Background
Methods
Study cohort and selection criteria
Collection of CSF by lumbar puncture
Amyloid, t-tau, and p-tau measurements
Protein measurements
Determination of APOE genotypes
Statistics
Results
Amyloid-negative CN | Preclinical AD | Prodromal AD | AD dementia | |
---|---|---|---|---|
n | 112 | 51 | 102 | 188 |
Age in years, mean ± sd | 58.6 ± 7.8abc | 63.7 ± 7.9ad | 66.9 ± 7.7bdf | 65 ± 7.2cf |
Sex, female (%) | 38 (34%) | 24 (47%) | 35 (34%) | 90 (48%) |
APOE ε4 carriership (%) | 34 (30%)abc | 30 (59%)a | 71 (70%)b | 115 (61%)c |
MMSE, mean ± sd | 28.4 ± 1.4bc | 28 ± 1.4de | 26.4 ± 2bdf | 21 ± 4.4cf |
Amyloid, pg/ml, mean ± sd | 1144 ± 167abc | 651 ± 109ae | 625 ± 100bf | 593 ± 100cf |
T-tau, pg/ml, mean ± sd | 227 ± 85abc | 500 ± 307ae | 554 ± 319bf | 717 ± 398cf |
P-tau, pg/ml, mean ± sd | 40.3 ± 14abc | 72.1 ± 39ae | 75.4 ± 34bf | 86.2 ± 36cf |
T-tau abnormal (%) | 8 (7.1%)abc | 31 (61%)ae | 73 (72%)b | 152 (81%)c |
P-tau abnormal (%) | 9 (8%)abc | 30 (59%)ae | 70 (69%)b | 147 (78%)c |
Demographic comparisons of p-tau subgroups
Characteristics per p-tau subgroup | p-values of p-tau subgroup comparisons | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Controls (n = 98) | Subgroup 1: p-tau ≤ 56 pg/ml (n = 94) | Subgroup 2: p-tau 57–96 pg/ml (n = 147) | Subgroup 3: p-tau 97–159 pg/ml (n = 89) | Subgroup 4: p-tau > 159 pg/ml (n = 11) | p-value of group difference | Control-subgroup 1 | Control-subgroup 2 | Control-subgroup 3 | Control-subgroup 4 | Subgroup 1–2 | Subgroup 1–3 | Subgroup 1–4 | Subgroup 2–3 | Subgroup 2–4 | Subgroup 3–4 | |
Preclinical AD, n (percentagea) | 0 (0%) | 21 (22%) | 20 (14%) | 9 (10%) | 1 (9.1%) | 7.2E−05 | n.t. | n.t. | n.t. | n.t. | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 |
Prodromal AD, n (percentagea) | 0 (0%) | 32 (34%) | 46 (31%) | 21 (24%) | 3 (27%) | 2.4E−08 | n.t. | n.t. | n.t. | n.t. | 1.4E−02 | 0.524 | 0.931 | 0.524 | 1.000 | 1.000 |
AD dementia, n (percentagea) | 0 (0%) | 41 (44%) | 81 (55%) | 59 (66%) | 7 (64%) | 1.1E−21 | n.t. | n.t. | n.t. | n.t. | 0.0E+00 | 0.0E+00 | 8.9E−03 | 0.178 | 0.977 | 1.000 |
Age in years, mean ± sd | 58.2 ± 7.9 | 63.6 ± 7.8 | 65.5 ± 6.9 | 66.6 ± 7.8 | 68.5 ± 8.6 | 6.0E−13 | 1.3E−05 | 2.0E−10 | 3.4E−10 | 7.4E−04 | 0.119 | 1.5E−02 | 0.080 | 0.179 | 0.208 | 0.581 |
