eTable 1 Drug history of the participants in NACC and MCSA

(1)

eTable 1 Drug history of the participants in NACC and MCSA

NACC MCSA

Reverters Non-reverters Reverters Non-reverters

(n = 280) (n = 542) (n = 164) (n = 127)

Drug history Yes No Yes No P

values Yes No Yes No P

values Drug

Alprazolam 12 (4.3%) 268 (95.7%) 21 (3.9%) 521 (96.1%) 0.92 1 (0.6%) 163 (99.4%) 1 (0.8%) 126 (99.2%) 1.00 Amitriptyline 4 (1.4%) 276 (98.6%) 10 (1.8%) 532 (98.2%) 0.88 4 (2.4%) 160 (97.6%) 5 (3.9%) 122 (96.1%) 0.70 Bupropion 22 (7.9%) 258 (92.1%) 26 (4.8%) 516 (95.2%) 0.11 3 (1.8%) 161 (98.2%) 4 (3.1%) 123 (96.9%) 0.73 Carbidopa Levodopa 10 (3.6%) 270 (96.4%) 29 (5.4%) 513 (94.6%) 0.33 11 (6.7%) 153 (93.3%) 6 (4.7%) 121 (95.3%) 0.64 Clonazepam 13 (4.6%) 267 (95.4%) 17 (3.1%) 525 (96.9%) 0.37 1 (0.6%) 163 (99.4%) 9 (7.1%) 118 (92.9%) 0.007 Divalproex Sodium 2 (0.7%) 278 (99.3%) 6 (1.1%) 536 (98.9%) 0.87 0.0 (0.0%) 164 (100.0%) 0 (0.0%) 127 (100.0%) NA Donepezil 18 (6.4%) 262 (93.6%) 164 (30.3%) 378 (69.7%) < 0.001 6 (3.7%) 158 (96.3%) 17 (13.4%) 110 (86.6%) 0.005 Escitalopram 18 (6.4%) 262 (93.6%) 51 (9.4%) 491 (90.6%) 0.18 2 (1.2%) 162 (98.8%) 3 (2.4%) 124 (97.6%) 0.77 Fluoxetine 11 (3.9%) 269 (96.1%) 15 (2.8%) 527 (97.2%) 0.49 4 (2.4%) 160 (97.6%) 7 (5.5%) 120 (94.5%) 0.29 Gabapentin 26 (9.3%) 254 (90.7%) 57 (10.5%) 485 (89.5%) 0.67 18 (11.0%) 146 (89.0%) 14 (11.0%) 113 (89.0%) 1.00 Galantamine 3 (1.1%) 277 (98.9%) 12 (2.2%) 530 (97.8%) 0.38 1 (0.6%) 163 (99.4%) 0 (0.0%) 127 (100.0%) 1.00 GingkoBiloba 0 (0.0%) 280 (100.0%) 0 (0.0%) 542 (100.0%) NA 4 (2.4%) 160 (97.6%) 1 (0.8%) 126 (99.2%) 0.54 Lorazepam 14 (5%) 266 (95%) 32 (5.9%) 510 (94.1%) 0.71 5 (3.0%) 159 (97.0%) 3 (2.4%) 124 (97.6%) 1.00 Memantine 11 (3.9%) 269 (96.1%) 107 (19.7%) 435 (80.3%) < 0.001 1 (0.6%) 163 (99.4%) 3 (2.4%) 124 (97.6%) 0.44 Mirtazapine 11 (3.9%) 269 (96.1%) 34 (6.3%) 508 (93.7%) 0.22 5 (3%) 159 (97.0%) 11 (8.7%) 116 (91.3%) 0.068 Olanzapine 11 (3.9%) 269 (96.1%) 107 (19.7%) 435 (80.3%) < 0.001 2 (1.2%) 162 (98.8%) 0 (0.0%) 127 (100.0%) 0.59 Paroxetine 9 (3.2%) 271 (96.8%) 16 (3.0%) 526 (97.0%) 1.00 2 (1.2%) 162 (98.8%) 2 (1.6%) 125 (98.4%) 1.00 Quetiapine 4 (1.4%) 276 (98.6%) 20 (3.7%) 522 (96.3%) 0.11 3 (1.8%) 161 (98.2%) 2 (1.6%) 125 (98.4%) 1.00 Risperidone 0 (0.0%) 280 (100.0%) 10 (1.8%) 532 (98.2%) 0.051 0.0 (0%) 164 (100.0%) 1 (0.8%) 126 (99.2%) 0.90 Rivastigmine 1 (0.4%) 279 (99.6%) 32 (5.9%) 510 (94.1%) < 0.001 0.0 (0%) 164 (100.0%) 1 (0.8%) 126 (99.2%) 0.90 Sertraline 17 (6.1%) 263 (93.9%) 57 (10.5%) 485 (89.5%) 0.048 13 (7.9%) 151 (92.1%) 14 (11.0%) 113 (89%) 0.48 Trazodone 17 (6.1%) 263 (93.9%) 32 (5.9%) 510 (94.1%) 1.00 9 (5.5%) 155 (94.5%) 10 (7.9%) 117 (92.1%) 0.56 Venlafaxine 10 (3.6%) 270 (96.4%) 13 (2.4%) 529 (97.6%) 0.46 9 (5.5%) 155 (94.5%) 3 (2.4%) 124 (97.6%) 0.30

