Research: risk reduction & prevention, cognitive testing and dementia in the workplace

Prof Craig RitchieCentre for Dementia Prevention

University of Edinburgh

www.centrefordementiaprevention.com

Overview• Why Prevention?

• What is secondary prevention?

• What is EPAD?

Why Prevention?

Age

60 65 70 75 80 85 900

10

20

30

40

50

60

70

Current Incidence5-year delay

Ritchie et al. 2015 Lancet Psychiatry (In Press)

Biomarkers and Alzheimer’s Dementia

• Amyloid Pathology• Tau Pathology• Cerebrovascular Changes• a-synuclein• Blood Brain Barrier Integrity• Glial activation and inflammation• Oxidative stress• Mitochondrial dysfunction• Synaptic dysfunction• Metal dyshomeostasis• Apoptosis• Insulin resistance• mTOR signalling• b-HSD function

SECONDARY PREVENTIONPRIMARYPREVENTION

PREVENTION PREMISED ON UNDERSTANDING DISEASE BEFORE DEMENTIA

Risk factors

Dementia

Familial aggregation

APOE, other genes

DyslipidemiaHypertension

Obesity

Cognitive reserve

Neuronal damage

0 20Adult life

60Mid-life

75Late-lifeA

cros

s th

e lif

espa

n

Vascular insults

Brain reserveEducation

Physical activity

Cognitive and social activity

Unhealthy diet

Alcohol overuse

Smoking

Diabetes

Protective factors

Risk factors

Figure adapted from Sindi S , et al. F1000Prime Rep. 2015;7:50.

Secondary Prevention

The three steps to achieve secondary prevention:

STEP 1: Identifying the ‘at risk’ person1. Risk factors (fixed and modifiable)2. Cognitive profile (not ‘symptoms’)3. Biomarker evidence of disease4. Changes in these over time

Can we develop an accurate prediction algorithm/score?

Secondary Prevention

The three steps to achieve secondary prevention:

STEP 2: Tailoring treatment1. Reducing modifiable risk factors2. Enhancing resilience3. Disease course modification through specific drug

intervention(s)

Secondary Prevention

The three steps to achieve secondary prevention:

STEP 3: Measuring success1. Individual’s risk status reduces

1. Cognition improves** (Karen Ritchie)2. Biomarkers normalise3. Risk of dementia decreases

2. Population level success1. Incidence decreases2. Trajectory of decline at early stage ameliorated

The European Prevention of Alzheimer's Dementia (EPAD) project aims to develop an infrastructure that efficiently enables the undertaking of adaptive, multi-arm Proof of Concept studies for early and accurate decisions on the ongoing development of drug candidates or drug combinations for the prevention of AD dementia.

European Prevention of Alzheimer’s Dementia (EPAD) Goal

EPAD Consortium

Current Grant Funding from IMI = €64M until end 2019

EPAD funnell

The EPAD Longitudinal Cohort Study

14

Loss to Follow Up

Maintained at N=6,000

Data

EPAD Cohort Baseline• Clinical• Biomarker• Imaging

Data

Data

1st Follow Up 2nd Follow Up

?

Enter Other Clinical Trial

Enter EPAD Trial

Replenishment from Virtual EPAD Register

The EPAD PoC Trial (n=1,500)

15

Allows early decisions on progression to longer term clinical outcomes by impact on pre-defined and target-specific intermediary phenotype.

2016 2023

Memantine, AChEIs, combination

Improved and earlier risk prediction

Precision Medicine

Other cognitive enhancers

Disease-modifying therapies

Community-wide prevention initiatives (diet, exercise…)

Alzheimer’s Disease treatment 2016 and beyond

2016 2023

Memantine, AChEIs, combination

Improved and earlier risk prediction

Precision Medicine

Other cognitive enhancers

Secondary Prevention therapies

Community-wide prevention initiatives (diet, exercise…)

Alzheimer’s Disease treatment 2016 and beyond (with EPAD)

National LeadsRitchie/Gallacher - UK & IrelandMiia Kivipelto - Scandinavia José Luis Molinuevo – Spain/Portugal Philip Scheltens - Benelux Giovanni Frisoni - Switzerland/Italy Bruno Vellas - France

AcknowledgementsWork Package LeadsWP1Simon Lovestone (UOXF) Andrew Satlin (Eisai) Gary Romano (JPNV)WP2Adrian Mander (MRC) Shobha Dhadda (Eisai) Scott Berry (BERRY) Kristian Windfeld (Lundbeck) WP3Pieter Jelle Visser (VU-VUmc) Gerald Luscan (Pfizer) WP4Craig Ritchie (UEDIN) Catherine Debove (BI) Miia Kivipelto (KI) Mila Etropolski (JPNV)

WP5Carlos Díaz (SYNAPSE) Serge Van der Geyten (JPNV) WP6Jean Georges (AE) Sean Knox (NOV) WP7José Luis Molinuevo (BBRC) Frank Tennigkeit (UCB) Saira Ramasastry (SYNAPSE)WP8Edo Richard (RUMC) Luc Truyen (JPNV) Carol Brayne (UCAM) Shirlene Badger (UCAM

Executive Committee & PMOSerge Van der Geyten (JPNV)Luc Truyen (JPNV)Andrew Satlin (Eisai)Craig Ritchie (UEDIN)Simon Lovestone (UOXF)José Luis Molinuevo (BBRC)Carlos Díaz (Project Manager)

Sandra Pla (member of PMO) Lennert Steukers (member of PMO) Mila Eltropolski (JPNV – member of PMO)Judi Syson (UEDIN – member of PMO)

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115736, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

Acknowledgment