde, RN Karen Hyde, RN Jamie Iliff Jamie Iliff Jake Kulstad Jake Kulstad Marcos Marques, MD Marcos Marques, MD Pamela McMillan, PhD Pamela McMillan, PhD Amy Morgan Amy Morgan Mark Reger, PhD Mark Reger, PhD Stennis Watson, PhD Stennis Watson, PhD Magdalena Magdalena Wojtowicz Pamela Pamela Asberry Asberry, RN , RN Laura Baker, PhD Laura Baker, PhD Meabh Meabh Carter Carter Darla Chapman, RN Darla Chapman, RN Brenna Cholerton, PhD Brenna Cholerton, PhD Tracia Tracia Clark Clark Donna Davis, RN Donna Davis, RN Karen Enstrom, RN Karen Enstrom, RN Mark Fishel, MD Mark Fishel, MD Laura Fisher Laura Fisher Laura Frank, PhD Wojtowicz Laura Frank, PhD

Exclusionary Criteria Exclusionary Criteria

• Significant neurological disease other than AD
• Use of antidepressants, antipsychotics, anticonvulsants,

anticoagulants, anxiolytics or sedatives

• Major psychiatric disorders
• Severe head trauma with LOC >30 min or with permanent sequelae
• Uncontrolled chronic pain
• Radiation treatment (current or recent)
• CVA
• CHF
• COPD
• Vision loss
• Diabetes (diagnosed)
• Alcohol and drug abuse/dependence
• Liver disease
• Severe medical illness (e.g., uncontrolled HTN, cancer not in remission

> 1 year, thyroid disease, cardiac arrhythmia, renal and hepatic disease)

Model Model-

• adjusted Mean Change from Baseline

adjusted Mean Change from Baseline in ADAS in ADAS-

• cog by APOE4 status

cog by APOE4 status

• 2.0
• 1.0

0.0 1.0 2.0 Mean change in ADAS-cog score 4 8 12 16 20 24

E4-, placebo E4-, RSG 2mg E4-, RSG 4mg E4-, RSG 8mg E4+, placebo E4+, RSG 2mg E4+, RSG 4mg E4+, RSG 8mg

Weeks of Treatment

Clinical improvement Clinical decline

Safety Data Safety Data

• Safety monitoring (labs, physical exam)

Safety monitoring (labs, physical exam) at weeks 2 and 4, then monthly at weeks 2 and 4, then monthly

• No changes in fasting glucose, lipids,

No changes in fasting glucose, lipids, LFTs LFTs, renal indices , renal indices

• Two

Two SAEs SAEs: Myocardial infarction (1 : Myocardial infarction (1 placebo) and placebo) and lacunar lacunar infarction (1 infarction (1 rosi rosi) )

• Other

Other AEs AEs: mild anemia (1 placebo, 3 : mild anemia (1 placebo, 3 rosi rosi), mild edema (1 ), mild edema (1 rosi rosi) )

AVA100193: Key Safety Results, I TT Population AVA100193: Key Safety Results, I TT Population

Placebo Placebo (N = 124) (N = 124) RSG 2mg RSG 2mg (N = 128) (N = 128) RSG 4mg RSG 4mg (N = 131) (N = 131) RSG 8mg RSG 8mg (N = 135) (N = 135) Any Tx emergent AE Any Tx emergent AE 44 (35% ) 44 (35% ) 36 (28% ) 36 (28% ) 41 (31% ) 41 (31% ) 46 (34% ) 46 (34% ) Any SAE Any SAE 7 (6% ) 7 (6% ) 6 (5% ) 6 (5% ) 3 (2% ) 3 (2% ) 9 (7% ) 9 (7% )

Summary of AEs/ SAEs

AEs of Special Interest AEs of Special Interest

Placebo Placebo (N = 124) (N = 124) RSG 2mg RSG 2mg (N = 128) (N = 128) RSG 4mg RSG 4mg (N = 131) (N = 131) RSG 8mg RSG 8mg (N = 135) (N = 135) Oedema Oedema 3 (2% ) 3 (2% ) 1 (< 1% ) 1 (< 1% ) 3 (2% ) 3 (2% ) Anaemia Anaemia 1 (< 1% ) 1 (< 1% ) 2 (1% ) 2 (1% ) Oedema peripheral Oedema peripheral 4 (3% ) 4 (3% ) 3 (2% ) 3 (2% ) Eyelid oedema Eyelid oedema 1 (< 1% ) 1 (< 1% ) 1 (< 1% ) 1 (< 1% ) Periorbital oedema Periorbital oedema 1 (< 1% ) 1 (< 1% ) Cardiac failure Cardiac failure 1 (< 1% ) 1 (< 1% ) 1 (< 1% ) 1 (< 1% ) Cardiac failure (acute) Cardiac failure (acute) 1 (< 1% ) 1 (< 1% ) Alanine Alanine aminotransferase aminotransferase ↑ ↑ 1 (< 1% ) 1 (< 1% ) Aspartate Aspartate aminotransferase aminotransferase ↑ ↑ 1 (< 1% ) 1 (< 1% ) No new safety concerns identified in AVA100193 compared with the well established safety profile of rosiglitazone