Prevention of dementia Leon Flicker Western Australian Centre for Health & Ageing, Western Australian Institute of Medical Research, University of Western Australia Royal Perth Hospital

Overview Why prevention of cognitive decline and dementia are important but recent assistance provided by the NIH has been counterproductive Antihypertensives and 6 lifestyle influences Physical activity Education & cognitive stimulation Social engagement Smoking Diet Alcohol

What would happen if there is a constant improvement in life expectancy? Men Women

Projected populations – pyramid to coffin? Not just an increase in life expectancy but migration!

Years of Life Lost to Disability

Global prevalence of dementia Ferri et al, Lancet 2005; 366:2112

Alzheimer’s Disease & Vascular Dementia - Are they distinct diagnoses? Small strokes are a frequent accompaniment of ageing. Whether these strokes produce significant cognitive impairment is debatable. Recent studies indicate that leukoariosis is associated with definite and perceptible changes in memory. AD and VD may share other risk factors in addition to ageing such as systolic blood pressure. Midlife systolic BP has been shown to be associated with cognitive decline, decreased brain volume, and increased white matter hyperintensities. This suggests that chronic high blood pressure may have consequences that are not limited to cerebrovascular disease.

The “Alzheimerization” of dementia This is the idea that dementia is nearly all due to Alzheimer’s Disease There are comparatively little data to support this. Reports have increasingly found less correlation of Alzheimer pathology with dementia than the original report, Blessed et al Br J Psych 1968; 114:797

Association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects Blessed et al B J Psych1968; 114:797

Age, neuropathology and dementia Savva et al N Engl J Med 2009; 360:2302 The association between the presence of dementia and Alzheimer pathology decreases with age

Preventing Dementia – An Unobtainable Goal? Wrong! It is often said (by all sorts of commentators some of whom should know better) that dementia is an unavoidable consequence of ageing.

Conclusions from the NIH (2010) Currently, firm conclusions cannot be drawn about the association of any modifiable risk factor with cognitive decline or Alzheimer’s disease. Highly reliable consensus-based diagnostic criteria for cognitive decline, mild cognitive impairment, and Alzheimer’s disease are lacking, and available criteria have not been uniformly applied. Evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease.

NIH Suggestions for Future Research For example, ongoing studies including (but not limited to) studies on antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement may provide new insights into the prevention or delay of cognitive decline or Alzheimer’s disease. Large-scale population-based studies and RCTs are critically needed to investigate strategies to maintain cognitive function in individuals at risk for decline, to identify factors that may delay the onset of Alzheimer’s disease among persons at risk, and to identify factors that may slow the progression of Alzheimer’s disease among persons in whom the condition is already diagnosed.

Universal or Targeted? There are three main considerations in evaluation of interventions in the prevention of dementia. Efficacy Risks or side-effects, cost. These three facets will determine whether the intervention will eventually be made available universally, or targeted at a high risk group.

Spectrum of Possibilities We will develop a series of interventions which will be effective, cheap and these interventions will not be prone to side-effects. We will then provide these interventions universally e.g. BP treatment, vitamins, physical activity, smoking cessation, cognitive stimulation…. The major disease process causing dementia is a single disease process, called Alzheimer Disease. This disease process has a stable pathogenic pathway with specific inhibitors. It is thus possible to devise a specific strategy to target those individuals who are highly likely to develop the disease.

… and AD relevant Aß42 may be generated The Alzheimer Amyloid Precursor protein (APP) - processing … and AD relevant Aß42 may be generated  a Aß  p3 40 The 2 amino acid long fragment (light red) has never been reported and may very well not exist in nature. 42 amyloidogenic non amyloidogenic

The NIA and Alzheimers Association convened three separate working groups to “address recent advances in AD” http://www.alz.org/research/diagnostic_criteria/

The Evidence Free Zone

The Evidence Free Zone What is happening here

What does the evidence show? Aβ 42

Anti-hypertensives A recent systematic review (Peters et al, HYVET-COG Lancet Neurol 2008; 7:683–9) included one additional randomized trial to the Cochrane meta-analysis and demonstrated a 13% reduction in the rate of incident dementia with the use of anti-hypertensives. This may be the best evidence that we will ever obtain on this subject due to the bias to the null hypothesis because of the large number of control subjects who require treatment with antihypertensives The experience from the HYVET study that these trials are no longer able to be performed in the developed world because of the understandable reluctance of clinicians to randomize hypertensive older people to placebo.

Physical Activity Laurin et al. (2001) explored the relationship between physical activity and cognitive impairment in 4615 community dwellers participating in the Canadian Study of Health and Aging who were followed-up for 5 years. High activity levels were associated with reduced risk of cognitive impairment (OR=0.58, 95% CI 0.41-0.83), AD (OR=0.50, 95% CI 0.28-0.90), and dementia of any type (OR=0.63, 95% CI 0.40-0.98).

Systematic review of physical activity and dementia Hamer and Chida Psychological Medicine 2009 39:3

Cochrane Review (Angevaren M et al 2008) Mean Duration 14 weeks Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment (up to 12/05) Visual Attention

Fitness for the Ageing Brain Study Lautenschlager et al JAMA 2008; 300:1027 n= 170 RCT Control Usual activity Unsupervised WALK or activity Exercise Monitored Unsupervised Time (Months) 6 12 18

Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer’s Disease: Randomized Trial. Lautenschlager et al JAMA 2008; 300:1027

The intervention is simple and safe. Fitness for the Ageing Brain Study Conclusions The intervention resulted in 142 min more physical activity per week (20 min per day or 9000 steps/week) compared to usual care. The improvement on the ADAS cog score is modest, 1.3 points on the ADAS-cog but remarkable considering the amount of physical activity undertaken. The benefits were apparent after 6 months and persisted for at least another 12 months after the end of the supervised intervention. The intervention is simple and safe. Physical activty is a modifiable lifestyle factors which might be able help to delay the clinical onset and progression of cognitive decline.

