Alzheimer's Disease – Current Status; Future Perspectives Nicola Oliver AMUS Meeting, 6th March 2013

How does Life Guide approach this problem? Overview Dementia – what is it? Alzheimer’s Disease Current Status History Neuropathology Risk factors Life expectancy Current treatments Prevention Future Perspectives Aging society Future prevalence Advances in diagnostics Pharma developments Challenges How does Life Guide approach this problem?

Dementia Not a single disease Affects memory, attention, language, and problem solving Alzheimer's disease, vascular dementia, fronto- temporal dementia, semantic dementia and dementia with Lewy bodies reduces the ability to learn, reason, retain or recall past experience also loss of patterns of thoughts, feelings and activities symptoms must be present for at least six months to support a diagnosis Test Sensitivity Specificity MMSE 71%-92% 56%-96% 3MS 83%-93.5% 85%-90% AMTS 73%-100% 71%-100% Non-specific syndrome

Auguste Deter – Alois Alzheimer's patient in History First officially identified in 1901 by German psychiatrist Dr Alois Alzheimer It is an incurable, degenerative and terminal disease Characterised by protein tangles in the brain which lead to cell degeneration and death Age is the greatest risk factor with incident risk doubling every 5 years after the age of 65 In general, a diagnosis of Alzheimer’s disease halves life-expectancy Auguste Deter – Alois Alzheimer's patient in 1902. Hers was the first described case of what became known as Alzheimer's disease

Neuro-pathology of Alzheimer's Disease

Magnetic Resonance Imaging (MRI) in Alzheimer’s disease Normal older individual (age = 77) Patient with mild AD dementia (age = 77) AMUS 6TH mARCH 2013

Cardiovascular Disease, Head Injury, Diabetes & Down Syndrome Risk Factors Cardiovascular Disease, Head Injury, Diabetes & Down Syndrome Familial/Genetic APOE ε4, PSEN1 & 2 Increasing Age

Alzheimer’s Disease Trajectory Normal Aging Cognitive function Asymptomatic Early symptomatic MCI (prodromal) Preclinical Clinical Dementia Mild Moderate Severe Age AMUS 6TH mARCH 2013

Baltimore Longitudinal Study of Aging BALSA   Men Women Age (yrs) Cases of Alzheimer's Disease BLSA US Life Tables 60 9.3 28.5 20.0 10.6 32.5 24.1 65 7.8 23.5 16.1 8.9 27.5 19.8 70 6.5 18.7 12.5 7.5 22.6 15.6 75 5.5 14.1 9.4 63 17.7 11.9 80 4.6 10.3 6.7 5.2 13.2 8.6 85 3.8 7.3 4.7 4.4 5.9 90 3.2 5.1 3.3 3.7 6.4 4.1 95 2.7 3.6 3.1 4.3 2.8 Source: Brookmeyer R et al (2002) Survival following a diagnosis of Alzheimer Disease Archives of Neurology 59:1764-1767

Current Treatment Approaches for AD 1993 1997 2000 2001 2003 tacrine (Cognex®) donepezil (Aricept®) rivastigmine (Exelon®) galantamine (Razadyne®) memantine (Namenda®) AMUS 6TH mARCH 2013

Modifiable Risk Factors   Population Prevalence Relative Risk (95% CI) PAR (confidence range) Number of cases attributable (thousands; confidence range) Worldwide Diabetes Mellitus 6.4% 1.39 (1.17-1.66) 2.4% (1.1-4.1) 826 (365-1374) Midlife Hypertension 8.9% 1.61 (1.16-2.24) 5.1% (1.4-9.9) 1746 (476-3369) Midlife Obesity 3.4% 1.60 (1.34-1.92) 2.0% (1.1-3.0) 678 (387-1028) Depression 13.2% 1.90 (1.55-2.33) 10.6% (6.8-14.9) 3600 (2295-5063) Physical Inactivity 17.7% 1.82 (1.19-2.78) 12.7% (3.3-24.0) 4297 (1103-8122) Smoking 27.4% 1.59 (1.15-2.20) 13.9% (3.9-24.7) 4718 (1338-8388) Low Education 40.0% 1.59 (1.35-1.86) 19.1% (12.3-25.6) 6473 (4163-8677) Combined (maximum) 50.7% 17,187,028 * USA 8.7% 3.3% (1.5-5.4) 174 (77-288) 14.3% 161 (1.16-2.24) 8.0% (2.2-15.1) 425 (119-798) 13.1% 7.3% (4.3-10.8) 386 (226-570) 19.2% 14.7% (9.6-20.3) 781 (506-1078) 32.5% 21.0% (5.8-36.6) 1115 (308-1942) 20.6% 10.8% (3.0-19.8) 574 (159-1050) 13.3% 159 (1.35-1.86) 7.3% (4.4-10.3) 386 (236-544) 54.1% 2,866,951* Source: Barnes D and Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence Lancet Neurology 10:819-828

Potential number of AD cases that could be prevented through risk factor reduction Source: Barnes D and Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence Lancet Neurology 10:819-828

Future Perspectives

Changes in Population by Age-group

Future Prevalence – by age group - UK Source: Alzheimer’s Society (2007) Dementia UK – The full report. A report to the Alzheimer’s Society on the prevalence and economic cost of dementia in the UK produced by King’s College London and the London School of economics Abbo Litho. London

Future Prevalence – by gender - UK Source; Alzheimer’s Society (2007) Dementia UK – The full report. A report to the Alzheimer’s Society on the prevalence and economic cost of dementia in the UK produced by King’s College London and the London School of economics Abbo Litho. London

Pharmaceutical Developments every anti-Abeta drug which has reached late stage development has failed in clinical studies Both Bapineuzumab and Solanezumab failed to meet primary endpoints, though Solanezumab may be effective in mild AD DIAN have selected 2 investigational monoclonal antibodies for clinical trials in pre-clinical AD (Gantenerumab and Solanezumab) in a randomized controlled trial This trial will include 160 mutation carriers in their 30's, 40's or 50's who range from 15 years before to 10 years after the expected onset of symptoms To commence early 2013

Advances in early diagnosis Biomarkers Identification of tau and amyloid in blood, urine and CSF Biomarker signatures in CSF in particular correlate with the course of AD Brain Imaging MRI for functional and structural assessments Contrast PET imaging using F-18 or PiB to identify amyloid deposition FDA approval of Florbetapir

Florbetapir-PET Imaging Low amyloid on PET and autopsy Source: Clark et al (2011) use of Florbetapir-PET for Imaging β-Amyloid Pathology JAMA 305(3):275-283 Intermediate amyloid on PET and autopsy High amyloid on PET and autopsy AMUS 6TH mARCH 2013

Colombian Cohort

Challenges Ahead Large and lengthy trials – need patients and families willing to volunteer “Surrogate markers” of disease modifying effects may shorten duration of trial (Neuroimaging, CSF) Trials in mild-moderate AD dementia are failing Nine phase III trial failures over the past decade Are we targeting the wrong mechanism of action or is it too late in the disease course? Disease modifying therapies may work best prior to dementia (and stage of irreversible brain cell loss) MCI/prodromal or even preclinical stage Delaying dementia by 5 years would reduce projected Medicare costs by nearly 50% AMUS 6TH mARCH 2013 30 22

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