1. Update on Cognitive Health and Dementia Victor W. Henderson Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences Stanford University Stanford, California, USA General Secretary, International Menopause Society No relevant conflict of interest

2. Outline I.Normal and abnormal brain aging II.Midlife strategies to prevent abnormal brain aging and cognitive decline III.Cognitive health: potential risks and benefits of menopausal hormone therapy (MHT)

3. Outline I.Normal and abnormal brain aging II.Midlife strategies to prevent abnormal brain aging and cognitive decline III.Cognitive health: potential risks and benefits of menopausal hormone therapy (MHT)

4. Normal brain aging (cognitive aging)  Changes associated with age that do not cause dementia. Abnormal brain aging (Minimal Cognitive Impairment (MCI) and dementia)  Changes associated with age that may eventually lead to dementia.  Dementia represents cognitive impairment that interferes with usual occupational and social activities, or with independence. Normal and abnormal brain aging Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650

5. Some cognitive abilities are well maintained or improve with age  Abilities that draw largely on acquired skills, knowledge, and experience (sometimes referred to as “crystallized intelligence”).  Vocabulary is an example that, on average, is better in middle- age than in younger adulthood, and better in older adulthood than middle age. Cognitive skills change with normal aging Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650

6. Other cognitive abilities decline, beginning insidiously during – or even before – midlife  Abilities based on new learning, abstract reasoning, and problem solving (sometimes referred as “fluid intelligence”).  Tasks that draw on these abilities tend to be performed better by adults in their 20s than middle-aged or older adults. Cognitive skills change with normal aging Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650

7. Cognitive skills change with normal aging Age 25 years 75 years Test Score Fluid Crystallized Crystallized intelligence versus fluid intelligence

8. Mild cognitive impairment (MCI) and dementia  Abnormal brain aging represents changes associated with age that may eventually lead to dementia.  Dementia is caused by specific pathologies.  MCI represents an intermediate stage of abnormal brain aging.  The clinical distinction between normal cognitive aging and MCI is sometimes clear, but at times it can be difficult to discern. Abnormal brain aging Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650

9. Cognitive aging, MCI, and dementia Henderson, Climateric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650

10. Substrates of abnormal brain aging Specific dementia pathologies Alzheimer’s disease Vascular dementia Lewy body dementia Frontotemporal dementia Other specific pathology Abnormal Aging (Specific pathologies) Mild Cognitive Impairment Dementia

11. Alzheimer’s disease  In most regions of the world, Alzheimer’s disease is the most common cause of dementia.  It affects more women than men, primarily because more women than men survive to late old age, when the incidence is greatest.  It remains controversial whether women are more often affected than men, after age is taken into consideration.

12. Alzheimer’s disease (continued)  The pathology includes neuritic plaques and neurofibrillary tangles.  The biochemistry includes b-amyloid in plaque cores and hyperphosphorylated tau protein in tangles.  Alzheimer’s pathology often co-exists with other dementia pathologies, such as macro- and microinfarcts (leading cause of vascular dementia) and cortical Lewy bodies.

13. Key Points, 1 Normal and abnormal brain aging  Cognitive abilities change over the lifespan  Abnormal brain aging reflects pathological processes, which over time can cause symptoms of mild cognitive impairment and, ultimately, dementia.  On a global basis, Alzheimer’s disease is the most common cause of dementia.  The pathology of Alzheimer’s disease often does not occur in isolation and may be accompanied by vascular pathology or other pathologies that can cause dementia.

14. Outline I.Normal and abnormal brain aging II.Midlife strategies to prevent abnormal brain aging and cognitive decline III.Cognitive health: potential risks and benefits of menopausal hormone therapy (MHT)

15. Three strategies to protect against cognitive decline due to Alzheimer’s disease pathology Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 1 2 3

16. Strategies to protect against cognitive decline  Cigarette cessation.  Treatment of hypertension.  Diabetes prevention and treatment.  Reducing LDL cholesterol.  Reducing obesity and the metabolic syndrome. 1. Reducing vascular pathology in the brain will raise the threshold for dementia caused by other pathologies Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 Improving the cardiovascular profile lowers the risk for both vascular dementia and for Alzheimer’s disease.