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eTable 2 Demographics of imaging sub-cohorts in MCSA

MRI FDG-PET Amyloid-PET Tau-PET

Characteristics Reverters (n = 94)

Non-reverters (n = 83)

Reverters (n = 54)

Reverters (n = 59)

Reverters (n = 14)

Male, No. (%) 53 (56.4%) 52 (62.7%) 30 (55.6%) 23 (67.6%) 33 (55.9%) 26 (66.7%) 7 (50.0%) 8 (72.7%)

Education,

Median (IQR), y 13.0 (12.0-15.8) 13.0 (12.0-15.5) 12.0 (12.0-15.0) 13.0 (12.0-15.8) 13.0 (12.0-16.0) 13.0 (12.0-15.5) 14.5 (13.0-16.8) 12.0 (12.0-15.0) Copy number of APOE4

allele, No. (%)

0 66 (70.2%) 59 (71.1%) 35 (64.8%) 25 (73.5%) 37 (62.7%) 29 (74.4%) 9 (64.3%) 7 (63.6%)

1 27 (28.7%) 23 (27.7%) 18 (33.3%) 8 (23.5%) 21 (35.6%) 9 (23.1%) 5 (35.7%) 4 (36.4%)

2 1 (1.1%) 1 (1.2%) 1 (1.9%) 1 (2.9%) 1 (1.7%) 1 (2.6%) 0 (0%) 0 (0%)

Age at baseline,

median (IQR), y 76.7 (72.5-81.8) 80.4 (75.2-82.8) 74.6 (72.2-78.6) 77.0 (74.0-81.6) 74.4 (71.8-78.4) 76.9 (74.3-81.3) 71.6 (66.0-75.3) 75.3 (73.8-76.6) Age at MCI onset,

median (IQR), y 81.9 (76.1-86.3) 83.5 (78.2-86.5) 79.2 (75.3-84.1) 81.6 (77.7-85.0) 79.1 (75.0-84.1) 81.2 (77.8-84.9) 75.9 (70.3-81.7) 80.8 (76.1-83.1) Age at last visit,

Median (IQR), y 86.5 (82.5-90.5) 88.0 (83.7-91.7) 85.3 (80.9-88.6) 85.8 (82.3-89.4) 85.1 (80.1-88.6) 86.6 (82.6-89.4) 80.3 (72.2-86.2) 87.8 (81.5-89.4) Total imaging,

No. (%)

2 25 (26.6%) 26 (31.3%) 26 (48.1%) 19 (55.9%) 25 (42.4%) 19 (48.7%) 8 (57.1%) 5 (45.5%)

