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Prevention of Cognitive Impairment: What looks Promising in 2007?. Kristine Yaffe, MD University of California, San Francisco San Francisco VA Medical Center. Projected Prevalence of Alzheimer Disease in the U.S. U.S. Prevalence of AD (millions). Year.

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prevention of cognitive impairment what looks promising in 2007

Prevention of Cognitive Impairment: What looks Promising in 2007?

Kristine Yaffe, MD

University of California, San Francisco

San Francisco VA Medical Center

projected prevalence of alzheimer disease in the u s
Projected Prevalence of Alzheimer Disease in the U.S.

U.S. Prevalence of AD (millions)


Brookmeyer et al. American Journal of Public Health. 1998; 88:1337-1342.

possible strategies for dementia prevention based on risk factor modification
Possible strategies for dementia prevention based on risk factor modification
  • Cardiovascular disease (CVD) risk
  • Obesity/metabolic dysregulation
  • Physical activity
  • Intellectual activity
  • Depression

(While we wait for disease modifying new pharmacological strategies)

cardiovascular risk factors and dementia
Cardiovascular Risk Factors and Dementia
  • Increasing evidence that AD has a vascular component
  • Increasing evidence that dementia is often “mixed” with AD and vascular pathology
  • CVD risk factors may be “modifiable”
  • Control of CVD would be beneficial in multiple organ systems
hypertension and risk of dementia mid life studies
Hypertension and Risk of Dementia: Mid-Life Studies
  • Fairly consistent finding between mid-life HTN and late-life dementia
  • Findings strongest in those without treatment of HTN
  • Supported by neuropath studies with greater plaques and tangles in those with mid-life HTN
hypertension and risk of dementia late life studies
Hypertension and Risk of Dementia: Late-Life Studies
  • Prospective studies with conflicting findings
  • Some suggest increased risk, others no effect and many suggest an inverse association
  • Several studies suggest antihypertensive medications reduce risk of AD
  • Several RCTs of various agents found mixed results on risk of dementia


  • co-morbidity
  • medication
  • genetic
  • predisposition

Underlying Mechanisms



↓ breakdown of


  • Microvascular
  • disease
  • insidious
  • ischemia
  • microinfarcts
  • Glucose
  • toxicity
  • advanced
  • protein
  • glycation
  • oxidative
  • stress
  • Macrovascular
  • disease
  • brain infarcts

Brain pathology

Accelerated aging

Vascular dementia

Alzheimer disease

diabetes and incident dementia
Diabetes and Incident Dementia

Ott, 1996

Leibson, 1997

Yaffe, 2004

Whitmer, 2005











Risk (Odds) Ratio and 95% Confidence Interval

diabetes and risk of ad vs vad
Diabetes and risk of AD vs VAD

Curb, 1999

Luchsinger, 2000

Hassing, 2002

Macknight, 2002

Xu, 2004
















Risk (Odds) Ratio and 95% Confidence Interval



markers of glucose control and cognitive impairment
Markers of Glucose Control and Cognitive Impairment
  • An association between measures of glucose control and incident cognitive impairment would support the causal argument between DM and dementia
  • May suggest pathways for intervention
  • May suggest those at risk (eg secondary prevention)
  • We studied Impaired Fasting Glucose (IFG) and glycosylated hemoglobin (HbA1C)

Diabetes, impaired fasting glucose, & cognitive impairment in 7027 women

Yaffe et al, Neurology 2004


Association of HbA1C and Risk of Developing Cognitive Impairment

Yaffe et al. J Nutr Health Aging 2006

diabetes and dementia summary
Diabetes and Dementia: Summary
  • Most studies suggest an association between diabetes and dementia
  • Stronger association with VaD than AD
  • Markers of glucose control also support the association
  • Need trials aimed at treating diabetes or those at risk and including cognitive outcomes and trials of diabetic agents in MCI and dementia
pilot trial of rosiglitizone for mci
Pilot Trial of Rosiglitizone for MCI

Watson et al. Am J Geriatr Psychiatry 2005.