17. 2. Raise the threshold for dementia by increasing brain (cognitive) reserve  Cognitive reserve implies greater capacity, efficiency or redundancy in terms of brain areas and nerve pathways used during cognitive performance. Strategies to protect against cognitive decline Stern, Lancet Neurology 2012;11:1006

18.  Environmental enrichment  Higher education  Intellectually challenging occupation  Intellectually challenging leisure activities  Social engagement 2. Raise the threshold for dementia by increasing brain (cognitive) reserve Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 Higher cognitive reserve lowers the risk for Alzheimer’s disease and other causes of dementia. Strategies to protect against cognitive decline

19.  There is no evidence that one type of intellectually challenging activity is more protective than another.  Patients should be encouraged to seek out activities that they enjoy and are likely to continue over time.  Examples include art lessons, learning to play a new musical instrument, studying a foreign language, playing games of skill, reading, writing, computer-based brain-training, meaningful social interactions, and much else. Intellectually challenging leisure activities Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 Strategies to protect against cognitive decline

20.  Aerobic activity has multiple effects.  One effect is to reduce cardiovascular risk, raising the threshold for dementia.  Aerobic activity may also affect the brain directly, reducing  - amyloid accumulation in the brain. (continued) 3. Reduce the burden of Alzheimer pathology through regular aerobic activity Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 Strategies to protect against cognitive decline

21. (continued)  Evidence comes from experimental animal research and from human research, which is still largely observational.  A meta-analysis of 9 observational studies suggests physical activity is associated with 28% reduction in Alzheimer risk. Plassman et al. Ann Intern Med 2010;153:182-93. 3. Reduce the burden of Alzheimer pathology through regular aerobic activity Henderson, Climacteric 2014;17 (suppl 2):38-46. doi: 10.3109/13697137.2014.929650 Strategies to protect against cognitive decline

22. Physical activity recommendations * TypeExamplesExposure Aerobic, moderate intensity, or Brisk walking, bicycling (<10 mph), social dancing, doubles tennis 150+ min/ wk Aerobic, vigorous intensity, and Jogging, swimming, bicycling (10+ mph), hiking uphill, singles tennis 75+ min/wk Resistance training Resistance bands, free weights or weight machine, calisthenics 2+ days/wk Moderate = 3.0 to 5.9 METs; vigorous = >6 METs *Physical activity guidelines for Americans, Washington: US DHHS, 2008.

23. Strategies to protect against cognitive decline  Nutrition  Fruits and vegetables  Mediterranean diet  Omega-3-fatty acids  Adequate sleep  Prevention or treatment of depressive disorders There are a number of other potential strategies, but the level of supportive evidence is low

24. Key Points, 2 Strategies to protect against cognitive decline  A midlife strategy focused on reducing cardiovascular risk, enhancing cognitive reserve, and engagement in regular aerobic exercise may reduce the risk of late-life dementia.  Cognitive reserve might best be enhanced through education (at any age), intellectually stimulating occupation, and intellectually engaging leisure activity.

25. Outline I.Normal and abnormal brain aging II.Midlife strategies to prevent abnormal brain aging and cognitive decline III.Cognitive health: potential risks and benefits of menopausal hormone therapy (MHT)

26. MHT and Alzheimer’s disease symptoms Mulnard et al., JAMA 2000;283:1007; Henderson et al., Neurology 2000;54:295; but see Wharton et al., J. Alzheimers Dis. 2011;26:495.  Relatively small clinical trials generally fail to show consistent improvement in symptoms of Alzheimer’s patients randomized to receive hormone therapy.  The largest trial included 120 hysterectomized women with Alzheimer’s disease followed for 12 months, and found no treatment effect. Mulnard, JAMA 2000