3 25 (26.6%) 19 (22.9%) 19 (35.2%) 10 (29.4%) 19 (32.2%) 11 (28.2%) 6 (42.9%) 5 (45.5%)

Over 3 44 (46.8%) 38 (45.8%) 9 (16.7%) 5 (14.7%) 15 (25.4%) 9 (23.1%) 0 (0%) 1 (9.1%)

Last diagnosis, No (%)

Normal 59 (62.8%) 20 (24.1%) 32 (59.3%) 7 (20.6%) 37 (62.7%) 9 (23.1%) 6 (42.9%) 2 (18.2%)

MCI 31 (33.0%) 38 (45.8%) 19 (35.2%) 16 (47.1%) 19 (32.2%) 18 (46.2%) 8 (57.1%) 4 (36.4%)

Dementia 4 (4.3%) 25 (30.1%) 3 (5.6%) 11 (32.4%) 3 (5.1%) 12 (30.8%) 0 (0%) 5 (45.5%)

Abbreviations: APOE, apolipoprotein E; MRI, magnetic resonance imaging; PiB, Pittsburgh compound B; PET, positron emission tomography; FDG, F-18 fluorodeoxyglucose

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eTable 3 Mixed effect model estimate of neuroimaging changes in different brain regions

FDG-PET (n = 88) Amyloid-PET (n = 98) Tau-PET (n = 25)

Brain region

Coefficient (95% CI) P value Coefficient (95% CI) P value Coefficient (95% CI) P value Reversion: reverters 0.064

(0.02 to 0.105) 0.005 -0.162

(-0.363 to 0.024) 0.093 -0.04

(-0.134 to 0.045) 0.38 Time to MCI onset ×

reverters

0.001

(-0.005 to 0.008) 0.65 0

(-0.017 to 0.016) 0.96 0

(-0.017 to 0.017) 0.99 Time to MCI onset, y -0.012

(-0.018 to -0.007) < 0.001 0.042

(0.029 to 0.055) < 0.001 -0.003

(-0.015 to 0.009) 0.64 Cingulum

Sex: female 0.026

(-0.018 to 0.07) 0.24 0.036

(-0.149 to 0.23) 0.69 -0.04

(-0.122 to 0.047) 0.36 APOE4 allele copy

number

0.003

(-0.038 to 0.045) 0.9 0.227

(0.057 to 0.395) 0.009 -0.048

(-0.135 to 0.038) 0.24

Education, y 0.003

(-0.004 to 0.011) 0.37 0.017

(-0.011 to 0.049) 0.24 0.007

(-0.008 to 0.023) 0.33

Reversion: reverters 0.064 0.005 -0.116 0.14 -0.023 0.62

(0.026 to 0.111) (-0.266 to 0.032) (-0.121 to 0.07)

Time to MCI onset × 0.001

reverters (-0.005 to 0.008) 0.63 -0.001 (-0.014 to 0.011) 0.83 -0.004

0.63 (-0.022 to 0.014)

Time to MCI onset, y -0.011

< 0.001

(-0.016 to -0.007) 0.032 (0.022 to 0.042) < 0.001 -0.001

0.82 (-0.014 to 0.01)

Insula

Sex: female 0.003

0.88

(-0.039 to 0.046) -0.016 (-0.153 to 0.135) 0.825 -0.05

0.25 (-0.132 to 0.043)

APOE4 allele copy 0.031

number (-0.011 to 0.071) 0.15 0.147 (0.013 to 0.276) 0.031 -0.019

0.64 (-0.106 to 0.067)

Education, y 0.003

0.35

(-0.004 to 0.011) 0.019 (-0.005 to 0.04) 0.12 0.008

0.28 (-0.007 to 0.024)

