Table E-1. Demographic Characteristics of Participants and Diagnostic Procedures of Dementia

NEUROLOGY/2016/757526 1

Table e-1. Demographic characteristics of participants and diagnostic procedures of dementia in 5 prevalence surveys Year of survey 1985 1992 1998 2005 2012 (n = 887) (n = 1,189) (n = 1,437) (n = 1,566) (n = 1,904) Age, years, mean (SD) 74 (6) 74 (7) 75 (7) 76 (7) 76 (8) Women, % 60.2 60.1 60.3 60.9 59.0

Participation rate, % 94.6 96.6 99.7 91.5 93.5 Neuropsychological test HDS HDS HDS-R HDS-R HDS-R HDS-R MMSE MMSE MMSE Diagnosis of dementia DSM-III DSM-III-R DSM-III-R DSM-III-R DSM-III-R HDS = Hasegawa’s Dementia Rating Scale, HDS-R = HDS, revised version, MMSE = Mini-Mental State Examination, DSM-III = Diagnostic and Statistical Manual of Mental Disorders, third edition, DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, revised third edition, SD: standard deviation. NEUROLOGY/2016/757526 2

Table e-2. Secular trends in the prevalence of dementia and its subtypes by sex from 1985 to 2012 Year of survey p for 1985 1992 1998 2005 2012 trend Men Population at risk 353 475 571 612 780 All-cause dementia No. of cases 19 17 25 54 107 Crude prevalence, % 5.4 (3.0-7.8) 3.6 (1.9-5.3) 4.4 (2.7-6.1) 8.8 (6.5-11.2) 13.7 (11.1-16.3) <0.01 Age-standardized prevalence, % 6.7 (3.3-10.0) 3.8 (2.0-5.6) 4.3 (2.6-6.0) 7.6 (5.5-9.6) 10.6 (8.5-12.6) <0.01 Alzheimer’s disease No. of cases 2 4 7 20 60 Crude prevalence, % 0.6 (-0.2-1.4) 0.8 (0-1.7) 1.2 (0.3-2.1) 3.1 (1.7-4.5) 7.7 (5.7-9.6) <0.01 Age-standardized prevalence, % 1.3 (-0.5-3.0) 1.1 (0-2.1) 1.2 (0.3-2.1) 2.8 (1.5-4.0) 5.8 (4.3-7.3) <0.01 Vascular dementia No. of cases 9 7 10 23 32 Crude prevalence, % 2.5 (0.9-4.2) 1.5 (0.4-2.6) 1.8 (0.7-2.8) 3.9 (2.4-5.5) 4.0 (2.6-5.4) <0.01 Age-standardized prevalence, % 2.7 (0.8-4.7) 1.4 (0.4-2.5) 1.5 (0.5-2.6) 3.2 (1.9-4.6) 3.3 (2.1-4.5) 0.06 Other/unclassified dementia No. of cases 8 6 8 11 15 Crude prevalence, % 2.3 (0.7-3.8) 1.3 (0.3-2.3) 1.4 (0.4-2.4) 1.8 (0.7-2.9) 1.9 (0.9-2.9) 0.87 Age-standardized prevalence, % 2.7 (0.6-4.8) 1.3 (0.2-2.4) 1.4 (0.4-2.4) 1.6 (0.6-2.5) 1.5 (0.7-2.3) 0.48 Women Population at risk 534 714 866 954 1,124 All-cause dementia No. of cases 40 51 77 141 234 Crude prevalence, % 7.5 (5.2-9.8) 7.1 (5.2-9.1) 8.9 (6.9-10.9) 14.8(12.3-17.2) 20.8 (18.2-23.5) <0.01 Age-standardized prevalence, % 7.0 (4.8-9.1) 5.5 (4.0-7.0) 6.3 (4.8-7.8) 9.2 (7.6-10.8) 12.1 (10.4-13.8) <0.01 Alzheimer’s disease No. of cases 10 17 43 76 173 Crude prevalence, % 1.9 (0.7-3.0) 2.4 (1.2-3.5) 5.0 (3.5-6.4) 8.1 (6.3-9.9) 15.3 (13.0-17.6) <0.01 NEUROLOGY/2016/757526 3

