APPGD 27 November 2013
Modifying risk factors for dementia: where are we now and where do we need to go?
A. David Smith, University of Oxford firstname.lastname@example.org
What progress has been made in identifying potential risk factors for dementia (mainly Alzheimer’s disease)?
• Several genetic risk factors, not modifiable
• Many non-genetic risk factors postulated, few proven. Best evidence for:
─ Low education
─ Mid-life high blood pressure, high cholesterol and obesity
─ Physical inactivity
─ Diabetes & high blood sugar
─ Low intake of omega-3 fatty acids
─ High blood homocysteine (due to low-normal B vitamin status)
• Modifying non-genetic risk factors can prevent disease, e.g. heart disease has declined by 70%, half of decline due to vascular risk factor modification
• Since vascular risk factors are also linked to dementia, has prevalence of dementia also declined: yes, in the UK it appears to have declined by 24% in last 20 years (MRC CFAS study)
• About half of all Alzheimer’s disease cases world-wide might be attributable to known nongenetic risk factors
An update on clinical trials that test modifying risk factors
• Most trials have been done on people with dementia and have failed; need trials at an earlier stage, such as mild cognitive impairment (MCI)
• Pilot trials in USA and Germany on omega-3 fatty acids have shown benefit
• Pilot trials in Australia and USA on exercise have shown benefit
• Pilot trial on homocysteine-lowering by B vitamins in UK has shown a marked slowing of disease progression (see description further below)
Where do we need to go now? Are there any public health implications?
• Urgent need for more funding of dementia research overall, in particular prevention
• UK has poor record of supporting dementia prevention research. Only 0.1% of Research Council expenditure on dementia since 2006 was for prevention; none from NIHR since 2000
• Ways of promoting the funding of prevention research should be considered
• We need a cultural change in attitudes: instead of almost exclusively focussing dementia research on unravelling disease mechanisms and genetics, we need a more holistic attitude in which the search for risk factors plays an important role
• Identify subgroups of the population at risk, using a simple screening test
• Trials to modify risk factors should be done in two stages:
─ A pilot trial in one centre on people with MCI in which the main end-point is the slowing of brain atrophy; this may help to identify a sub-group that will benefit
─ A larger multicentre trial in MCI, ideally in the vulnerable sub-group, in which the main endpoint is conversion to dementia
• Adopt public health policies based upon the trial results:
─ screening for those at risk, using biomarkers of the risk factors, (e.g. homocysteine)
─ followed by appropriate treatment (e.g. B vitamins)
─ possible public health intervention (e.g. fortification of food with a vitamin)
─ develop ways of encouraging changes in population behaviour towards a better life-style
Evidence suggests that we may be able to reduce the incidence of dementia considerably in the next 15 years, so saving much suffering and a large sum of money.
Example: a trial of high-dose B vitamins in Mild Cognitive Impairment (VITACOG) Douaud, G., et al. Proc Natl Acad Sci U S A (2013) 110: 9523-9528.
• Raised blood levels of the amino acid homocysteine are associated with an increased risk of developing cognitive impairment and later, Alzheimer’s disease
• The main determinant of blood homocysteine is the body’s status of 3 of the B vitamins (folate, vitamins B6 and B12). Homocysteine levels can be lowered by administering these vitamins
• 270 people over 70 with Mild Cognitive Impairment living in the community were recruited. MRI scans were done at recruitment and half participants were given high doses of the 3 B vitamins, half took a placebo tablet. After 2 years, everyone was scanned again
• The two MRI scans were analysed to find the rate of shrinkage (atrophy) of the whole brain
• The rate of brain atrophy in those treated with the B vitamins was on average 30% slower than those taking placebo
• The effect of B vitamin treatment was more marked in those whose blood homocysteine level was highest at baseline; in these people the B vitamins slowed the atrophy by 53%
• At the same time, the rate of decline in several cognitive tests, including memory, was markedly slowed by the B vitamins in those with high starting homocysteine
• The brain scans were analysed in more detail to see which parts of the brain were protected by the B vitamin treatment. The result is shown below; yellow indicates areas with atrophy after 2 years
• In the B vitamin group there was a 90% slowing of brain atrophy in the regions highlighted
• These are the same regions that are atrophied in Alzheimer’s disease
• Thus, it is possible markedly to slow down the disease process in people with raised blood homocysteine levels
• About half the elderly population have such raised levels of homocysteine
• Screening for blood homocysteine would identify those at risk of increased brain atrophy and eventual dementia
• They could be offered treatment with high-dose B vitamins, which are considered safe
This trial shows the feasibility of prevention trials, the importance of selecting a vulnerable subgroup, and establishes the principle that the Alzheimer’s disease process can be slowed down by modifying a risk factor.
Some key references to the literature:
The projected effect of risk factor reduction on Alzheimer's disease prevalence. Barnes, D. E. and K. Yaffe. Lancet Neurol (2011) 10: 819-828.
Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Ahlskog, J. E., et al.. Mayo Clin Proc (2011) 86: 876-884.
Mediterranean diet, cognitive function, and dementia: a systematic review. Lourida, I., et al. Epidemiology (2013) 24: 479-489.
Long-chain omega-3 fatty acids improve brain function and structure in older adults. Witte, A. V., et al.. Cereb Cortex (2013) June, Epub ahead of print.
Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Douaud, G., et al. Proc Natl Acad Sci U S A (2013) 110: 9523-9528.
Nonpharmacologic treatment and prevention strategies for dementia. Yaffe, K. and T. Hoang. Continuum (Minneap Minn) (2013) 19: 372-381.
A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Matthews, F. E., et al., on behalf of the Medical Research Council Cognitive Function and Ageing Study. Lancet (2013). 10.1016/S0140-6736(13)61570-6. Epub ahead of print.
The worldwide economic impact of dementia 2010. Wimo, A., et al. Alzheimer Disease. Alzheimers Dement (2013) 9: 1-11 e13.