composite cv risk factors dementia risk
Composite CV Risk Factors & Dementia Risk
  • May be greater than individual components
  • Often occur together (e.g. metabolic syndrome)
  • May have interactions with genetics eg ApoE e4 (Haan M et al Jama 2000)
  • Offer strategies to modify as a group
the metabolic syndrome








The ‘Metabolic Syndrome’

Also known as:

  • Syndrome X
  • Insulin Resistance Syndrome
  • The Deadly Quartet
  • The Dysmetabolic Syndrome
metabolic syndrome prevalence
Metabolic Syndrome Prevalence




Park, Arch Int Med, 2003

metabolic syndrome and inflammation background
Metabolic Syndrome and Inflammation: Background
  • Negative outcomes of the metabolic syndrome may be linked to increased inflammation.
  • Inflammation is associated with AD and cognitive decline as well.
  • Thus, we determined if the metabolic syndrome was associated with cognitive decline and if this was mediated by inflammation.
odds of cognitive decline comparing participants with high vs low level of inflammatory marker
Odds of Cognitive Decline comparing Participants with High vs Low Level of Inflammatory Marker

Yaffe et al, Neurology 2003

metabolic syndrome and cognitive impairment health abc study
Metabolic Syndrome and Cognitive Impairment: Health ABC Study
  • 2949 participants in Health ABC; 43% African-American; followed for 4 years
  • Metabolic syndrome definition  3 criteria (NCEP guidelines):
    • Waist: > 102 cm ♂, > 88 cm ♀
    • HDL: < 40 for men,< 50 for women
    • Triglycerides: ≥ 150 mg/dL
    • BP: ≥ 130/ ≥ 85 (or med use)
    • Fasting glucose: ≥ 110 mg/dL (or med use)
likelihood of cognitive decline metabolic syndrome
Likelihood of Cognitive Decline & Metabolic Syndrome

High Inflammation


Low Inflammation


P for interaction = 0.04

Yaffe et al JAMA 2004

conclusions metabolic syndrome and cognition
Conclusions: Metabolic Syndrome and Cognition
  • Metabolic syndrome is associated with cognitive decline
  • Especially for those with high inflammation
  • Need to determine if reducing metabolic syndrome or inflammation could prevent cognitive decline
  • Need imaging studies to help determine mechanisms
obesity and dementia why is fat bad

Complement Factors

    • Adipsin
    • C3
  • Lipoproteins
    • LPL
    • CETP
    • Apo E
    • PLTP
  • Growth Factors
    • TGF-ß
    • IGF-1
    • VEGF
  • Hormones
  • Leptin
  • Cortisol
  • Estradiol
  • Peptides
  • Adiponectin
  • PAI-1
  • Angiotensinogen
  • Resistin
  • Visfatin
  • Cytokines
  • TNF
  • IL-6
Obesity and Dementia: Why is Fat Bad?



proposed mechanisms linking obesity to dementia
Proposed Mechanisms Linking Obesity to Dementia

Vascular Inflammation

IL-6 & TNF-α










Resistin & Adiponectin


Insulin Resistance

Rosenson, 2005

association between obesity dementia among kaiser patients
Association between Obesity & Dementia among Kaiser Patients

22,612 Kaiser Permanente Subscribers had MHC exam between 1964-73 and were between ages of 40-45

-11,262 who were not members or alive in January 1994

-9 members with incomplete demographic data

713 Diagnosed with Dementia

10,456 No Dementia

obesity and risk of dementia
Obesity and Risk of Dementia

Whitmer R, …Yaffe K; BMJ, 2005.

quintiles of sagittal abdominal diameter and thigh circumference and risk of dementia
Quintiles of Sagittal Abdominal Diameter and Thigh Circumference and Risk of Dementia

Whitmer R….Yaffe K: Under Review

use it or lose it
Use it or Lose it???
  • Physical activity
  • Intellectual activity
intellectual activity cognition potential mechanism
Intellectual Activity & Cognition: Potential Mechanism
  • Hippocampal neurogenesis in mice by long-term environmental enrichment and improved learning


