SUPPLEMENTARY TABLES

Supplementary table 1 Included neuropsychological tests per cohort

ADC ADNI DCN UCSF

ME

MO

RY

RAVLT immediate recall RAVLT immediate recall WL immediate recall CVLT immediate recall

RAVLT delayed recall RAVLT delayed recall WL delayed recall CVLT delayed recall

LM immediate recall LM immediate recall DS forward

LM delayed recall LM delayed recall

Figure recall

NO

N-M

EM

OR

Y

ABCD naming Boston naming Boston naming Boston naming

Language Animal fluency Animal fluency Animal fluency Animal fluency

VAT naming Repetition

TMT TMT TMT Modified trails

Digit span Digit span

Attention and Stroop Stroop

Executive functioning Letter fluency Letter fluency

LDST Design fluency

FAB Abstraction

Comparative questions

Number location Clock drawing Clock drawing Number location

Visuospatial functioning Dot counting Figure copy Figure copy

Fragmented letters

Calculation

Abbreviations: ABCD = Arizona Battery for Communication Disorders of Dementia, ADC = Amsterdam Dementia Cohort, ADNI = Alzheimer’s Disease Neuroimaging Initiative, CVLT = California Verbal Learning Test, DCN = German Dementia Competence Network, DS = Digit Span, FAB = Frontal Assessment Battery, LDST = Letter Digit Substitution Test, LM = Logical Memory, RAVLT = Rey Auditory Verbal Learning Test, TMT = Trail Making Test, UCSF = University of California – San Francisco, VAT = Visual Association Test, WL = Word List.

Supplementary table 2 Cluster characteristics mildly demented subjects (MMSE ≥ cohort median)

ADC

n = 288

ADNI

n = 234

DCN

n = 314

UCSF

n = 326

Pooled

n = 1.162

mem

n = 196

(68%)

non-mem

n = 92

(32%)

mem

n = 146

(62%)

non-mem

n = 88

(38%)

mem

n = 164

(52%)

non-mem

n = 150

(48%)

mem

n = 225

(69%)

non-mem

n = 101

(31%)

mem

n = 431

(37%)

non-mem

n = 731

(63%)

Demographics

Age 68.7 ± 7.7 66.0 ± 9.0 75.4 7.0 73.3 8.5 71.9 7.9 71.7 8.5 72.3 ± 9.5 68.5 ± 10.5‡ 71.9 ± 8.5 70.0 ± 9.4*

Female 94 (48%) 39 (42%) 72 (49%) 32 (36%) 91 (55%) 86 (57%) 119 (53%) 50 (50%) 376 (51%) 207 (48%)

Education 0.04 ± 0.99 -0.08 ± 1.02 -0.14 0.98 0.24 0.99 0.10 1.00 -0.11 0.99 -0.04 1.00 0.08 1.00 -0.01 ± 1.00 0.01 ± 1.00

Duration complaints 2.9 ± 2.0 2.6 ± 1.8 - - 3.0 ± 2.7 2.4 ± 1.6 - - 2.9 ± 2.3 2.5 ± 1.7‡

Global cognition

MMSE 24.6 ± 1.9 24.2 ± 1.9 24.5 1.2 24.9 1.4 25.0 1.5 25.0 1.8 26.1 1.7 27.0 1.8† 25.1 ± 1.8 25.3 ± 2.0

APOE ε4 genotype

APOE ε4 positive 130 (72%) 40 (50%)† 61 (70%) 21 (54%) 90 (70%) 54 (50%) 48 (79%) 19 (40%)† 329 (72%) 134 (49%)*

CSF biomarkers

Amyloid β1-42 -0.04 ± 0.98 0.09 ± 1.05 -0.05 ± 0.97 0.09 ± 1.07 -0.01 1.07 0.01 0.92 - - -0.03 ± 1.00 0.06 ± 1.00

tau 0.06 ± 0.99 -0.13 ± 1.02 -0.02 ± 0.92 0.04 ± 1.15 0.20 1.17 -0.14 0.91 - - 0.06 ± 1.00 -0.10 ± 1.00

ptau 0.03 ± 0.97 -0.07 ± 1.06 0.03 ± 1.01 -0.06 ± 1.00 0.20 1.17 -0.23 0.70 - - 0.07 ± 1.03 -0.13 ± 0.93‡