Reversion: reverters 0.037

(0.006 to 0.065) 0.017 -0.013

(-0.077 to 0.048) 0.68 -0.098

reverters

0.003

(-0.001 to 0.006) 0.20 0.001

(-0.007 to 0.008) 0.83 0

(-0.013 to -0.006) < 0.001 0.009

(0.004 to 0.015) 0.002 0.002

(-0.014 to 0.019) 0.81 Medial temporal cortex

Sex: female 0.002

(-0.026 to 0.03) 0.88 0.005

(-0.054 to 0.062) 0.87 -0.032

number

-0.002

(-0.028 to 0.023) 0.87 0.051

(-0.005 to 0.108) 0.074 -0.023

(-0.139 to 0.083) 0.67

Education, y -0.001

(-0.006 to 0.004) 0.74 0.008

(-0.002 to 0.018) 0.12 0.017

(-0.005 to 0.038) 0.12

Occipital lobe Reversion: reverters 0.065

(0.004 to 0.124) 0.042 -0.083

(-0.193 to 0.035) 0.18 -0.058

(-0.153 to 0.023) 0.19

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Time to MCI onset × Reversion

-0.001

(-0.01 to 0.01) 0.91 -0.003

(-0.014 to 0.009) 0.58 -0.002

(-0.021 to -0.006) 0.002 0.032

(0.023 to 0.04) < 0.001 0.006

(-0.012 to 0.022) 0.52

Sex: female 0.046

(-0.014 to 0.11) 0.14 0.046

(-0.051 to 0.156) 0.40 -0.023

number

-0.017

(-0.078 to 0.042) 0.57 0.045

(-0.062 to 0.147) 0.38 -0.056

(-0.127 to 0.019) 0.16

Education, y 0.003

(-0.007 to 0.013) 0.51 0.01

(-0.009 to 0.028) 0.26 0.009

(-0.005 to 0.024) 0.20 Reversion: reverters 0.06

(0.012 to 0.104) 0.009 -0.182

(-0.389 to 0.04) 0.11 -0.05

Reversion

0.004

(-0.001 to 0.01) 0.15 0

(-0.018 to 0.02) 0.97 0.003

(-0.017 to 0.023) 0.75

Orbitofrontal cortex

Time to MCI onset, y Sex: female

-0.014

(-0.018 to -0.009) -0.002

(-0.045 to 0.042)

< 0.001

0.92

0.04

(0.026 to 0.054) -0.001

(-0.224 to 0.222)

< 0.001

0.99

-0.007

(-0.023 to 0.008) -0.042

(-0.133 to 0.057)

0.33 0.37 APOE4 allele copy

number

0.007

(-0.034 to 0.048) 0.76 0.242

(0.048 to 0.428) 0.017 -0.017

(-0.115 to 0.074) 0.72

Education, y 0.002

(-0.005 to 0.009) 0.61 0.02

(-0.01 to 0.055) 0.24 0.003

(-0.027 to 0.076) 0.36 -0.145

(-0.285 to -0.002) 0.042 -0.01

Reversion

-0.003

(-0.01 to 0.005) 0.42 -0.008

(-0.02 to 0.006) 0.23 -0.007

(-0.012 to 0) 0.027 0.036

(0.025 to 0.046) < 0.001 0.008

(-0.005 to 0.022) 0.24 Paracentral Lobule

Sex: female 0.023

(-0.027 to 0.077) 0.38 0.044 (-0.084 to 0.169) 0.5 -0.038

number

-0.039

(-0.086 to 0.009) 0.13 0.085

(-0.038 to 0.207) 0.17 -0.051

(-0.129 to 0.032) 0.22

Education, y 0.008

(0 to 0.016) 0.063 0.015

(-0.007 to 0.036) 0.15 0.008

(0.019 to 0.131) 0.012 -0.195

(-0.398 to 0.016) 0.061 -0.061

(-0.175 to 0.055) 0.28

Parietal cortex

Time to MCI onset × reverters

Time to MCI onset, y

0.006

(-0.002 to 0.015) -0.019

(-0.025 to -0.012)

0.16

< 0.001

-0.006

(-0.023 to 0.01) 0.05

(0.038 to 0.064)

0.47

< 0.001

-0.004

(-0.03 to 0.024) 0.008

(-0.01 to 0.028)

0.78 0.4

Sex: female 0.032

(-0.023 to 0.091) 0.27 0.019

(-0.168 to 0.21) 0.84 -0.03

(-0.144 to 0.072) 0.57

(5)