Education & Cognitive Stimulation In a longitudinal cohort study of 801 older Catholic nuns, priests and brothers without dementia, cognitively stimulating activities were documented at baseline and the cohort followed-up for 4.5 years (Wilson et al., 2002). A 1-point increase in the cognitive activity score was associated with reduced decline in global cognition (by 47%), working memory (by 60%) and perceptual speed (by 30%), and a 33% reduction in the risk of AD (hazard ratio, 0.67, 95% CI 0.49-0.92). Cognitive reserve or protection (future proof)?

Predicted 12-year paths of change in global cognition in persons with 8, 12, or 16 years of education (Chicago Health and Aging Project Wilson et al 2009) Cognitive Reserve?

Cognitive Stimulation The effect of cognitive training on normal older people has also been reviewed (Valenzuela & Sachdev AJGP 2009) . Seven studies were included in the meta-analysis with six of these studies using neuropsychological tests as the main outcomes. There were positive results seen in these studies but the results of these neuropsychological tests in normal older people are difficult to extrapolate to everyday function or to prevention of dementia.

ACTIVE Study Willis et al JAMA 2006; 296:2805

Here we report the results of a six-week online study in which 11,430 participants trained several times each week on cognitive tasks designed to improve reasoning, memory, planning, visuospatial skills and attention. Although improvements were observed in every one of the cognitive tasks that were trained, no evidence was found for transfer effects to untrained tasks, even when those tasks were cognitively closely related

Social engagement It has been demonstrated that rodents reared in “enriched” environments have enhanced cognitive abilities in spatial and non spatial memory tests and enhanced hippocampal neurogenesis . In humans some studies found no association whereas associations were founds with diverse factors, e.g. social disengagement, emotional support, social and “productive” activities. Six studies examined the association between social networks and the onset of dementia, the studies often found diverse associations. E.g. The relationships studied included never married as opposed to number of social contacts or quality of social networks.

SMOKING Summary of selected case-control studies looking at the association between ever smoking and AD. Favours smoking Favours not smoking

Summary of selected cohort studies looking at the association between ever smoking AD Favours smoking Favours not smoking

Smoking Is Associated With Reduced Cortical Regional Grey Matter Density In Brain Areas Associated With Incipient Alzheimer’s Disease Smokers showed decreased grey matter density relative to controls in the posterior cingulate and precuneus (Figure A), as well as the left parahippocampal gyrus (Figure B).

Summary We are what we Eat! Largely we rely on observational data The effect of micronutrient supplements may not be the same as that obtained from foodstuffs Vitamin E supplements in high doses may have risks and no micronutrient has been demonstrated in RCT to prevent dementia. Saturated fat may also have risks, possibly associated with obesity. What we drink may also be good for us!!

Pathogenesis of Hcy

Framingham Study

Baseline and Changes of Hcy at 24 months for the intervention and placebo groups

Changes in Aβ1-40 over 24 months (pg/ml) There have been 2 recently reported studies, one +ve and one -ve, examining cognitive outcomes with tHcy lowering supplements

A Controlled Trial of Homocysteine Lowering and Cognitive Performance NEJM 2006; 354: 2764

Durga et al Lancet 2007; 369:208

Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial (Smith et al 2010 PLoS ONE 5:9) The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001).

Results of prospective studies of antioxidants as a protection factor for AD, dementia or cognitive decline (Jorm 2002)

Miller, E. R. et. al. Ann Intern Med 2005;142:37-46 Mortality of low and high dose Vitamin E Miller, E. R. et. al. Ann Intern Med 2005;142:37-46

Association between alcohol consumption at baseline and follow-up MMSE 6 years later in 80+ year old men in Perth Cognitive impairment MMSE < 24

Alcohol, dementia and cognitive decline in the elderly: A systematic review (Peters R et al Age and ageing 2008)

Other dietary factors Barbreger-Gateau et al. (2002) reported data from the PAQUID study that followed-up a French cohort of 1416 older adults for up to 7 years. Participants who ate seafood at least once a week had a reduced risk of developing dementia (OR = 0.7, 95% CI 0.5-0.9). This “protective” effect was partly explained by higher education levels of seafood consumers. One hypothesis to explain this effect is that the n-3 fatty acids contained in fish oil reduce inflammatory processes in the brain.

The Kimberley region 65% of the total population of 32,625 live in very remote areas, 47% of the population are Indigenous Contains over 200 remote Indigenous communities and six larger towns Cross-sectional, point prevalence, 367 people, all community members 45 years or older. Selection and training of indigenous health workers. Assessment with KICA. Within 3 months: clinical assessment of selected participants (100% with scores <37, 50% of 37 and 5% of subjects with 38-40) by geriatrician or psychogeriatrician, then consensus diagnosis

Dementia Prevalence in Kimberley Indigenous people Indigenous Australians may be exhibiting a preventable disease 20 years before Non-Indigenous Australians and may reflect a multitude of deleterious risk factors

Collaborators and Funding John Acres Osvaldo P. Almeida David Atkinson Kay Cox Anna Dwyer Griselda Garrido Kathryn Greenop Graeme Hankey Gary Hulse Konrad Jamrozik Funding: National Health and Medical Research Council Nicola T. Lautenschlager David Lawrence Dina LoGiudice Ralph Martins Paul Norman Kate Smith Kevin Taddei Jenny Thomas Samuel D Vasikaran Alex Xiao