Prevention of Cognitive Impairment:
What looks Promising in 2007?
Kristine Yaffe, MD
University of California, San Francis...
Projected Prevalence
of Alzheimer Disease in the U.S.
1997 2007 2017 2027 2037 2047
0
2
4
6
8
YearYear
U.S.PrevalenceofADU...
Possible strategies for dementia
prevention based on risk factor
modification
• Cardiovascular disease (CVD) risk
• Obesit...
Cardiovascular Risk Factors and
Dementia
• Increasing evidence that AD has a
vascular component
• Increasing evidence that...
Hypertension and Risk of
Dementia: Mid-Life Studies
• Fairly consistent finding between mid-life
HTN and late-life dementi...
Hypertension and Risk of
Dementia: Late-Life Studies
• Prospective studies with conflicting
findings
• Some suggest increa...
Underlying Mechanisms
Macrovascular
disease
• brain infarcts
Microvascular
disease
• insidious
ischemia
• microinfarcts
Gl...
Diabetes and Incident Dementia
Dementia
Dementia
MCI
Dementia
Dementia
Ott, 1996
Leibson, 1997
Yaffe, 2004
Whitmer, 2005
....
Diabetes and risk of AD vs VAD
Curb, 1999
Luchsinger, 2000
Hassing, 2002
Macknight, 2002
Xu, 2004
VaD
AD
VaD
AD
AD
VaD
AD
...
Markers of Glucose Control and
Cognitive Impairment
• An association between measures of glucose
control and incident cogn...
Glucose Group Women with outcome (%)
MCI & dementia
OR (95% CI)
Normal 273 (5.9)
Impaired Fasting
Glucose
(>110mg/dL)
22 (...
HbA1C at baseline,
per 1% increase
Unadjusted
(N=1983)
Age-Adjusted
(N=1983)
Multivariate
Adjusted*
(N=1921)
Mild Cognitiv...
Diabetes and Dementia: Summary
• Most studies suggest an association
between diabetes and dementia
• Stronger association ...
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. metabol...
The ‘Metabolic Syndrome’
Glucose
Intolerance,
Diabetes
Visceral
Obesity
Hypertension
Dyslipidemia
Also known as:
– Syndrom...
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
2...
Metabolic Syndrome and
Inflammation: Background
• Negative outcomes of the metabolic
syndrome may be linked to increased
i...
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-...
Metabolic Syndrome and Cognitive
Impairment: Health ABC Study
• 2949 participants in Health ABC; 43% African-
American; fo...
Likelihood of Cognitive Decline &
Metabolic Syndrome
No Metabolic
Syndrome N=1534
1.0 1.0
Metabolic
Syndrome N=964
1.94 (1...
Conclusions:
Metabolic Syndrome and Cognition
• Metabolic syndrome is associated
with cognitive decline
• Especially for t...
Obesity and Dementia: Why is Fat Bad?
Adipose
Tissue
Complement Factors
•Adipsin
•C3
Growth Factors
•TGF-ß
•IGF-1
•VEGF
Cy...
Proposed Mechanisms Linking Obesity to
Dementia
Visceral
Adipose
tissue
IL-6 & TNF-α
FFAPAI-1
Resistin & Adiponectin
Vascu...
Association between Obesity & Dementia
among Kaiser Patients
22,612 Kaiser Permanente Subscribers had MHC exam
between 196...
Obesity and Risk of Dementia
Adjusted for age at
midlife exam and
education
Adjusted for age at
midlife exam, age at
case ...
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
Quintile...
Use it or Lose it???
• Physical activity
• Intellectual activity
Intellectual Activity & Cognition:
Potential Mechanism
• Hippocampal neurogenesis in mice by long-term
environmental enric...
ACTIVE: Advanced Cognitive Training
for Independent and Vital Elderly
• 2802 non-demented elderly (mean age 74)
randomized...
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
DifferencefromC...
Summary of 5-Year Results
• Effects of training maintained over 5 years
– Enhanced by ‘booster’ at 3 years
– Less self-rep...
Physical Activity & Cognition:
Potential Mechanisms
• associated with ↓ mortality, CAD
∀↓ lipids, HTN and ↑ fitness
∀↑ cer...
Decline in age-adjusted mMMSE over 6-8 years as a
function of physical activity
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Low Second...
Women with more daytime movement
(actigraphy) have better cognitive
performance
115
120
125
130
135
140
145
150
155
160
Lo...
Physical & Intellectual Activity: Conclusions
• Both may prevent cognitive decline
• Possibly confounded by healthy lifest...
Depressive Symptoms and
Dementia Incidence
• Growing evidence that depressive
symptoms may be a risk factor for dementia
•...