APOE4 allele copy number

-0.019

(-0.072 to 0.032) 0.48 0.156

(-0.015 to 0.32) 0.079 -0.028

(-0.126 to 0.075) 0.57

Education, y 0.002

(-0.007 to 0.011) 0.70 0.026

(-0.005 to 0.058) 0.096 0.011

(-0.008 to 0.029) 0.22

Prefrontal cortex

Reversion: reverters 0.05

0.043

(-0.001 to 0.097) -0.095 (-0.203 to 0.023) 0.098 0.01

0.83 (-0.085 to 0.101)

Time to MCI onset × -0.002

Reversion (-0.01 to 0.006) 0.63 -0.002 (-0.014 to 0.01) 0.77 -0.012

0.28 (-0.033 to 0.011)

0.015

(-0.015 to -0.002) 0.03 (0.022 to 0.039) < 0.001 0.011

0.17 (-0.004 to 0.026)

Precentral gyrus

Sex: female 0.016

0.49

(-0.029 to 0.066) 0.029 (-0.086 to 0.132) 0.59 -0.043

0.32 (-0.13 to 0.046)

APOE4 allele copy -0.018

number (-0.063 to 0.03) 0.42 0.075 (-0.026 to 0.174) 0.14 -0.051

0.21 (-0.133 to 0.029)

Education, y 0.006

0.15

(-0.002 to 0.013) 0.014 (-0.003 to 0.03) 0.12 0.009

0.25 (-0.007 to 0.024)

Precuneus Reversion: reverters 0.064

(-0.003 to 0.129) 0.054 -0.204

(-0.454 to 0.013) 0.090 -0.116

(0.002 to 0.099) 0.070 -0.122

(-0.253 to 0.025) 0.082 0.015

Reversion

-0.002

(-0.009 to 0.007) 0.68 -0.005

(-0.018 to 0.007) 0.43 -0.006

(-0.024 to 0.011) 0.45

Postcentral gyrus

-0.008

(-0.014 to -0.002) 0.034

(-0.017 to 0.082)

0.021

0.19

0.037

(0.026 to 0.047) 0.037

(-0.085 to 0.155)

< 0.001

0.56

0.006

(-0.006 to 0.018) -0.022

(-0.103 to 0.058)

number

-0.008

(-0.053 to 0.036) 0.74 0.079

(-0.041 to 0.2) 0.19 -0.023

(-0.097 to 0.056) 0.53

Education, y 0.006

(-0.003 to 0.014) 0.18 0.018

(-0.002 to 0.04) 0.081 0.005

0.008 (0.018 to 0.131)

-0.196

(-0.402 to 0.013) 0.073 -0.002

0.97 (-0.11 to 0.101)

Time to MCI onset × 0.005 0.27

Reversion (-0.004 to 0.013)

-0.001

(-0.019 to 0.017) 0.88 -0.009

0.38 (-0.027 to 0.01)

< 0.001 (-0.024 to -0.01)

0.048

(0.035 to 0.062)

< 0.001 0.008

0.23 (-0.006 to 0.021)

Sex: female 0.012

0.64 (-0.037 to 0.064)

-0.003

(-0.203 to 0.199) 0.98 -0.036

0.43 (-0.13 to 0.055)

APOE4 allele copy 0.007

number (-0.043 to 0.059) 0.78

0.276

(0.103 to 0.469)

0.005 -0.032

0.46 (-0.122 to 0.056)

Education, y 0.002

0.70 (-0.007 to 0.011)

0.022

(-0.014 to 0.055)

0.20 0.009

0.24 (-0.006 to 0.025)

