The Challenge of Dementia: Prospects for Prevention
A 100 year journey from discovery to prevention trials?
Alzheimer and Auguste D
Amyloid Plaque Brain atrophy Neurofibrillary Tangle
Dementia is not the same as Alzheimer’s disease
Dementia and Alzheimer’s disease • Dementia: impairment of cognitive functions – Usually progressive – Sufficient to interfere with daily life • Alzheimer’s disease is the most common cause but many others – including treatable and preventable causes
Causes of Dementia • Neurodegenerative – Alzheimer ’ s Disease (AD) – Parkinson’s Dementia & Dementia with Lewy Bodies (DLB) – Frontotemporal lobar degeneration (FTLD) – Huntington ’ s disease • Vascular (VaD) • Other causes – Brain tumours, infections (HIV, syphilis), vitamin and hormone deficiencies, Creutzfeldt Jakob disease (CJD),
Causes of dementia Vascular dementia 15% Alzheimer ’ s disease Dementia with 50-60% Lewy bodies 15% Frontotemporal Dementia 5% HIV, Head injury, Prion diseases/CJD, Corticobasal degeneration, Other PSP, Huntington ’ s, alcohol-related dementia, tumours, infections, vitamin & hormone deficiencies, … ~2%
Dementia Research Group
Dementia: a demographic time bomb with aging populations Age (Years) Prevalence 40-65 0.1% (1 in 1,000) 65-70 2.0% (1 in 50) 70-80 4.0% (1 in 25) 80 Plus 20.0% (1 in 5) Prevalence doubles with every 5 years of age over 65 Source: Alzheimer's Society
Those born in 2013 can expect to live to over 90y Office of National Statistics & Christensen et al (2009) Lancet
Dementia is common and getting more common • 800,000 people with dementia in UK • 160,000 new cases per year - one every ~3 minutes • ~40% of the population have a family member or close friend with dementia Matthews F et al. (2005) The Incidence of Dementia PLoS Medicine, 2, e193 Alzheimer ’ s Research Trust / YouGov, 2008
Dementia 4% of 70-74y 8% of 75-79y 16% of 80-84y olds 2014 • £23 billion cost to UK • ¼ of hospital beds • ¾ of those in residential care • ½ of us will care for someone …
Risk Factors – those we cannot do much about • Age • Family history (RR ~ 2) • Genetic risk – Rare familial cases – Genetic risk modifiers • Female > male “Choose your parents carefully and die young” - Selkoe
AD: Genetics and Risk • Risk related to family history depends on detail: numbers affected, age at onset … • APOE – is the major genetic risk factor – ~1/5 of the population have an E4 allele – ~2/3 of AD patients have an E4 allele • Familial AD accounts for only 1% but has given great insights into the disease – Three different genes – each is rare – Onset may be as early as 30 yrs
Risks we can do something about? • Smoking • Diabetes • Raised blood pressure • Raised cholesterol • Head injury • Exercise • Depression • Education – use it or lose it?
Prevalence is increasing but is there evidence that it is not increasing as fast as expected in developed economies? Changes in UK age-specific prevalence 1990-2010
A range of proposed interventions… Can walking keep your mind young?
But when do we need to act to prevent, delay or reduce the risk of diseases that cause dementia: e.g. Alzheimer’s disease and vascular dementia?
When do we need to treat ? • When does the disease start to cause irreversible losses? • When most to save? • When we (individuals or society) would want disease modification? • Failure of trials to date in AD? Too little … too late?
Brain imaging – MRI – allows us to “see” the brain in life Healthy control Alzheimer’s
Benefits of earlier intervention Fewer neurons lost = more to save I n moderate AD some parts of the brain have already lost 1/3 of their volume
H Time 0 18months 36months Serial MRI of an individual with initially mild AD
Scan 1
Scan 2 – 1 year later
In “ mild ” AD the hippocampus is on average already ~20% smaller than controls Seab ’88, De Leon ’89, Scheltens ’92, Soininen ’94, Jack ’99, Du ’01, Killiany ’02
How and when does Alzheimer’s disease begin? • Recognition of a preclinical period to AD • Isolated memory or other deficits – 5-10% progression to AD per year • Could we see changes with imaging? • Would that offer an opportunity for treatments to prevent symptoms? • How could we study people before symptoms?
Rarely Alzheimer’s is inherited - usually young onset ? Allows us to study “ at-risk ” subjects
94 95 93 4/97 96 11/97 AD: At risk subject - serial scans registered to 1993 baseline
93 11/97 Red = loss
Brain Volume as percentage of TIV 90 85 Normal range: 95%CI 80 Symptoms 75 70 65 2500 0 500 1000 1500 2000 Time since first scan (days)
Could we image amyloid plaques? [ 11 C] PIB, Flutemetamol, Florbetapir, Florbetaben
And now – tau – the tangles that Alzheimer saw
Amyloid increases some years before AD symptoms – perhaps more than 10y before Remains well Subsequently converted to AD Brooks, Archer, Okello
So if we can detect and track presymptomatic changes … • Could we trial treatments at this stage? • What would their chances of success be? A window of opportunity to delay onset of Alzheimer’s disease
100 years on from Alzheimer and Auguste D • We can now see what Alzheimer could not – changes in the brain in life • We know there is a long pre-clinical period – perhaps 10-15 years • We can see and track changes before symptoms And finally we are starting trials to slow or delay the onset of disease
• I would like to acknowledge the tremendous and selfless contributions of patients and at risk subjects and their families in taking part in research And thank you for listening
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