Kempermann, et al 2002


active advanced cognitive training for independent and vital elderly
ACTIVE: Advanced Cognitive Training for Independent and Vital Elderly
  • 2802 non-demented elderly (mean age 74) randomized to cognitive training (memory, reasoning or processing speed) or to unspecified control for 10 week classes
  • Participants received booster training after 11 months
  • Each intervention improved the targeted cognitive ability compared with baseline over 2 yrs. f/up. (p<0.001)

Ball, 2002

summary of 5 year results
Summary of 5-Year Results
  • Effects of training maintained over 5 years
    • Enhanced by ‘booster’ at 3 years
    • Less self-reported difficulty with daily activities in training groups after 5 years

Willis S et al Jama 2006

physical activity cognition potential mechanisms
Physical Activity & Cognition:Potential Mechanisms
  • associated with  mortality, CAD
  •  lipids, HTN and  fitness
  •  cerebral blood flow
  •  neuronal growth in rodents (Gage lab)
  •  inflammatory markers
  • BDNF
decline in age adjusted mmmse over 6 8 years as a function of physical activity
Decline in age-adjusted mMMSE over 6-8 years as a function of physical activity

P<0.001 overall

% Decline on mod MMSE

Quartile of Blocks Walked

Yaffe et al, Arch Intern Med 2001

women with more daytime movement actigraphy have better cognitive performance
Women with more daytime movement (actigraphy) have better cognitive performance

Barnes….Yaffe : Under Review

physical intellectual activity conclusions
Physical & Intellectual Activity: Conclusions
  • Both may prevent cognitive decline
  • Possibly confounded by healthy lifestyle
  • Need for long-term trials to evaluate if physical and intellectual activity prevents cognitive decline or improves MCI or dementia
depressive symptoms and dementia incidence
Depressive Symptoms and Dementia Incidence
  • Growing evidence that depressive symptoms may be a risk factor for dementia
  • Prospective studies
    • Depressive symptoms associated with increased risk of cognitive decline and dementia
  • Meta-analysis
    • Risk of dementia doubled in older adults with depressive symptoms
prospective studies of depression and risk of dementia

Prospective Studies of Depression and Risk of Dementia

Buntix, 1996

Devanand, 1996

Henderson, 1997

Chen, 1999

Palsson, 1999

Geerlings, 2000

Summary estimate












Jorm, 2001

Risk (Odds) Ratio and 95% Confidence Interval



prospective study of depressive symptoms and risk of cognitive decline in older women
Prospective Study of Depressive Symptoms and Risk of Cognitive Decline in Older Women

*Adjusted for age, education, health status, exercise, alcohol, functional status. Adapted from Yaffe et al., Arch Gen Psychiatry, 1999.

potential mechanisms for depression and dementia
Potential Mechanisms for Depression and Dementia
  • Depressive symptoms may reflect:
    • Etiologic risk factor for dementia
    • Early symptom of neurodegeneration
    • Reaction to early cognitive deficits
  • Potential mechanisms for etiology:
    • Vascular (especially frontal-subcortical)
    • Alterations in cortisol regulation
    • Others?
association between depressive symptoms mci is not attributable to vascular factors
Association between Depressive Symptoms & MCI is Not Attributable to Vascular Factors

Depressive Symptoms

Odds Ratio

Barnes D…Yaffe K. Archives of General Psychiatry 2006

  • If association reflects risk factor or early symptom of neurodegeneration:
    • Suggests older adults should be monitored more aggressively for onset of new depressive symptoms.
    • Future studies should determine whether treatment of depressive symptoms reduces risk ofdementia.
current preventative strategies
Current Preventative Strategies
  • Both depression and CV risk factors offer potential avenues for prevention of AD and other dementias
  • Intellectual and physical activity seem promising and low risk!
  • May offer insight into etiology and treatment of AD
  • Need large RCTs!
  • Implications for early and mid-life interventions

"Alice: It would be so nice if something made sense for a change."

(Alice’s Adventures in Wonderland; July4, 1865- Charles L.Dodgson)


Thank You




NIH “Healthy

Brain Initiative”