Prevention of Cognitive Impairment: What looks Promising in 2007?

1. Prevention of Cognitive Impairment: What looks Promising in 2007? Kristine Yaffe, MD University of California, San Francisco San Francisco VA Medical Center

2. Projected Prevalence of Alzheimer Disease in the U.S. U.S. Prevalence of AD (millions) Year Brookmeyer et al. American Journal of Public Health. 1998; 88:1337-1342.

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. 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. 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. 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. Diabetes • co-morbidity • medication • genetic • predisposition Underlying Mechanisms Insulin ↑secretion ↓ breakdown of βamyloid • Microvascular • disease • insidious • ischemia • microinfarcts • Glucose • toxicity • advanced • protein • glycation • oxidative • stress • Macrovascular • disease • brain infarcts Brain pathology Accelerated aging Vascular dementia Alzheimer disease

8. Diabetes and Incident Dementia Ott, 1996 Leibson, 1997 Yaffe, 2004 Whitmer, 2005 Dementia Dementia MCI Dementia Dementia .01 .05 1.0 5.0 10.0 Risk (Odds) Ratio and 95% Confidence Interval

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 5.0 .01 1.0 10.0 .05 Risk (Odds) Ratio and 95% Confidence Interval .05 5.0

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. Diabetes, impaired fasting glucose, & cognitive impairment in 7027 women Yaffe et al, Neurology 2004

12. Association of HbA1C and Risk of Developing Cognitive Impairment Yaffe et al. J Nutr Health Aging 2006

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. Pilot Trial of Rosiglitizone for MCI Watson et al. Am J Geriatr Psychiatry 2005.

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. Glucose Intolerance, Diabetes Dyslipidemia Hypertension Visceral Obesity The ‘Metabolic Syndrome’ Also known as: • Syndrome X • Insulin Resistance Syndrome • The Deadly Quartet • The Dysmetabolic Syndrome

17. Metabolic Syndrome Prevalence Men Women % Park, Arch Int Med, 2003

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. Odds of Cognitive Decline comparing Participants with High vs Low Level of Inflammatory Marker Yaffe et al, Neurology 2003

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. Likelihood of Cognitive Decline & Metabolic Syndrome High Inflammation N=618 Low Inflammation N=1880 P for interaction = 0.04 Yaffe et al JAMA 2004

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. 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? Adipose Tissue

24. Proposed Mechanisms Linking Obesity to Dementia Vascular Inflammation IL-6 & TNF-α Dyslipidemia Visceral Adipose tissue Reduced Thrombolysis PAI-1 FFA Hypertension Resistin & Adiponectin Dementia Insulin Resistance Rosenson, 2005

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 713 Diagnosed with Dementia 10,456 No Dementia

26. Obesity and Risk of Dementia Whitmer R, …Yaffe K; BMJ, 2005.

27. Quintiles of Sagittal Abdominal Diameter and Thigh Circumference and Risk of Dementia Whitmer R….Yaffe K: Under Review

28. Use it or Lose it??? • Physical activity • Intellectual activity

29. Intellectual Activity & Cognition: Potential Mechanism • Hippocampal neurogenesis in mice by long-term environmental enrichment and improved learning P=.002 Kempermann, et al 2002 **P<0.01

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. Effect of Training After 1 Year * Training Group * *

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. 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. 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

35. Women with more daytime movement (actigraphy) have better cognitive performance Barnes….Yaffe : Under Review

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. 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. 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 .5 1.0 5.0 10.0 Jorm, 2001 Risk (Odds) Ratio and 95% Confidence Interval .05 5.0

39. 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.

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. Association between Depressive Symptoms & MCI is Not Attributable to Vascular Factors Depressive Symptoms Odds Ratio Barnes D…Yaffe K. Archives of General Psychiatry 2006

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 ofdementia.

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. Recent Studies have Questioned the Following for Prevention: • Statins • Vitamin E • Estrogen • NSAIDS

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. Thank You Thanks…. NIA NIDDK NIH “Healthy Brain Initiative” NARSAD