Age-standardized prevalence, % 1.7 (0.7-2.8) 1.7 (0.9-2.5) 3.6 (2.5-4.8) 5.1 (3.9-6.4) 8.6 (7.2-9.9) <0.01 Vascular dementia No. of cases 12 15 15 28 26 Crude prevalence, % 2.2 (1.0-3.5) 2.1 (1.0-3.2) 1.7 (0.9-2.6) 2.8 (1.8-3.9) 2.4 (1.5-3.3) 0.52 Age-standardized prevalence, % 2.1 (0.9-3.3) 1.7 (0.8-2.6) 1.2 (0.6-1.8) 1.6 (1.0-2.3) 1.5 (0.9-2.1) 0.30 Other/unclassified dementia No. of cases 18 19 19 37 35 Crude prevalence, % 3.4 (1.8-4.9) 2.7 (1.5-3.9) 2.2 (1.2-3.2) 3.9 (2.6-5.1) 3.1 (2.1-4.1) 0.57 Age-standardized prevalence, % 3.2 (1.7-4.6) 2.1 (1.1-3.1) 1.5 (0.8-2.2) 2.4 (1.6-3.3) 2.1 (1.3-2.9) 0.21 Values in parenthesis are the 95% confidence intervals. NEUROLOGY/2016/757526 4

Table e-3. Crude and age- and sex-adjusted baseline mean values (SD) and frequencies of risk factors in the 1988 and 2002 cohort

1988 (n = 803) 2002 (n = 1,231) P Crude Adjusted Crude Adjusted Age, years 74 (6) 73 (6) 0.23 0.28 Men, % 39.0 43.0 0.07 0.09 Hypertension, % 62.0 62.9 0.75 0.63 Antihypertensive agents, % 28.8 38.6 <0.01 <0.01 Systolic blood pressure in 158 (20) 149 (18) <0.01 <0.01 hypertensives, mmHg Diastolic blood pressure in 80 (11) 84 (10) <0.01 <0.01 hypertensives, mmHg Electrocardiogram abnormalities, % 23.0 23.0 0.89 0.91 Obesity, % 17.4 24.6 <0.01 <0.01 Diabetes mellitus, % 13.6 22.4 <0.01 <0.01 Hypercholesterolemia, % 35.2 39.3 0.04 0.01 History of stroke at entry, % 6.2 5.9 0.96 0.93 Education ≤ 9 years, % 73.3 58.1 <0.01 <0.01 Current smoker, % 19.8 8.8 <0.01 <0.01 Current drinker, % 22.0 26.8 <0.01 <0.01 Regular exercise, % 16.7 14.0 0.13 0.11 All values are given as the mean or as a percent. SD: standard deviation. Mean age was sex-adjusted. Percentage of men was age-adjusted. Hypertension: blood pressure ≥140/90 mmHg or current use of antihypertensive agents. Electrocardiogram abnormalities: Minnesota Code 3-1, 4-1, 4-2, 4-3, or 8-3. Diabetes mellitus: fasting plasma glucose ≥126 mg/dl, 2-hour post-load glucose concentrations or post-prandial glucose concentrations ≥200 mg/dl, or current use of insulin or oral medication for diabetes. Hypercholesterolemia: serum total cholesterol ≥220 mg/dl or current use of lipid-lowering agents. Obesity: body mass index ≥25 kg/m2. NEUROLOGY/2016/757526 5

Table e-4. Comparison of adjusted all-cause mortality (per 1,000 person-years) between the 1988 and 2002 cohort Adjusted hazard 1988 cohort (1988-1998) 2002 cohort (2002-2012) ratio (vs.1988 cohort) Age Adjuste stratum, d years Person-years Number of Adjusted Number of mortalit at risk events mortality Person-years at risk events y (95% CI) (95% CI) 36.2 All a) 6478 288 50.6 (42.9-54.2) 10365 335 (31.8- 0.68 (0.58-0.79)** 39.6)

12.0 65-69b) 2017 37 19.0 (12.7-25.3) 3526 41 (8.3- 0.64 (0.41-0.99)* 15.6)

23.9 70-74b) 2032 60 32.5 (24.1-40.9) 2990 67 (18.1- 0.75 (0.53-1.02)Ɨ 29.8)

40.8 75-79b) 1407 82 66.6 (51.3-81.8) 2230 88 (32.2- 0.61 (0.45-0.83)** 49.4)

108.9 (81.9- 70.5 80-84b) 731 70 1085 64 (51.9- 0.61 (0.43-0.85)** 135.9) 89.2)

158.0 85-b) 291 39 163.5 (104.1- 534 75 (118.9- 0.83 (0.55-1.26) 223.0) 197.2) a) Age- and sex-adjusted. b) Age-adjusted. 95% CI = 95% confidence interval. Ɨp<0.1, *p <0.05, **p <0.01 vs. the 1988 cohort. Table e-5. Comparison of 5-year all-cause mortality between incident dementia cases and randomly selected age- and sex-matched participants without incident dementia in the 1988 and 2002 cohort

Population Number of Hazard ratio at risk events (95% CI) P

1988 cohort without 1.0 incident dementia 102 16 (reference) incident dementia 102 34 2.35 (1.30-4.25) <0.01

2002 cohort without 1.0 incident dementia 267 42 (reference) incident dementia 267 69 1.76 (1.20-2.59) <0.01

p for heterogeneity between the 1988 and 0.49 2002 cohorts 95% CI = 95% confidence interval.