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0.007

(-0.003 to 0.018) 0.17 -0.01

(-0.029 to 0.008) 0.33 0.002

(-0.03 to -0.013) < 0.001 0.058

(0.043 to 0.075) < 0.001 0.006

(-0.014 to 0.025) 0.55

Sex: female 0.029

(-0.037 to 0.089) 0.37 0.046

(-0.171 to 0.246) 0.67 -0.076

number

-0.053

(-0.111 to 0.005) 0.088 0.177

(-0.029 to 0.377) 0.083 -0.055

(-0.179 to 0.077) 0.39

Education, y 0.002

(-0.008 to 0.013) 0.67 0.03

(-0.006 to 0.065) 0.096 0.016

(0.063 to 0.218) 0.001 -0.042

(-0.171 to 0.079) 0.54 -0.01

Reversion

-0.004

(-0.019 to 0.011) 0.61 -0.005

(-0.017 to 0.006) 0.42 0.005

(-0.013 to 0.023) 0.61

Primary visual cortex

-0.015

(-0.028 to -0.003) 0.023

(-0.054 to 0.106)

0.018

0.55

0.031

(0.022 to 0.041) 0.056

(-0.052 to 0.168)

< 0.001

0.32 0

(-0.014 to 0.012) -0.025

(-0.101 to 0.046)

number

0.001

(-0.07 to 0.075) 0.99 0.015

(-0.095 to 0.115) 0.78 -0.051

(-0.122 to 0.018) 0.15

Education, y 0.008

(-0.006 to 0.02) 0.24 0.013

(-0.006 to 0.032) 0.15 0.003

(0.027 to 0.128) 0.003 -0.141

(-0.299 to 0.018) 0.088 -0.023

Reversion

0.002

(-0.006 to 0.01) 0.61 -0.001

(-0.015 to 0.015) 0.90 0

(-0.015 to -0.003) 0.009 0.035

(0.022 to 0.047) < 0.001 -0.007

(-0.019 to 0.005) 0.23 Rolandic oper

Sex: female 0.006

(-0.044 to 0.06) 0.81 -0.002

(-0.155 to 0.136) 0.97 -0.052

number

0.015

(-0.033 to 0.062) 0.53 0.114

(-0.023 to 0.245) 0.097 -0.035

(-0.123 to 0.05) 0.42

Education, y 0.005

(-0.003 to 0.013) 0.22 0.017

(-0.007 to 0.043) 0.15 0.007

(0 to 0.099) 0.045 -0.193 (-0.385 to -0.03) 0.034 -0.001

(-0.11 to 0.111) 0.98

Supplementary motor area

Time to MCI onset, y

-0.001

(-0.01 to 0.008) -0.01

(-0.017 to -0.002)

0.87 0.011

-0.004

(-0.021 to 0.012) 0.041

(0.029 to 0.054)

0.64

< 0.001

-0.014

(-0.041 to 0.014) 0.014

(-0.005 to 0.033)

0.29 0.12

Sex: female 0.029

(-0.017 to 0.077) 0.23 0.005

(-0.165 to 0.165) 0.96 -0.036

(-0.142 to 0.068) 0.47

(7)

-0.023

(-0.072 to 0.023) 0.31 0.17

(0.013 to 0.326) 0.034 -0.054

(-0.143 to 0.03) 0.23

Education, y 0.006

(-0.002 to 0.014) 0.16 0.019

(-0.008 to 0.045) 0.18 0.01

(0.009 to 0.103) 0.020 -0.127

(-0.311 to 0.043) 0.16 -0.036

Reversion

0.005

(-0.001 to 0.013) 0.14 -0.007

(-0.022 to 0.007) 0.35 -0.003

(-0.02 to -0.009) <0.001 0.046

(0.034 to 0.058) <0.001 0.009

(-0.011 to 0.03) 0.37 Temporal cortex

0.024

(-0.023 to 0.071)

0.026

(-0.133 to 0.186)

-0.063

(-0.173 to 0.049)

Sex: female 0.32 0.75 0.24

0.002

(-0.043 to 0.048) 0.95 0.088

(-0.071 to 0.236) 0.24 -0.045

(-0.139 to 0.055) 0.37

Education, y -0.001

(-0.009 to 0.007) 0.78 0.023

(-0.004 to 0.049) 0.078 0.011

(-0.006 to 0.03) 0.20 Abbreviations: APOE, apolipoprotein E; MRI, magnetic resonance imaging; PET, positron emission tomography; FDG, F-18 fluorodeoxyglucose; CI, confidence interval Coefficients, 95% CIs, and p-values result from mixed effect models accounting for random slopes and intercepts