MRI

Hippocampus -0.05 ± 1.04 0.10 ± 0.91 -0.2 ± 0.99 0.36 ± 0.93 -0.13 0.99 0.16 0.99 - - -0.11 ± 1.01 0.19 ± 0.94*

Posterior cortex 0.13 ± 0.95 -0.30 ± 1.05† - - 0.07 1.03 -0.08 0.97 - - 0.10 ± 0.99 -0.16 ± 1.00*

Data are presented in number (%) or mean ± standard deviation, also when not-normally distributed enabling clearer comparison between clusters. p-values are based on t-tests, χ2, or Kruskal Wallis analyses when appropriate. Normalized values are given for education, CSF biomarkers, and MRI characteristics. When MRI characteristics were measured using a visual rating scale in which a higher score reflects more severe atrophy, results were inverted so that higher scores reflect larger volume / less atrophy. Differences between memory and non-memory clusters are shown in bold and indicated as follows: *p ≤ 0.001, †p ≤ 0.01, ‡p ≤ 0.05. Interpretation: The non-memory clusters were younger (pooled sample, UCSF), had shorter duration of complaints (pooled sample), lower MMSE scores (UCSF), were more often APOE e4 negative (pooled sample, UCSF), had lower CSF ptau concentrations (pooled sample), less hippocampal atrophy (pooled sample), but more severe atrophy of the posterior cortex (ADC, pooled sample).

Supplementary table 3 Cluster characteristics moderately demented subjects (MMSE < cohort median)

ADC

n = 208

ADNI

n = 142

DCN

n = 207

UCSF

n = 263

Pooled

n = 820

mem

n = 137

(66%)

non-mem

n = 71

(34%)

mem

n = 60

(42%)

non-mem

n = 82

(58%)

mem

n = 121

(58%)

non-mem

n = 86

(42%)

mem

n = 135

(51%)

non-mem

n = 128

(49%)

mem

n = 367

(45%)

non-mem

n = 453

(55%)

Demographics

Age 66. 7 (7.4) 63.2 (7.7)‡ 76.4 ± 7.7 75.4 ± 8.4 72.6 ± 7.2 71.2 ± 9.7 74.5 ± 9.9 68.4 ± 11.0 71.9 ± 8.9 69.6 ± 10.4†

Female 78 (57%) 47 (66%) 20 (33%) 41 (50%) 80 (66%) 56 (65%) 80 (59%) 79 (62%) 258 (57%) 223 (61%)

Education -0.01 ± 1.00 0.02 ± 1.01 0.23 ± 0.97 -0.17 ± 1.0 0.02 ± 0.98 -0.02 ± 1.03 0.02 ± 0.98 -0.02 ± 1.02 0.04 ± 0.98 -0.04 ± 1.01

Duration complaints 3.4 ± 2.5 3.0 ± 1.8 - - 2.5 ± 1.8 2.3 ± 1.9 - - 3.0 ± 2.3 2.6 ± 1.9

Global cognition

MMSE 19.4 ± 1.3 18.9 ± 1.4 20.8 ± 1.07 21.0 ± 0.8 20.6 ± 1.3 20.3 ± 1.5 20.8 ± 1.7 19.7 ± 2.0 20.3 ± 1.5 20.0 ± 1.7‡

APOE ε4 genotype

APOE ε4 positive 78 (64%) 51 (77%) 17 (63%) 29 (67%) 70 (71%) 41 (67%) 15 (56%) 18 (45%) 180 (66%) 139 (66%)

CSF biomarkers

Amyloid β1-42 0.02 ± 1.07 -0.04 ± 0.87 0.21 ± 1.47 -0.09 ± 0.75 -0.16 ± 0.96 0.23 ± 1.03 - - -0.02 ± 1.06 0.03 ± 0.90

tau -0.07 ± 0.90 0.13 ± 1.16 -0.04 ± 0.96 0.02 ± 1.04 0.06 ± 1.11 -0.09 ± 0.82 - - -0.03 ± 0.96 0.04 ± 1.05

ptau -0.04 ± 1.02 0.07 ± 0.97 -0.03 ± 1.30 0.01 ± 0.88 0.15 ± 1.09 -0.22 ± 0.82 - - 0.02 ± 1.05 -0.02 ± 0.92

