Prevention of Dementia and the Lancet Commission

Gill Livingston

February 2017

Email :An invitation from The Lancet

I am one of the editors at The Lancet and I am writing to invite you to participate in an exciting project that we are planning…We would like to invite you to be the Chair of the Commission and take the lead on this project.The content is entirely up to you but our initial thoughts are…

Our sponsors • UCL• Alzheimer's Society• ESRC • ARUK

And…..The Lancet editors

Helen Frankish and Sabine Best

The commissioners

Gill Livingston Andrew Sommerlad Vasiliki Orgeta Sergi Costafreda Jonathan Huntley David Ames Clive Ballard Sube Banerjee Alistair Burns Jiska Cohen-Mansfield Claudia Cooper Nick Fox Laura Gitlin Robert Howard Helen Kales Eric Larson Karen Ritchie Kenneth Rockwood Elizabeth Sampson Quincy Samus Lon Schneider Geir Selbӕk Linda Teri, Naaheed Mukadam https://www.ucl.ac.uk/psychiatry/research/olderpeople/lancet-international-commission

And then from the Lancet

A new systematic review or model would be great

and so we became

The Lancet international Commission on Dementia Prevention and Care

Why do some people not develop dementia?

• Dementia is by no means an inevitable consequence of reaching retirement age, or even of entering the ninth decade.

• There are lifestyle factors that may reduce, or increase, an individual’s risk of developing dementia.

• In some populations dementia is already being delayed for years; while in others the numbers of people living with it has increased

Prevention is better than cure

Two ways forward • Make people more resilient• Prevent damage

Population Attributable Fraction for modifiable risk factors

The percentage reduction in new cases over a given time if a particular risk factor were completely eliminated.

Ritchie et al BMJ 2010

Barnes and YaffeLancet Neurology

2011

Lamplight research?

65+ cohorts = 65+ risk factors65+ biobanks = 65+ biomarkers

Lancet analysisLifecourse analysis- when should intervene

Taking into account new risk factors with evidence

Split into

Early life

Midlife aged 45-65 years

Late life as aged > 65.

Risk factors from

UK National Institute of Health and Care Excellence (NICE) US National Institute of Health (NIH)

Used systematic reviews and meta-analyses and when there was not one we calculated.

PAF depends on relative risk and prevalence

BUT

People have lots of risks factors together

So we had to adjust for communality

Formula for individual Population Attributable Fraction (PAF)PAF = Pe (RRe-1) / [1 + Pe (RRe-1)]Pe = prevalence of the exposure RRe = relative risk of disease due to that exposureCalculation of communalityInput data on all nine risk factors in our model - Calculate tetrachoric correlation to generate correlation coefficients and a correlation matrix. Conduct a principal-component analysis on the correlation matrix to generate eigenvectors, which are directions mapped onto the data points and from which variance to the data is measured. These represent unobserved factors underlying all the variables that explain the variance observed.Components with eigenvalues ≥1 were retained in the model Communality was calculated as the sum of the square of all factor loadings (i.e. how much each unobserved component explained each measured variable).

Calculation of overall Population Attributable Fraction (PAF)We then calculated overall PAF: PAF = 1-[(1-PAF1)(1-PAF2)(1-PAF3)…] Each individual risk factor’s PAF was weighted according to its communality using the formula:Weight (w) = 1-communalityWeighting was included in the calculation of overall PAF using the formula:PAF = 1-[(1-w*PAF1)(1-w*PAF2)(1-w*PAF3)...]

So we calculated life course potentially modifiable risk factors

through the life coursrSorry can’t give you new meta-analysis and life course model today

Thanks Naaheed MukadamAndrew Sommerlad, Sergi Costafreda

Just because it flies it doesn’t make it a bird

Limitations• The PAF model assumes a causal association between a risk

factor and dementia,

• The most convincing evidence of causality would be randomised controlled trials in humans.

• This is not possible for many proposed dementia risk factors such as education; but we know that falling age-specific incidence is associated with more education

• Without experimental human evidence, causality criteria are: strength, temporality, plausibility, biological gradient, consistency

Antihypertensives • RCT in non-demented but hypertensive aged >80 (160-200/<110mmHg)

stopped as CVAs in TAU• Underpowered (as stopped) but dementia risk= HR 0.87, 95% CI [0.76-

1.00]• Peters et al 2008

• Meta-analysis of antihypertensive treatment groups (weighted mean difference = 0.42; 95% CI [0.30-0.53])

• Cochrane 2009

• Pre- Diva trial found significant difference only in those with hypertension• Moll van Charante 2016

Exercise• Longitudinal studies show a strong relationship between taking exercise

and not developing dementia: meta-analysis hazard ratio 0.62 (95% CI 0.54-0.70). Dose dependent protection• Sofi et al 2011

• Postulated to have a neuroprotective effect, potentially through promoting release of Brain Derived Neurotrophic Factor, reducing cortisol and reducing vascular risk

• One RCT of 40 minutes walking three times weekly for a year (versus stretching and conditioning) showed exercise training increased hippocampal size and improved memory in healthy adults aged 55-80

• Conflicting RCT findings about exercise- ? Too short or not adaptive or other differences

BUT trials of • non-steroidal anti-inflammatory drugs (NSAID) • a 24 week RCT of an oral hypoglycaemic drug,

rosiglitazone• oestrogen hormone replacement therapy, statins• vitamins • statins• and ginkgo biloba extract Have all been negative

Studies in

Low risk volunteers (PRE-DIVA) have been negative or weakly positive

(FINGER)

Dementia intervention: what, when, for how long and for whom?

• Not feasible to completely eliminate risk factors• Future strategies either to target the whole

population over a long period• Or those at higher risk.

Purpose of Lancet commission

• “Philosophers have only interpreted the world in various ways; the point, however, is to change it.”

Karl Marx

Theses on Feuerbach

11th thesis

(And Sube Banerjee)

Be ambitious about prevention

• Thus while trials, which by their nature are relatively short and include a smaller number of people, are disappointing,

• Results from risk factor modification for whole populations or high risk populations have been more hopeful.

• Delaying dementia for some years for even a small percentage of people would be an enormous achievement

• It looks like it may be within our reach

ThanksTo all commissioners

To sponsors

To those whose slides I have used

July 2017 Launch of commission