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eMethod 1 Cognitive tests included in composite score construction in each cohort

MCSA ROSMAP NACC

Wechsler Memory Scale-Revised Logical Memory-II (delayed recall)

Immediate recall of the East Boston Story and Story A from Logical Memory

Wechsler Memory Scale-Revised Logical Memory-II (delayed recall)

Memory composite score

Wechsler Memory Scale-Revised Visual Reproduction-II (delayed recall)

Auditory verbal learning test (delayed recall)

Immediate recall of Story A from Logical Memory

Delayed recall of the East Boston Story and Story A from Logical Memory

Delayed recall of Story A from Logical Memory Word List Memory

Word List Recall Word List Recognition

Wechsler Memory Scale-Revised Logical Memory-II (immediate recall)

Working memory/attention composite score

Language composite score

Trail-Making Test, Part B Digit Span Forward Digit Span Forward

WAIS-R Digit Symbol Substitution Test Digit Span Backward Digit Span Backward

Digit Ordering tests

Boston Naming Test Boston naming Animal naming

Category fluency Category fluency Vegetable naming

Reading test Boston naming

The domain-specific scores were calculated as the mean z score of each component, which was further scaled by themselves with age- and sex- weighted mean and standard deviation (SD)

The score for each test was scaled with the baseline mean and standard deviation (SD) of all participants. These scaled scores were averaged for the construction of composite scores

Each test was scaled with the baseline mean and SD from cognitively normal subjects aged over 65. The domain-specific composite scores were scaled mean of the component scores.

Z score calculation

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eMethod 2 Neurological diagnosis criteria

MCSA^{1,2, 3} ROSMAP NACC

Cognitively normal The participants had cognitive performances in the normative range and did not meet the criteria for

MCI or dementia The diagnosis of cognitively normal was given

by the clinician based on cognitive tests and cognitive impairment ratings generated by the algorithm

Normal cognition was diagnosed for individuals who had a global CDR = 0, and their

neuropsychological tests were within the normal range.

MCI 1) there was a cognitive concern for the participant;

2) the participant showed cognitive impairment in one or more cognitive domains;

3) the participant had normal functional activities and were absent of dementia.

4) MCI patients were further classified as amnestic MCI (aMCI) if the memory domain was impaired or non-amnestic MCI (Non-aMCI) if the memory domain is intact.

5) The patient was also classified as single- or multi-domain MCI depending on the number of cognitive domains affected

MCI was diagnosed when the participant had cognitive impairment but did not meet the criteria for dementia

1) a concern about the change in cognition;

2) one or more cognitive domains (memory, language, executive function, attention, and visuospatial function) were impaired;

3) functional independence was preserved.

Dementia 1) The participant receives a CDR >=1;

2) The participant meets the DSM-IV criteria for dementia

The diagnosis of dementia and dementia due to AD followed the criteria of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related

Disorders Association (NINCDS/ADRDA).

Individuals who had cognitive impairment that affected their functional activity were diagnosed with dementia

Diagnosis procedures

The diagnosis for each participant was made by a consensus committee in MCSA

In ROSMAP, all participants were diagnosed with a 3-step process. Briefly, a domain- specific impairment score was generated by the computer-based on cognitive test batteries. With the impairment score and other clinical information, a neuropsychologist gave judgments about the participant with respect to the presence of impairment and dementia. Finally, a clinician gave a diagnosis classification with all available data.

Participants from NACC were diagnosed by a single or a group of clinicians, or a formal consensus panel

eReferences

1. Petersen, R.C., Mild cognitive impairment as a diagnostic entity. J Intern Med, 2004. 256(3): p. 183-94.

2. Bell, C.C., DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. JAMA, 1994. 272(10): p. 828-829.

3. Roberts, R.O., et al., Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol, 2018. 75(8): p.

970-979.