Supplemental Table 1. Characteristics of non-AD patients.

Cognitive disorders / N = 188
Subjective memory complaint / 28
Depression / psychiatric disorders / 25
Alcohol dementia / 25
Frontotemporal dementia / 15
Vascular dementia / 12
Non neurological controls / 10
Lewy Body dementia / 8
Other degenerative dementiaa / 32
Other non degenerative dementiab / 33
aCorticobasal degeneration, Parkinson's disease, progressive supranuclear palsy,
focal atrophy, Huntington disease, motor neuron disease.
b toxic related dementia, normal pressure hydrocephalus, infectious diseases,
vitamin deficiency.

Supplemental Table 2. Characteristics of AD and non-AD patients according to APOE genotype.

AD patients / Non AD patients
Characteristics / Non E4 / E4 / P-value / Non E4 / E4 / P-value
N (%) / 94 (45.0) / 115 (55.0) / 98 (76.6) / 30 (23.4)
Age, years, mean (SD) / 72.7 (10.1) / 71.8 (7.8) / 0.49 / 63.2 (11.4) / 66.5 (9.7) / 0.15
Women, n (%) / 55 (58.5) / 68 (59.1) / 0.93 / 50 (51.0) / 10 (33.3) / 0.09
High education level, n (%)a / 31 (36.9) / 30 (30.3) / 0.35 / 27 (35.1) / 9 (33.3) / 0.87
MMSE, years, mean (SD) / 21.3 (5.5) / 20.2 (6.2) / 0.18 / 24.4 (4.2) / 23.2 (4.9) / 0.20
Duration of AD, years, mean (SD) / 2.8 (1.7) / 2.6 (1.8) / 0.75 / — / —
CSF biomarkers, pg/mL, mean (SD)
Aβ 1-42 / 554.3 (273.9) / 433.9 (142.2) / <0.001 / 871.3 (260.8) / 770.5 (270.6) / 0.07
Total Tau / 610.7 (300.4) / 574.3 (288.5) / 0.37 / 224.8 (130.8) / 240.8 (107.2) / 0.54
p-Tau 181 / 99.4 (53.1) / 92.0 (35.9) / 0.23 / 44.7 (14.5) / 47.7 (10.8) / 0.35
aBaccalaureate degree and higher.

Supplemental Table 3. AUC and optimal thresholds of CSF biomarkers according to APOE E4 status.

AUC (SE) / Threshold, pg/mL / Sensitivity / Specificity
Aβ 1-42
AD vs non-AD / 0.83 (0.02) / 568 / 0.81 / 0.78
AD non E4 vs non-AD / 0.76 (0.03) / 515 / 0.87 / 0.61
AD E4 vs non-AD / 0.89 (0.02) / 568 / 0.81 / 0.89
Total Tau
AD vs non-AD / 0.92 (0.01) / 307 / 0.88 / 0.89
AD non E4 vs non-AD / 0.93 (0.02) / 307 / 0.93 / 0.89
AD E4 vs non-AD / 0.92 (0.02) / 321 / 0.87 / 0.89
p-Tau 181
AD vs non-AD / 0.93 (0.01) / 65 / 0.81 / 0.91
AD non E4 vs non-AD / 0.94 (0.01) / 65 / 0.86 / 0.91
AD E4 vs non-AD / 0.92 (0.02) / 61 / 0.87 / 0.86

Supplemental Table 4. CSF Tau levels according to APOE genotype.

Total Tau, pg/mL
APOE genotype / Mean (SD) / CV, %a / Unadjusted / Adjusted b
AD patients
E2/E2, E2/E3 / 593.5 (343.4) / 57.8 / 0.85 / 0.96
E3/E3 / 612.7 (297.1) / 48.5 / Ref. / Ref.
E2/E4, E3/E4 / 581.5 (295.0) / 50.7 / 0.49 / 0.48
E4/E4 / 549.5 (268.9) / 48.9 / 0.34 / 0.29
Non-AD patients
E2/E2, E2/E3 / 223.5 (134.8) / 60.3 / 0.81 / 0.94
E3/E3 / 232.2 (108.2) / 46.6 / Ref. / Ref.
E2/E4, E3/E4, E4/E4 / 240.8 (107.2) / 44.5 / 0.52 / 0.48
a Coefficient of variation = SD / mean.
b Adjusted on age, sex, MMSE score, education level, and duration of AD.