Prospective Studies of Depression
and Risk of Dementia
Buntix, 1996
Devanand, 1996
Henderson, 1997
Chen, 1999
Palsson, 199...
Prospective Study of Depressive Symptoms
and Risk of Cognitive Decline in Older
Women
Adjusted* OR (95% CI)
Cognitive
Decl...
Potential Mechanisms for
Depression and Dementia
• Depressive symptoms may reflect:
– Etiologic risk factor for dementia
–...
Association between Depressive Symptoms
& MCI is Not Attributable to Vascular Factors
0
0.5
1
1.5
2
2.5
U
nadjusted
D
em
o...
Implications
• If association reflects risk factor or early
symptom of neurodegeneration:
–Suggests older adults should be...
Current Preventative Strategies
• Both depression and CV risk factors offer
potential avenues for prevention of AD and oth...
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- Charl...
Thanks….
NIA
NIDDK
NIH “Healthy
Brain Initiative”
NARSAD
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  • <number>
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    These data come from the NHANES III data. Approximately 1/4 of the US adults meet the diagnostic criteria for MS.
    The prevalence of Met Sx varies among ethnic groups: Lowest rate of 13.9% in black men to the highest of 27.2% in Mex Am women.
    The prevalence of Met Sx increases with age…peak levels in 6th decade for men and 7th decade for women. This isn’t surprising since aging is associated with increased IR and increased visceral adiposity, both important in the pathogenesis of the MS.
    These ethnic differences persist even after adjustment for other contributing factors such as age, BMI, smoking, drinking habits, SES, physical inactivity, and menopausal status.
    An important question this raises is whether the uniform cut-off points and the equal weighting applied to each of the criteria for the Met Sx by the NCEP is adequate? The strength and cut-point of a risk factor may vary by ethnic group.
  • <number>
  • <number>
  • Depressive symptoms and dementia often co-occur and, in fact, at least 30% of dementia patients also have depressive symptoms
    There also is growing evidence that depressive symptoms may be a precursor to dementia in some older adults
    Several longitudinal studies have found that depressive symptoms are associated with increased risk of dementia in older adults
    In addition, a meta-analysis has concluded that the risk of dementia is approximately doubled in older adults with depressive symptoms
  • With respect to our primary objective, we found that depressive symptoms at baseline were associated with an increased risk of MCI
    This slide shows that, in subjects with low depressive symptoms at baseline, 10% developed MCI, compared to 13.3% in those with moderate depressive symptoms and 19.7% in those with high depressive symptoms
    In addition, the odds of MCI were significantly increased by 38% in subjects with moderate depressive symptoms and were more than doubled in subjects with high depressive symptoms.
  • However, the nature of the association between depressive symptoms and dementia remains controversial.
    In particular, it is unclear whether depressive symptoms reflect an etiologic risk factor for dementia, an early symptom of neurodegeneration, or a reaction to early cognitive deficits.
    For example, some studies have found that depressive symptoms coincide with or follow dementia onset, but do not precede it.
    It is important to clarify the nature of the association between depressive symptoms and dementia for several reasons
    If depressive symptoms are truly a risk factor or early symptom of dementia in some elders, then perhaps older adults should be monitored more closely or treated mor aggressively for new depressive symptoms
  • However, the association between depressive symptoms and MCI was not attributable to underlying vascular disease.
    This slide shows the odd ratio for MCI for subjects with low depressive symptoms, shown in white, moderate depressive symptoms, shown in grey and high depressive symptoms, shown in black.
    The left hand figure shows the unadjusted association, and you can see that the odds ratio was about 1.4 for moderate depressive symptoms and more than 2 for high depressive symptoms.
    Next you see these odds ratios adjusted for demographic factors, vascular events, subclinical vascular disease, MRI evidence of vascular disease and all variables, and you can see that the odds ratios are not changed appreciably by adjustment.
    In addition, the association between depressive symptoms and MCI was similar in subjects with and without a history of vascular disease.
  • However, the nature of the association between depressive symptoms and dementia remains controversial.
    In particular, it is unclear whether depressive symptoms reflect an etiologic risk factor for dementia, an early symptom of neurodegeneration, or a reaction to early cognitive deficits.
    For example, some studies have found that depressive symptoms coincide with or follow dementia onset, but do not precede it.
