Dementia Prevention: Pills vs. S neakers

1. Dementia Prevention: Pills vs. Sneakers Prasad R. Padala, MD, MS, FACHEAssociate Director for Clinical Programs VISN 16/CAVHS Geriatric Research Education and Clinical Center (GRECC) Associate Professor of Psychiatry and Geriatrics, UAMS

2. Disclosure of Conflict • None • All medication use discussed in this presentation is off-label

3. Goals and Objectives By the end of the conference audience will learn: • Discuss the prevalence of dementia • Review the impact of dementia • Discuss modifiable mid-life risk factors for dementia • Discuss current evidence on strategies to prevent dementia

4. Prevalence of dementia • 24.3 million worldwide in 2001 • 81.1 million by 2040 and doubling every 20 years • For people over age 60 • 2.6% Africa • 4% Asia • 6.2% Europe • 6.9% North America

5. AD • > 5 million Americans with AD • 6th leading cause of death • In 2012, 15.4 million caregivers provided more than 17.5 billion hours of unpaid care ( $216 billion) • In 2013, Alzheimer's will cost the nation $203 billion • $1.2 trillion by 2050

6. How do you diagnose • Clinical • Multi-disciplinary teams: “Memory clinics” • Detailed neuropsych testing • Detailed medical history and physical • Detailed behavioral assessments • Detailed social work and pharmacy assessment • Labs • Neuro-imaging

7. Natural history to differentiate types Case 1: 87 year old white male presenting with 10 years history Gradual onset STM > LTM On probing: Loss of smell about 10 years ago Repetitiousness, misplacing items, progressively needing more help with ADL Case 2: 76 year old AA male Sudden onset of memory problems on 7/7/2003 Went to the ER and found out that he had a stroke Was fine for two years and had another dip in memory in 2005 after TIA Case 3: 69 year old WM. Multiple altercations for insensitive comments. Recently made an inappropriate sexual comment on wife’s friend Family regarding his memory “Seems just fine”. Waxing and waning. Frontal release signs on exam

8. Neuropathologic ChangesCharacteristic of Alzheimer’s Disease Normal AD NFT AP AP = amyloid plaques. NFT = neurofibrillary tangles. Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation.

9. But what is clinical reality? • Not all patients with Amyloid burden clinically present with AD features • Treatments focused on amyloid reduction do not change clinical picture • Vascular component in AD pathology • Autopsy • Imaging • Biological • More mixed picture than believed

10. Impact of AD • Global burden for those above age 60 years • Disability years attributable to • Dementia (11.2%) • Stroke (9.5%) • Musculoskeletal disease (8.9%) • Cardiovascular disease (5%) • All forms of cancer (2.4%)

11. Behavioral Symptoms of AD Range (%) Median (%) Apathy 40-80 70% Hallucinations 21–49 28 Delusions 10–73 33 Agitation—global 10–90 44 Agitation—wandering 0–50 18 Verbal aggression 11–51 24 Physical aggression 0–46 14 Resistive/uncooperative 27–65 14

12. Burden of BPSD • 30% of the total annual costs of AD are invested in the direct management of BPSD • Patients with behavioral symptoms need significantly greater formal, informal and total direct costs than those without the behavioral symptoms • A difference up to $16,141/patient year

13. Why prevent • Approved meds for AD • Modest benefit in cognitive domains • Modest benefit in BPSD • Typically slowing the worsening of symptoms only 6-12 months at best • Prevention strategies also work for BPSD

15. Risk factors • Age • Risk for both AD and VaD doubling every five years after age 65 • Apo E4 • 3-4 fold increase in AD • Modifiable (50%) • Diabetes • HTN • Obesity • Inactivity • Smoking • Depression/PTSD/Apathy

16. When do we need to act? Villemagne et al. Lancet 2013

17. Who to target? At-Risk population • Genetic risk factors • Apo E4 • ABCA7 genotype • Lipid homeostasis • OR of 1.79 for African Americans • Family history • Washington University • Wisconsin ADRC • Behavioral risk factors • Apathy • Midlife risk factors • Diabetes • Obesity • HTN • Dyslipidemia Reitz et al. JAMA; 2013: 309, 1483-92

