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.

1997 2007 2017 2027 2037 20470

2

4

6

8

YearYear

U.S

. Pre

vale

nce

of

AD

U

.S. P

reva

len

ce o

f A

D

(mill

ion

s)(m

illio

ns)

Brookmeyer et al. Brookmeyer et al. American Journal of Public Health. American Journal of Public Health. 1998; 88:1337-1342.1998; 88:1337-1342.

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

• 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

• 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

• 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

Underlying Mechanisms

Macrovasculardisease

• brain infarcts

Microvasculardisease

• insidious ischemia• microinfarcts

Glucose toxicity

• advanced protein glycation• oxidative stress

Insulin

↑ secretion↓ breakdown of β amyloid

Brain pathology

Accelerated aging Alzheimer diseaseVascular dementia

Diabetes

• co-morbidity• medication

• geneticpredisposition

Diabetes and Incident Dementia

Dementia

Dementia

MCI

Dementia

Dementia

Ott, 1996

Leibson, 1997

Yaffe, 2004

Whitmer, 2005

.01 1.0 10.05.0

Risk (Odds) Ratio and 95% Confidence Interval

.05

Diabetes and risk of AD vs VAD

Curb, 1999

Luchsinger, 2000

Hassing, 2002

Macknight, 2002

Xu, 2004

VaD

AD

VaD

AD

AD

VaD

AD

VaD

AD

VaD

.01 1.0 10.0

.05 5.0Risk (Odds) Ratio and 95% Confidence Interval

.05 5.0

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)

Glucose Group Women with outcome (%)

MCI & dementia

OR (95% CI)

Normal 273 (5.9)

Impaired Fasting Glucose (>110mg/dL)

22 (10.1) 1.64 (1.03-2.61)

Diabetes 24 (12.1) 1.79 (1.14-2.81)

Trend 1.40 (1.14-1.72)

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

Yaffe et al, Neurology 2004

HbA1C at baseline, per 1% increase

Unadjusted (N=1983)

Age-Adjusted (N=1983)

Multivariate Adjusted* (N=1921)

Mild Cognitive Impairment (MCI)

1.56 (1.21, 2.02)

1.50 (1.14, 1.97)

1.37 (1.00, 1.88)

Any cognitive problem (MCI, dementia, low cognitive score)

1.48 (1.16, 1.90)

1.40 (1.08, 1.83)

1.27 (0.94, 1.73)

*Adjusted for age, education, race, depression, smoking, alcohol, body mass index, history of MI, and raloxifene.

Association of HbA1C and Risk of Developing Cognitive Impairment

Yaffe et al. J Nutr Health Aging 2006

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

Watson et al. Am J Geriatr Psychiatry 2005.

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’

GlucoseIntolerance,

Diabetes

VisceralObesity

Hypertension

Dyslipidemia

Also known as:

– Syndrome X

– Insulin Resistance Syndrome

– The Deadly Quartet

– The Dysmetabolic Syndrome

Metabolic Syndrome Prevalence

0

10

20

30

40

50

60

20 30 40 50 60 70 80

Black White Mex. Am

Park, Arch Int Med, 2003

0

10

20

30

40

50

60

20 30 40 50 60 70 80

Men Women

%

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

0

0.5

1

1.5

2

IL-6 CRP TNF-α

Inflammatory Marker

OR

(±

95

%C

I) fo

r C

og

niti

ve D

ecl

ine

Yaffe et al, Neurology 2003

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

No Metabolic Syndrome N=1534

1.0 1.0

Metabolic Syndrome N=964

1.94 (1.25-3.00) 1.13 (0.87-1.47)

P for interaction = 0.04

High High InflammationInflammationN=618N=618

Low Low InflammatioInflammationnN=1880N=1880

Yaffe et al JAMA 2004

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?

