Is preventing Alzheimer’s Disease a practical proposition?

Epidemiological studies are now showing consistent falls in the age-standardized incidence of  Alzheimer’s Disease – attributed to better control of cardiovascular risk factors in middle age, and perhaps also to rising levels of education. So the rising tide of dementia is not inevitable. But, with the rapidly aging world population, demography is pulling powerfully in the opposite direction. 

At the moment, 36  million people worldwide have dementia. On current trends, there will be 115 million by 2050; and two-thirds will be in low or middle-income countries. So this is a truly global problem; and there is no denying the need for prevention.

Given the time lag between the first evidence of tau accumulating in the brain and the onset of even mild cognitive impairment, there is ample time to intervene. But how would we set about doing it?

Hypertension and obesity in mid-life are among the factors we can control

Let’s address the risk factors we can control

There is nothing we can change about ApoE4 as a risk factor. However, data from studies in southern France suggest that eliminating diabetes and depression and widespread adoption of a Mediterranean diet could – in theory -- decrease the incidence of dementia by twenty percent. In currently less healthy northern France, the reduction might be 35%.

But we need to demonstrate by prospective study that intervention works. We cannot wait for a reduction in dementia as the outcome measure. Hence the need to look at biomarkers for the signal that will give us the confidence to proceed, and to convince health authorities to provide the massive funding needed for nationwide dementia prevention strategies.

According to Karen Ritchie (University of Montpellier, France), the window of opportunity for prevention lies between the ages of 40 and 59. And observational data suggest that the biomarkers to look at include loss of hippocampal volume and early signs of cognitive decline.

The window of opportunity for prevention lies between the ages of 40 and 59

To gather confirmatory evidence on these and other candidate markers – including amyloid beta and tau in CSF and signs of neuroinflammation --  she and colleagues have designed the prospective PREVENT study.

The study also includes structural and functional MRI (both resting and task-related), and markers of dysregulation of the HPA axis – because of its association with stress. Biomarkers in mid-life will be related to outcome in risk groups defined by ApoE4 and family history.

Validating biomarkers

Based on its high rates of metabolic syndrome and AD, west London was chosen as the first area in which to recruit subjects. To date, the study has enrolled 210 people, half with at least one parent having a diagnosis of AD. Recruitment is now being extended to three other UK centres, and the target is one thousand subjects.

Tom Russ, of the Centre for Dementia Prevention at the University of Edinburgh, Scotland, is also busy recruiting subjects. The European Prevention of Alzheimer’s Disease (EPAD) project is aiming for a register of twentyfour thousand people. Six thousand of them will form a longitudinal cohort to act as a source of subjects – initially for proof of concept studies of preventive interventions, both lifestyle and pharmacological, and then – hopefully for phase III trials.

To date prevention trials have recruited slowly; and this resource is designed to speed the process.

The initial phase of EPAD will again look at potential biomarkers, with promising candidates moving into trials with a cognition outcome. Centers in Toulouse, Barcelona and Amsterdam have now joined the recruitment drive.

There is no shortage of enthusiasm, nor of good ideas. But will there be the money?

“Towards a dementia free world” is a slogan that attracts attention. But moving quickly towards the Promised Land will not be easy. Does anyone now remember the WHO’s aim of “Health for all by the year 2000”? Will lack of resources also be the stumbling block on the road to a brighter cognitive future?