How does exercise compare to

other lifestyle interventions?

Leon Flicker

Western Australian Centre for Health & Ageing,

Western Australian Institute of Medical

Research, University of Western Australia

Royal Perth Hospital

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!

Projected number of people with dementia

Source: Calculations by AIHW based on data from Lobo et al. 2000 and

Harvey et al. 2003

Years of Life Lost to Disability

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

Dementia - ICD 10• Syndrome due to disease of the brain

• Usually chronic and progressive - at least 6 months for a confident diagnosis

• Involves a decline in multiple higher cortical functions including memory.

• Should attempt to avoid false positive diagnoses, especially depression.

• Decline in intellectual functioning affecting personal activities.

• No clouding of consciousness (delirium)

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 dementiaSavva et al N Engl J Med 2009; 360:2302

The association between the presence of dementia and

Alzheimer pathology decreases with age

Cognitive Impairment not

Dementia• In a well-conducted community study, (Graham et

al, 1997) the Canadian Study of Health in Ageing,

for people > 65 years this entity was more

common than dementia (16.8% versus 8%)

• Clearly associated with less burden to the affected

individuals and their carers.

• Specific conditions identified included delirium,

alcohol use, drug intoxication, depression,

psychiatric disease, memory impairment

associated with the ageing process and mental

retardation.

Mild Cognitive Impairment • Subjective memory complaints

• Performance on memory functioning < 1.5

SD below mean for age

• Not dementia

• At this stage prognosis uncertain

especially distinguishing between Memory

Clinic versus unselected cases

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.

• There is now good evidence that treating

hypertension reduces the risk of developing

cognitive impairment and dementia.

Risk Factors

Established LikelyOld age Female

Down’s syndrome Head injury

Family history Vascular risk

(some very rare mutations) factors - mid-life

APOE genotype - ε4 genotype hypertension,

AMI etc

Less Likely

- Exposure to electromagnetic radiation

– Exposure to aluminium

– Family history of Down’s

– Hyperhomocysteinemia

– Depression

Protective Factors• ? Likely

Anti-inflammatory Drugs??

Hormone replacement therapy - NO!

Physical Activity

Social engagement

Higher education and intelligence

Ongoing intellectual stimulation

Other dietary factors ? Omega 3, antioxidants

Alcohol

Smoking?? – NOW A RISK FACTOR

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 Possibilities1. 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….

2. 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.

non amyloidogenicamyloidogenic

The Alzheimer Amyloid Precursor protein (APP) - processing

40

42

p3Aß

a

… and AD relevant Aß42 may be generated

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

Time (Months)

Control

Exercise

Usual activity

WALK or

activity

Monitored Unsupervised

0 6 12 18

Unsupervised

Fitness for the Ageing Brain Study Lautenschlager et al JAMA 2008; 300:1027

n= 170 RCT

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 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.

Conclusions

Fitness for the Ageing Brain Study

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 StudyWillis 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.

. Summary of selected case-control studies looking at

the association between ever smoking and AD.

Amaducci et al, 1986

Brenner et al, 1993

Broe et al, 1990

Canadian Study, 1994

Chandra et al, 1987

Graves et al, 1990

vanDuijn et al, 1991

Wang et al, 1999

POOLED OR

6421.8.6.4.2

Favours smoking Favours not smoking

Summary of selected cohort studies looking at the

association between ever smoking AD

Launer et al, 1999

Merchant et al, 1999

Wang et al., 1999

POOLED RR

6421.8.6.4.2

Favours smoking Favours not smoking

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

Placebo Group

(n=149)

Supplements

Group

(n=150)

Difference in mean

(95% Confidence

Interval)

Age 78.68 (2.73) 79.26 (2.71) 0.58 (-0.04, 1.20)

Serum folate

(nmol/L)

24.44 (7.44) 24.00 (7.50) -0.43 (-2.15, 1.28)

Serum B12 (pmol/l ) 253.3 (115.1) 253.1 (107.5) -0.2 (-25.8, 25.4)

Plasma Hcy (mol/l) 13.06 (3.83) 13.59 (4.43) 0.53 (-0.42, 1.47)

Change in Hcy at 24

months

1.4 (3.04) -2.80 (3.61) -4.20 (-5.04, -3.36)

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

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

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

Age (yrs) Dementia numbers (n)

Kimberley Australia

Dementia prevalence rates

Kimberley Australia

Dementia

prevalence

ratio

45-59 4 3539 0.021 0.001 21

60-69 12 12322 0.169 0.0085 19.88

70-79 12 49804 0.176 0.04 3.97

80+ 17 108713 0.567 0.19 3.06

total 45 174377 0.124 0.026 5.2

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 FundingJohn AcresOsvaldo P. Almeida David AtkinsonKay CoxAnna DwyerGriselda GarridoKathryn GreenopGraeme HankeyGary HulseKonrad Jamrozik

Funding: National Health and Medical Research Council

Nicola T. LautenschlagerDavid LawrenceDina LoGiudice Ralph Martins Paul NormanKate SmithKevin TaddeiJenny Thomas Samuel D VasikaranAlex Xiao