27.  Over the past two decades, approximately two dozen observational studies have examined associations between a woman’s use of MHT and her risk of developing Alzheimer’s disease.  Meta-analyses before the Women’s Health Initiative linked MHT to reductions in Alzheimer risk of about one-third. *  These observations are supported by strong biological plausibility.  However, the only clinical trial (Women’s Health Initiative Memory Study) showed an increased risk of dementia. MHT and dementia prevention *Yaffe et al., JAMA 1998;279:688; Hogervorst et al., Neuroscience 2000;101:485. Observational studies

28.  The Women’s Health Initiative Memory Study (WHIMS) was a WHI ancillary study of women age 65-79 years. This is the only source of clinical trial data for MHT on dementia prevention.  WHI included two parallel trials in relatively healthy postmenopausal women * :  Women without a uterus (active treatment with conjugated equine estrogens 0.625 mg/d)  Women with a uterus (active treatment with conjugated equine estrogens 0.625 mg/d in a continuous combined formulation with medroxyprogesterone acetate 2.5 mg/d) *Rosseau et al., JAMA 2002;288:321; Anderson et al., JAMA 2004;291:1701 Randomized controlled trials MHT and dementia prevention

29. Shumaker, et al. JAMA 2003;289:2651; 2004;291:2947 P = 0.2 CEE alone P = 0.01 CEE+MPA 1.0 3.0 0.5 2.0 Women’s Health Initiative Memory Study (WHIMS) MHT and dementia prevention

30.  There are two major explanations for apparent discrepancies between observational studies of MHT and Alzheimer risk and WHIMS clinical trial data on dementia prevention.  1. Compared to women who never used MHT, hormone users in observational studies were, on average, more likely to be healthier, better educated, and to endorse healthy lifestyle practices. These potential confounding effects may contribute to observed associations with lower Alzheimer risk. (or) Henderson, Neuroscience 2006;138:1031. MHT and dementia prevention Controversies

31. (continued)  2. MHT use in observational studies primarily reflects use by younger women, close to the time of menopause. MHT use in WHIMS was restricted to postmenopausal women aged 65+ years.  This difference has led to the timing, or critical window, hypothesis.  According to this hypothesis, the effects of MHT on risk of Alzheimer’s disease may differ when used by younger postmenopausal women closer to the time of menopause, compared to older women further from the time of menopause. Henderson, Neuroscience 2006;138:1031. MHT and dementia prevention Controversies

32. Zandi et al., JAMA 2002;288:2123; Henderson et al., J. Neurol. Neurosurg. Psychiatry 2005;76:103; Whitmer et al., Ann. Neurol. 2011;69:163.  The critical window hypothesis is not addressed by clinical trials but is addressed by three observational studies.  1. Cache County: Prior use of MHT, but not current use, is associated with reduced risk of late-life Alzheimer’s disease.  2. MIRAGE: MHT use by younger women, but not by older women, is associated with reduced risk of Alzheimer’s disease.  3. Kaiser Permanente: MHT use only at an early age is associated with lower dementia risk; MHT use at a late age is associated with increased dementia risk; MHT use at both times is unassociated with risk. observational findings in Cache County, MIRAGE, and Kaiser MHT and dementia prevention

33.  MHT: timing based on prior or current use, Cache County 1.0 3.0 0.5 0.1 2.0 youngest age tertile middle oldest prior use current use late-life only midlife use only midlife + late-life Zandi et al., JAMA 2002;288:2123; Henderson et al., J. Neurol. Neurosurg. Psychiatry 2005;76:103; Whitmer et al., Ann. Neurol. 2011;69:163.  MHT: timing based on midlife or late-life use, Kaiser Permenante  MHT: timing based on age, MIRAGE (Multi-Institutional Research in Alzheimer’s Genetic Epidemiology) observational findings in Cache County, MIRAGE, and Kaiser MHT and dementia prevention