18. Obesity • Midlife • BMI > 30: Doubled risk for AD in later life • BMI 25-30: 35% increased risk • Late life • Weight loss often seen as risk for AD or early presentation of AD

19. Diabetes/Metabolic syndrome • 2-5 fold increased risk of AD • Adult children of AD patients • Mean age 60 years • Overwhelmingly white • Brain effects of Insulin Resistance (HOMA-IR) • Brain Volume: Reduced grey volume at baseline and greater atrophy over 4 years • Cognitive function: IR associated with worse RAVLT learning • Brain effects of metabolic syndrome • Reduced CBF in frontal and parietal cortices • Cognitive function: worse Immediate memory Birdsillet al. (2013). Obesity, 21(7):1313-20 Willette et al. (2013). Diabetes Care, 36(2):443-9

20. Memory in Diabetes (MIND) • Memory and Diabetes Study (ACCORD MIND) 40 months • Intensive control of diabetes (Launer et al. Lancet Neurol. 2011; 10: 969-77) • 52 clinical sites, 2977 patients, mean age 62.5 years • No difference on Digit Symbol Substitution Test (DSST) • Treatment group had bigger total brain volume (TBV)

21. Hypertension • Midlife • Increased risk of dementia in four longitudinal studies • Associated with thinning of cortex • High DBP was associated with increased amyloid deposition • Latelife • Inverse association

22. Treatment of HTN to prevent dementia • Meta analysis of 19 randomized trials examining effect of antihypertensive therapy • Benefiton Cognition Effect size 0.05 CI: 0.02-0.07 (Levi Marpillat et al. J. Hypertens 2013; 31: 1073-82) • Reduce risk of all-cause dementia 9%

23. What are the benefits of changing lifestyle for those with genetic predisposition? • ApoE4 + HTN • RR for impaired cognition was 13 in individuals with HTN • RR reduced to 2 with effective HTN treatment • ApoE4 + HTN • Increased amyloid deposition in poorly controlled HTN • Reduced amyloid deposition in well controlled BP

24. Hyperlipidemia • Midlife • Increased risk of both AD and VaD • Increased amyloid deposition • Latelife • Inverse

25. Multi-Vitamins • Most commonly used dietary supplement in the United States • taken by more than one-third of Americans • vitamins C, E and beta-carotene may protect from oxidative damage • B-vitamins the synthesis of neurotransmitters, DNA, and neuronal membrane, and prevent the accumulation of homocysteine, a risk factor for cognitive decline • Vitamin A plays a role in neuronal survival and synaptic plasticity in the hippocampus

27. PHS II • Randomized, double-blind, placebo-controlled • 2×2×2×2 factorial • Beta-carotene, vitamin E, ascorbic acid, and a multivitamin • Prevention of chronic diseases • 14,641 male physicians aged ≥50 years • A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. • The secondary endpoint was a verbal memory score combining 4 tests of verbal memory, a strong predictor of Alzheimer disease. • No difference in the mean cognitive change over time between the multivitamin and placebo groups • No difference in the mean level of cognition at any of the four assessments

28. Behavioral problems • PTSD • Twice the rates of dementia • Depression • Apathy

29. Apathy • The most common of the BPSD • One of the earliest behavioral problem to appear in AD • Perhaps the most persistent of all the behavioral problems • Causes most disturbance to caregivers and • Has the greatest impact on a patient’s function Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry ClinNeurosci 1991; 3(3):243-254.

30. Apathy as a behavioral marker • Apathy is a behavioral marker for rapid progression of AD • ApoE epsilon4 allele • Greater neurofibrillary tangle burden in the anterior cingulate • Faster progression of cognitive, and functional impairment Starkstein SE, Jorge R, Mizrahi R, Robinson RG. A prospective longitudinal study of apathy in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):8-11. Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic correlates of apathy in Alzheimer's disease. Dement GeriatrCognDisord. 2006;21(3):144-7.