MRI

Hippocampus -0.07 ± 1.01 0.16 ± 0.96 -0.09 ± 1.01 0.05 ± 1.00 -0.08 ± 0.89 0.12 ± 1.16 - - -0.08 ± 0.98 0.10 ± 1.01

Posterior cortex 0.06 ± 0.99 -0.13 ± 1.03 - - 0.07 ± 0.98 -0.10 ± 1.03 - - 0.07 ± 0.98 -0.12 ± 1.03

Data are presented in number (%) or mean ± standard deviation, also when not-normally distributed enabling clearer comparison between clusters. p-values are based on t-tests, χ2, or Kruskal Wallis analyses when appropriate. Normalized values are given for education, CSF biomarkers, and MRI characteristics. When MRI characteristics were measured using a visual rating scale in which a higher score reflects more severe atrophy, results were inverted so that higher scores reflect larger volume / less atrophy. Differences between memory and non-memory clusters are shown in bold and indicated as follows: *p ≤ 0.001, †p ≤ 0.01, ‡p ≤ 0.05. Interpretation: The non-memory clusters were younger (pooled sample, ADC, UCSF), and had lower MMSE scores (pooled sample, UCSF).

Supplementary table 4 Demographical and neurobiological characteristics of cognitive clusters identified in a CSF AD biomarker confirmed subset

ADC

n = 357 (72%)

mem

n = 260 (73%)

non-mem

n = 97 (27%)

Demographics

Age (years) 66.6 ± 7.8 63.8 ± 8.0†

Female 135 (52%) 52 (54%)

Education§ 5.1 ± 1.3 4.9 ± 1.3

Duration complaints 2.9 ± 1.9 2.8 ± 1.7

Global cognition

MMSE 22.7 ± 3.0 20.9 ± 3.1*

APOE ε4 genotype

APOE ε4 positive 184 (74%) 55 (61%)‡

MRI¶

Hippocampus 1.38 ± 0.82 1.20 ± 0.78

Posterior cortex 1.13 ± 0.71 1.51 ± 0.82‡

WMH 1.1 ± 0.8 1.0 ± 0.9

Characteristics of clusters identified in a subset of Data are presented in number (%) or mean ± standard deviation, also when not-normally distributed enabling clearer comparison between clusters. p-values are based on t-tests, χ2, or Kruskal Wallis analyses when appropriate. Differences between memory and non-memory cluster are indicated as follows *p ≤ 0.001, †p ≤ 0.01, ‡p ≤ 0.05. Education is given according to the Verhage scale (1-7 resp. low-high educated[1]). ¶Atrophy of the hippocampus and posterior cortex, and white matter hyperintensities (WMH) are scored using visual rating scales in which higher scores reflect more severe atrophy or WMH [2-4]. Interpretation: Within this CSF AD biomarker confirmed subset, the non-memory cluster was younger, had lower MMSE scores, was less often APOE e4 positive, and had more severe atrophy of the posterior cortex compared with the memory cluster.

SUPPLEMENTARY FIGURES

Supplementary figure 1 Neuropsychological components in mildly demented strata. Memory tests are indicated in dark blue. Abbreviations: ABCD = Arizona Battery for Communication Disorders of Dementia, ADC = Amsterdam Dementia Cohort, ADNI = Alzheimer’s Disease Neuroimaging Initiative, BNT = Boston Naming Test, comp questions = comparative questions, CVLT = California Verbal Learning Test, DCN = German Dementia Competence Network, DS = Digit Span, FAB = Frontal Assessment Battery, LDST = Letter Digit Substitution Test, LM = CERAD Logical Memory, mem = memory-impaired, non-mem = memory-spared, NMF = Nonnegative Matrix Factorization, RAVLT = Rey Auditory Verbal Learning Test, TMT = Trail Making Test, UCSF = University of California – San Francisco, VAT = Visual Association Test, WL = CERAD Word List. In all cohorts, the optimal number of test clusters was two. In this figure, each row represents one neuropsychological test. The two columns represent the two found neuropsychological components. The warmer the colour, the higher the test loads to the component when test scores are high (relatively spared cognition); the colder the colour (darker blue), the lower the test loads to the component when test scores are high (relatively impaired cognition). Interpretation: In each cohort, one component is associated with relative impairment of memory tests, therefore called the memory component. The other component is associated with relative impairment of non-memory functions, therefore called the non-memory component.