34.  A number of high quality RCTs have addressed cognitive effects of MHT in women without dementia.  Most have been conducted in older postmenopausal women.  Two large, long-duration trials have now been completed involving healthy younger postmenpausal women:  KEEPS (662 women, 4 years)  ELITE (234 women in the early postmenopause group, 4.5 years)  A third large trial, COGENT, enrolled 180 women, followed for 4 months  Primary outcomes from all three suggest no overall cognitive benefit or harm. Asthana, in press; Henderson, unpublished; Maki, Neurology 2007;69:1322 MHT and normal cognitive aging

35. MHT and cognitive aging, RCTs Larger, longer duration randomized trials (N >100, treatment duration >1 year) of healthy postmenopausal women Resnick et al., J. Clin. Endocrinol. Metab. 2006;91:1802; 2009;94:4152; Grady et al., Am. J. Med. 2002;113:543; Viscoli et al., Am. J. Obstet. Gynecol. 2005;192:387; Yaffe et al., Arch. Neurol. 2006;63:945; Yaffe et al., N. Engl. J. Med. 2001;344:1207. StudyAuthorYearNo. Mean age, years Duration, yearsEstrogenPrimary outcome(s) Younger postmenopausal women KEEPS Asthana2012662534CEE or TD E2 No effect ELITE Mack201464356 (young) 64 (old) 4.8E2No effect in either age group or combined groups Older postmenopausal women WHIMS Espeland20042808725.4CEESmall adverse effect ― Greenspan2005373713CEENo effect WHIMS Rapp2003438165 to 794.2CEESmall adverse effect WHISCA Resnick20061416743CEEMixed; no overall effect WHISCA Resnick2009886743CEEMixed; no overall effect EMS Tierney2009128752E2No effect ULTRA Yaffe2006417672TD E2No effect CEE = conjugated equine estrogens; E2 = estradiol; TD = transdermal; women with a uterus received a progestogen or progestogen placebo

36. Key Points, 3 Cognitive health: potential risks and benefits of MHT  MHT does not improve symptoms of Alzheimer’s disease.  MHT with an estrogen + progestin initiated at age 65+ increases dementia risk.

37. Cognitive health: potential risks and benefits of MHT continued  Observational evidence, based largely on relatively short-term use by younger women closer to menopause, associates MHT with lower risk of Alzheimer’s disease.  Regardless, if increased risk in WHIMS is extrapolated to postmenopausal women age 50-59 years, the absolute risk of dementia from hormone therapy would be rare, about 1 additional case for each 1000 women using MHT for 5 years. Maki & Henderson, Climacteric 2012;15:256-62, 10.3109/13697137.2012.660613 Key Points, 3

38. Maki & Henderson, Climacteric 2012;15:256-62, 10.3109/13697137.2012.660613 Cognitive health: potential risks and benefits of MHT continued  For healthy older postmenopausal women, MHT does not have clinically important effects on cognition, but certain other risks of MHT are increased in this age group.  For healthy younger postmenopausal women, MHT does not have clinically important effects on cognition.  These findings do not pertain to women with premature menopause, where data are insufficient. Key Points, 3

39. Appendix: a word about MHT  In June 2016, the IMS provided updated recommendations on MHT and preventive strategies for midlife health. *  Governing principles enumerated within these recommendations are important whenever MHT is considered. *De Villiers et al., Climacteric 2013;16;316

40. References for Table on MHT and cognitive aging Larger (at least 100 women), longer duration (at least 1 year) randomized, placebo- controlled trials of MHT in healthy postmenopausal women Asthana et al., Menopause 2012;19:1364 [abstract]. Mack et al., Menopause 2014;21:1330 [abstract] Espeland et al., JAMA 2004;291:2959. Greenspan et al., Am. J. Med. 2005;118:1232 Rapp et al., JAMA 2003;289:2663 Resnick et al., J. Clin. Endocrinol. Metab. 2006;91:1802 Resnick et al., J. Clin. Endocrinol. Metab. 2009;94:4152 Tierney et al., Psychoneuroendocrinology 2009;37:1065 Yaffe et al., Arch. Neurol. 2006;63:945 Appendix: table references