31. Apathy and conversion to dementia • 7 times higher rates of conversion to dementia • 131 patients with amnestic MCI • Apathetic patients had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy (HR=6.9; 2.3-20.6) • The risk of developing AD increased 30% per point on the NPI apathy item • There was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression. • Palmer K, Di Iulio F, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Spalletta G. Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer's disease: the role of depression and apathy. J Alzheimers Dis. 2010;20(1):175-83.

32. Interventions that impact multiple risk factors

33. Education • Marker of Cognitive reserve • In a cohort of 500 patients with MCI, those with higher education were resistant to the harmful effects of WML on cognition • Protection against clinical presentation of memory problems independent of CSF amyloid levels

35. Physical Activity: Four dimensions • Duration (minutes/hours) • Frequency (time per week/per month) • Intensity (rate of energy expenditure) • Circumstances or Purpose

36. Current Recommendations for Physical Activity • 150 minutes of moderate-intensity aerobic activity every week AND • Muscle-strengthening activities on 2 or more days a week • 75 minutes of vigorous-intensity aerobic activity every week AND • Muscle-strengthening activities on 2 or more days a week

37. Moderate-intensity Aerobic Activity • Activity that increases breathing and heart rate • Subjects will be able to talk while doing activity but not sing • brisk walking • lawn moving • slow biking • ballroom dancing • tennis doubles • general gardening

38. Evidence for exercise • Midlife physical activity • Decreased risk of dementia 26 years later • Decreased cardiovascular risk profile • Reduction in brain tissue loss • High and moderate physical activity • Decreased risk of cognitive decline by 38% and 35% respectively • Prospective study of Mediterranean diet and higher level of physical activity • Protection against AD • CAIDE • Leisure time activity but not work related activity reduced risk of late life AD and dementia by 50% • This effect was more pronounced in ApoE4 carriers

39. Physical activity for those at risk for AD • Subjective memory complaints but no dementia • 170 subjects randomized, 138 completed 18 month assessment • 24 week home based physical activity program vs. usual care • 150 min moderate intensity physical activity • 3 sessions a week • Walking, aerobic, strength training as chosen by participant • Primary outcome was change in ADAS-Cog

40. Mean age 68.6 years • Education 12 years • participants in the intervention group improved 0.26 points (95% CI, −0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% CI, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. • The absolute difference of the outcome measure between the in- tervention and control groups was −1.3points (95% CI −2.38 to−0.22) at the end of the intervention. • At 18 months, participants in the intervention group im- proved 0.73points (95% CI −1.27 to 0.03)on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% CI −0.46 to 0.88).

41. Multimodal interventions

42. Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) • 60–77-year old • CAIDE Dementia risk score (6 point or higher) • CERAD neuropsychological test battery • 2-year multi-domain intervention • nutritional guidance • cognitive training • increased social activity • monitoring and management of metabolic and vascular risk factors • Primary outcome is cognitive decline • measured by a sensitive Neuropsychological Test Battery • the Stroop • Trail Making tests.

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46. Multidomain Alzheimer prevention study (MAPT) • France • 1680 70 years and above • Multicenter, randomized, placebo controlled study • Frail elderly people (defined by having subjective memory complaint, limitation in one IADL, slow walking speed) • All participants sub grouped into 4 groups, 3 based on treatment options (omega 3 alone, multidomain intervention alone, both combined) and one placebo group

47. Prevention of dementia by intensive vascular care (preDIVA) • Prevention of dementia by intensive vascular care • Netherlands • 3700 Non demented elderly from GP practices • 70–78 years • Multisite, open, cluster randomized parallel group study • every 4 month visit with practice nurse for life style and medical interventions, then 2,4 and final 6 years follow up

48. Healthy Aging Through Internet Counseling in the Elderly • started January 2013 • support management of vascular and life-style related risk factors in older adults, through an easily accessible Internet platform • readily available nurse-support • a randomized controlled clinical trial among 4600 elderly is planned (starting 2015)

49. Case • Vienna Transdanube Aging (VITA) Study • 76 yr woman MMSE 29 and high scores on tests • 81 yr MMSE 25 • Episodic memory tests declined by two standard deviations • MRI: medial temporal lobe atrophy worsened • Temporal cortical atrophy • Probable AD diagnosis given

50. MRI