    It is important to clarify the nature of the association between depressive symptoms and dementia for several reasons
    If depressive symptoms are truly a risk factor or early symptom of dementia in some elders, then perhaps older adults should be monitored more closely or treated mor aggressively for new depressive symptoms
  • "Prevention of Cognitive Impairment: Promising Directions in 2007"

    1. 1. Prevention of Cognitive Impairment: What looks Promising in 2007? Kristine Yaffe, MD University of California, San Francisco San Francisco VA Medical Center
    2. 2. Projected Prevalence of Alzheimer Disease in the U.S. 1997 2007 2017 2027 2037 2047 0 2 4 6 8 YearYear U.S.PrevalenceofADU.S.PrevalenceofAD (millions)(millions) Brookmeyer et al.Brookmeyer et al. American Journal of Public Health.American Journal of Public Health. 1998; 88:1337-1342.1998; 88:1337-1342.
    3. 3. 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)
    4. 4. 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
    5. 5. 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
    6. 6. 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
    7. 7. Underlying Mechanisms Macrovascular disease • brain infarcts Microvascular disease • 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 • genetic predisposition
    8. 8. 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
    9. 9. 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
    10. 10. 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)
    11. 11. 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
    12. 12. 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
    13. 13. 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
    14. 14. Pilot Trial of Rosiglitizone for MCI Watson et al. Am J Geriatr Psychiatry 2005.
    15. 15. 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
    16. 16. The ‘Metabolic Syndrome’ Glucose Intolerance, Diabetes Visceral Obesity Hypertension Dyslipidemia Also known as: – Syndrome X – Insulin Resistance Syndrome – The Deadly Quartet – The Dysmetabolic Syndrome
    17. 17. 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 %
    18. 18. 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.
    19. 19. 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%CI)for CognitiveDecline Yaffe et al, Neurology 2003
    20. 20. 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)
    21. 21. 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 HighHigh InflammationInflammation N=618N=618 LowLow InflammationInflammation N=1880N=1880 Yaffe et al JAMA 2004
    22. 22. 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
    23. 23. Obesity and Dementia: Why is Fat Bad? Adipose Tissue Complement Factors •Adipsin •C3 Growth Factors •TGF-ß •IGF-1 •VEGF Cytokines •TNFα •IL-6 Peptides •Adiponectin •PAI-1 •Angiotensinogen •Resistin •Visfatin Hormones •Leptin •Cortisol •Estradiol Lipoproteins •LPL •CETP •Apo E •PLTP
    24. 24. Proposed Mechanisms Linking Obesity to Dementia Visceral Adipose tissue IL-6 & TNF-α FFAPAI-1 Resistin & Adiponectin Vascular Inflammation Dyslipidemia Hypertension Insulin Resistance Reduced Thrombolysis Rosenson, 2005 Dementia
    25. 25. 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
    26. 26. 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.
    27. 27. 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 HazardsRatioofDementia SAD Fully Adjusted SAD Fully Adjusted + BMI Thigh Fully Adjusted Thigh Fuly Ajdusted + BMI Whitmer R….Yaffe K: Under Review
    28. 28. Use it or Lose it??? • Physical activity • Intellectual activity
    29. 29. Intellectual Activity & Cognition: Potential Mechanism • Hippocampal neurogenesis in mice by long-term environmental enrichment and improved learning Kempermann, et al 2002 P=.002 **P<0.0
    30. 30. 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
    31. 31. 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 DifferencefromControl(SDs) Memory Reasoning Speed * * * Training Group
    32. 32. 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
    33. 33. 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
    34. 34. Decline in age-adjusted mMMSE over 6-8 years as a function of physical activity 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Low Second Third High Quartile of Blocks Walked %DeclineonmodMMSE P<0.001 overall Yaffe et al, Arch Intern Med 2001
    35. 35. Women with more daytime movement (actigraphy) have better cognitive performance 115 120 125 130 135 140 145 150 155 160 Lo we s t T hird D a ytim e M o v e m e nt Q ua rtile Una djus te d A djus te d Barnes….Yaffe : Under Review
    36. 36. 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
    37. 37. 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
    38. 38. 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
    39. 39. 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.
    40. 40. 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?
    41. 41. Association between Depressive Symptoms & MCI is Not Attributable to Vascular Factors 0 0.5 1 1.5 2 2.5 U nadjusted D em ographics V ascular E vents S ubclinicalV ascular M R IV ascular A ll None Low High OddsRatio Depressive Symptoms Barnes D…Yaffe K. Archives of General Psychiatry 2006
    42. 42. 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.
    43. 43. 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
    44. 44. Recent Studies have Questioned the Following for Prevention: • Statins • Vitamin E • Estrogen • NSAIDS
    45. 45. " Alice: It would be so nice if something made sense for a change. " (Alice’s Adventures in Wonderland; July4, 1865- Charles L.Dodgson)
    46. 46. Thanks…. NIA NIDDK NIH “Healthy Brain Initiative” NARSAD

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