Supplemental Table 5. Repartition of APOEgenotype in AD patients, according to CSF biomarkers cut-offs.The use of more stringent cut-offs of CSF Aβ1-42 leads to progressively increase the proportion of ε4/ ε4 AD patients in the selected sample

AD patients / E2/E2 / E2/E4
Characteristics / N / E2/E3 / E3/E3 / E3/E4 / E4/E4 / Z-statistic / P-value
Overall, n (%) / 209 / 10 (4.8) / 84 (40.2) / 89 (42.6) / 26 (12.4) / Ref. / .
Aβ 1-42 cut-offs, pg/mL, n (%)
<600 / 168 / 6 (3.6) / 58 (34.5) / 79 (47.0) / 25 (14.9) / -0.69 / 0.49
<500 / 145 / 5 (3.5) / 50 (34.5) / 66 (45.5) / 24 (16.6) / -1.09 / 0.28
<450 / 110 / 2 (1.8) / 41 (37.3) / 46 (41.8) / 21 (19.1) / -1.59 / 0.11
<400 / 84 / 2 (2.4) / 31 (36.9) / 32 (38.1) / 19 (22.6) / -2.19 / 0.03
<350 / 54 / 0 / 21 (28.9) / 19 (35.2) / 14 (25.9) / -2.46 / 0.01
Total Tau cut-offs,pg/mL, n (%)
>250 / 196 / 9 (4.6) / 80 (40.8) / 83 (42.3) / 24 (12.2) / 0.06 / 0.95
>300 / 187 / 9 (4.8) / 78 (41.7) / 77 (41.2) / 22 (13.3) / 0.21 / 0.83
>350 / 167 / 6 (3.7) / 72 (43.1) / 69 (41.3) / 20 (12.0) / 0.14 / 0.89
>400 / 147 / 6 (4.1) / 62 (42.2) / 62 (42.2) / 17 (11.6) / 0.25 / 0.80
>450 / 123 / 6 (4.9) / 51 (41.5) / 51 (41.5) / 15 (12.2) / 0.07 / 0.94

Supplemental Table 6. Diagnosis among non-AD patients with isolated low CSF Aβ levels.

Diagnosis, n (%) / Non-AD patients with isolated low Aβ levels (N=32)
Vascular dementia / 6 (19)
Lewy Body dementia / 5 (16)
Frontotemporal dementia / 4 (13)
Depression / psychiatric disorders / 4 (13)
Normal pressure hydrocephalus / 3 (9)
Parkinson with dementia / 2 (6)
Alcohol dementia / 2 (6)
sleep apnea syndrome / 2 (6)
HIV / 2 (6)
Non neurological controls / 2 (6)

Supplemental Table 7. Discriminatory power of CSF biomarkers to distinguish AD patients from those with or without another neurodegenerative disease.

CSF biomarkers, pg/mL / AUC (SE) / Cut-off, pg/mL / Sensitivity / Specificity
AD (N=244) vs non-AD / neurodegenerative diseases (N=67)
Aβ 1-42 / 0.73 (0.04) / 606 / 0.81 / 0.63
Total Tau / 0.89 (0.03) / 288 / 0.9 / 0.83
p-Tau 181 / 0.92 (0.03) / 61 / 0.86 / 0.93
AD (N=244) vs non-AD / non-neurodegenerative diseases (N=121)
Aβ 1-42 / 0.86 (0.02) / 543 / 0.75 / 0.89
Total Tau / 0.93 (0.01) / 307 / 0.88 / 0.9
p-Tau 181 / 0.93 (0.01) / 65 / 0.81 / 0.91

Supplemental Figure 1. Part A. ROC curves. CSF Tau to discriminate between non-AD patients and AD with ε4 allele (black curve), AD without ε4 allele (grey curve), and all AD patients (long-dashed curve). Analysis are detailed in supplementary Table 3.

Part B.Distribution of CSF Taulevels in AD and non-AD patients, according to APOE genotype. Box plots represent mean (diamond), median, 25th, 75th percentiles, extreme values. Horizontal long-dashed line is the optimal cut-off for CSF Tau (307 pg/mL) based on previous ROC curve analyse in the overall population study.