Supplementary figure 2 Cognitive clusters in mildly demented strata. Abbreviations: ADC = Amsterdam Dementia Cohort, ADNI = Alzheimer’s disease Neuroimaging Initiative, DCN = German Dementia Competence Network, UCSF = University of California – San Francisco. Patients were assigned to either the memory or non-memory cluster based on the fit of their neuropsychological profile to the memory or

non-memory component (supplementary figure 1). Each column represents one patient. The warmer the colour, the better the fit of patients’ neuropsychological profile to the neuropsychological profile of that

component (rows).

Supplementary figure 3 Neuropsychological components in moderately demented strata. Memory tests are indicated in dark blue. Abbreviations: ABCD = Arizona Battery for Communication Disorders of Dementia, ADC = Amsterdam Dementia Cohort, ADNI = Alzheimer’s Disease Neuroimaging Initiative, BNT = Boston Naming Test, comp questions = comparative questions, CVLT = California Verbal Learning Test, DCN = German Dementia Competence Network, DS = Digit Span, FAB = Frontal Assessment Battery, LDST = Letter Digit Substitution Test, LM = CERAD Logical Memory, mem = memory-impaired, non-mem = memory-spared, NMF = Nonnegative Matrix Factorization, RAVLT = Rey Auditory Verbal Learning Test, TMT = Trail Making Test, UCSF = University of California – San Francisco, VAT = Visual Association Test, WL = CERAD Word List. In all cohorts, the optimal number of test clusters was two. In this figure, each row represents one neuropsychological test. The two columns represent the two found neuropsychological components. The warmer the colour, the higher the test loads to the component when test scores are high (relatively spared cognition); the colder the colour (darker blue), the lower the test loads to the component when test scores are high (relatively impaired cognition). Interpretation: In each cohort, one component is associated with relative impairment of memory tests, therefore called the memory component. The other component is associated with relative impairment of non-memory functions, therefore called the non-memory component.

Supplementary figure 4 Cognitive clusters in moderately demented strata. Abbreviations: ADC = Amsterdam Dementia Cohort, ADNI = Alzheimer’s disease Neuroimaging Initiative, DCN = German Dementia Competence Network, UCSF = University of California – San Francisco. Patients were assigned to either the memory or non-memory cluster based on the fit of their neuropsychological profile to the memory or non-memory component (supplementary figure 3). Each column represents one patient. The warmer the colour, the better the fit of patients’ neuropsychological profile to the neuropsychological profile of that component (rows).

Supplementary figure 5. Neuropsychological components in CSF biomarker confirmed subset. Memory tests are indicated in dark blue. Abbreviations: ABCD = Arizona Battery for Communication Disorders of Dementia, ADC = Amsterdam Dementia Cohort, BNT = Boston Naming Test, comp questions = comparative questions, CVLT = California Verbal Learning Test, DS = Digit Span, FAB = Frontal Assessment Battery, LDST = Letter Digit Substitution Test, LM = CERAD Logical Memory, mem = memory-impaired, non-mem = memory-spared, NMF = Nonnegative Matrix Factorization, RAVLT = Rey Auditory Verbal Learning Test, TMT = Trail Making Test, VAT = Visual Association Test, WL = CERAD Word List. The optimal number of test clusters was two. Each row represents one neuropsychological test. The two columns represent the two found neuropsychological components. The warmer the colour, the higher the test loads to the component when test scores are high (relatively spared cognition); the colder the colour (darker blue), the lower the test loads to the component when test scores are high (relatively impaired cognition). Interpretation: One component is associated with relative impairment of memory tests, therefore called the memory component. The other component is associated with relative impairment of non-memory functions, therefore called the non-memory component.

Supplementary figure 6 Cognitive clusters in CSF biomarker confirmed subset. Abbreviations: ADC = Amsterdam Dementia Cohort. Patients were assigned to either the memory or non-memory cluster based on the fit of their neuropsychological profile to the memory or non-memory component (supplementary figure 5). Each column represents one patient. The warmer the colour, the better the fit of patients’ neuropsychological profile to the neuropsychological profile of that component (rows).

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