AdiposeTissue

Complement Factors•Adipsin•C3

Growth Factors•TGF-ß•IGF-1•VEGF

Cytokines•TNF•IL-6

Peptides•Adiponectin•PAI-1•Angiotensinogen•Resistin•Visfatin

Hormones•Leptin•Cortisol•Estradiol

Lipoproteins•LPL•CETP•Apo E•PLTP

Proposed Mechanisms Linking Obesity to Dementia

VisceralAdiposetissue

IL-6 & TNF-α

FFAPAI-1

Resistin & Adiponectin

Vascular Inflammation

Dyslipidemia

Hypertension

Insulin Resistance

ReducedThrombolysis

Rosenson, 2005

Dementia

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

10,456 No Dementia

713 Diagnosed

with Dementia

Obesity and Risk of Dementia

Adjusted for age at midlife exam and education

Adjusted for age at midlife exam, age at case ascertainment, education, race, marital status & sex

Adjusted for all + midlife & late life co morbidity*

Body Mass Index-All**

Hazards Ratio (95 % Confidence Interval)

Hazards Ratio (95% Confidence Interval)

Hazards Ratio (95% Confidence Interval)

Obese 1.38(1.10 to 1.72) 1.56(1.24 to 1.96) 1.74(1.34 to 2.26)

Overweight 1.16(1.01 to 1.34) 1.22(1.04 to 1.42) 1.35(1.14 to 1.60)

Underweight 1.41(0.82 to 2.39) 1.46(0.84 to 2.54) 1.24(0.70 to 2.21)

Whitmer R, …Yaffe K; BMJ, 2005.

Quintiles of Sagittal Abdominal Diameter and Thigh Circumference and Risk of Dementia

0.5

1

1.5

2

2.5

3

1 2 3 4 5

Quintiles of SAD and Thigh Circumfrence

Hazard

s R

ati

o o

f D

em

en

tia

SAD FullyAdjusted

SAD FullyAdjusted + BMI

Thigh FullyAdjusted

Thigh FulyAjdusted + BMI

Whitmer R….Yaffe K: Under Review

Use it or Lose it???

• Physical activity

• Intellectual activity

Intellectual Activity & Cognition: Potential Mechanism

• Hippocampal neurogenesis in mice by long-term environmental enrichment and improved learning

Kempermann, et al 2002

P=.002

**P<0.01

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 et.al, 2002

Effect of Training After 1 Year

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Memory Reasoning Speed

Cognitive Function

Dif

fere

nce

fro

m C

on

tro

l (S

Ds)

Memory

Reasoning

Speed

*

*

*

Training Group

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

• 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

00.5

11.5

22.5

33.5

44.5

5

Low Second Third High

Quartile of Blocks Walked

% D

e cl in

e o n

mo d

MM

SE

P<0.001 overall

Yaffe et al, Arch Intern Med 2001

Women with more daytime movement (actigraphy) have better cognitive

performance

115

120

125

130

135

140

145

150

155

160

Lowest Third

Daytime Movement Quartile

Unadjusted

Adjusted

Barnes….Yaffe : Under Review

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

• 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

Buntix, 1996

Devanand, 1996

Henderson, 1997

Chen, 1999

Palsson, 1999

Geerlings, 2000

Summary estimate

Dementia

AD

Dementia

AD

Dementia

AD

.01 1.0 10.0

.05 5.0Jorm, 2001 Risk (Odds) Ratio and 95% Confidence Interval

.5 5.0

Prospective Study of Depressive Symptoms and Risk of Cognitive Decline in Older Women

Adjusted* OR (95% CI)

Cognitive Decline

Number of Depressive Symptoms

No. 0-2 3-5 6

3 MMSE point drop

653 1.00 1.6 (1.2-2.1) 2.1 (1.4-3.1)

Dementia 89 1.00 1.7 (0.9-3.5) 2.3 (0.9-5.9)

*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

• 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

0

0.5

1

1.5

2

2.5

None

Low

HighOd

ds

Rat

io

Depressive Symptoms

Barnes D…Yaffe K. Archives of General Psychiatry 2006

Implications

• 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 of dementia.

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

Recent Studies have Questioned the Following for Prevention:

• Statins

• Vitamin E

• Estrogen

• NSAIDS

"Alice: It would be so nice if something made sense for a change."(Alice’s Adventures in Wonderland; July4, 1865- Charles

L.Dodgson)  

                                                                                                                                                            

     

Thanks….

NIA

NIDDK

NIH “Healthy

Brain Initiative”

NARSAD