Sex, female (%) | 32 (33%) | 33 (35%) | 56 (38%) | 52 (58%) | 8 (73%) | 4.2E−04 | 0.836 | 0.661 | 6.9E−03 | 0.056 | 0.822 | 1.2E−02 | 0.073 | 1.2E−02 | 0.088 | 0.696 |
APOE ε4 carriership (%) | 28 (29%) | 62 (66%) | 93 (63%) | 54 (61%) | 7 (64%) | 1.2E−07 | 0.0E+00 | 0.0E+00 | 1.0E−04 | 0.108 | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 |
MMSE score, mean ± sd | 28.5 ± 1.4 | 24.6 ± 4.7 | 23.9 ± 4.2 | 22.4 ± 4.8 | 22.5 ± 4.3 | 1.3E−28 | 1.8E−12 | 2.1E−22 | 3.7E−22 | 3.5E−06 | 0.072 | 6.1E−04 | 0.086 | 2.5E−02 | 0.282 | 0.987 |
Amyloid in pg/ml, mean ± sd | 1139 ± 161 | 616 ± 119 | 607 ± 99 | 615 ± 95 | 596 ± 95 | 3.3E−48 | 2.7E−32 | 4.3E−39 | 1.4E−31 | 1.5E−07 | 0.846 | 0.953 | 0.846 | 0.846 | 0.846 | 0.846 |
t-tau in pg/ml, mean ± sd | 207 ± 59 | 286 ± 106 | 568 ± 154 | 982 ± 252 | 1732 ± 359 | 2.4E−77 | 6.3E−10 | 1.4E−38 | 1.7E−31 | 7.2E−08 | 1.7E−31 | 5.7E−31 | 7.2E−08 | 6.0E−29 | 4.8E−08 | 7.6E−07 |
p-tau in pg/ml, mean ± sd | 36.7 ± 9.3 | 42.9 ± 11 | 75.4 ± 11 | 116 ± 16 | 195 ± 23 | 4.0E−82 | 4.4E−06 | 4.2E−39 | 9.9E−32 | 7.8E−08 | 1.9E−38 | 3.2E−31 | 7.8E−08 | 2.2E−37 | 5.6E−08 | 7.8E−08 |
Abnormal t-tau status, n (%) | 0 (0%) | 15 (16%) | 141 (96%) | 89 (100%) | 11 (100%) | 2.2E−77 | n.t. | n.t. | n.t. | n.t. | 0.0E+00 | 0.0E+00 | 0.0E+00 | 0.17 | 1 | n.t. |
Abnormal p-tau status, n (%) | 0 (0%) | 0 (0%) | 147 (100%) | 89 (100%) | 11 (100%) | 1.0E−93 | n.t. | n.t. | n.t. | n.t. | n.t. | n.t. | n.t. | n.t. | n.t. | n.t. |
BACE1 in ng/ml, median (range) | 1.68 (.77–3.37) | 1.51 (.63–2.47) | 1.93 (1.04–3.48) | 2.51 (1.54–3.93) | 3.60 (2.61–4.34) | 2.1E−37 | 5.0E−03 | 2.0E−06 | 2.2E−18 | 1.3E−07 | 1.1E−13 | 2.2E−23 | 1.3E−07 | 7.0E−13 | 1.5E−07 | 7.4E−05 |
Aβ40 in ng/ml, median (range) | 6.09 (3.44–10.68) | 5.02 (2.0–8.92) | 6.71 (3.32–12.20) | 8.69 (3.59–13.95) | 9.40 (7.81–15.79) | 9.8E−34 | 2.8E−06 | 1.5E−02 | 8.4E−15 | 4.2E−06 | 3.3E−13 | 1.5E−23 | 2.2E−07 | 9.8E−13 | 1.1E−05 | 0.069 |
NfL in pg/ml, median (range) | 245 (113–1594) | 389 (147–1770) | 467 (169–2322) | 630 (304–1441) | 809 (413–1743) | 5.9E−37 | 5.5E−08 | 1.1E−20 | 3.4E−24 | 7.0E−07 | 4.5E−05 | 2.1E−14 | 3.1E−05 | 9.0E−09 | 4.1E−04 | 0.107 |
VAMP2 in pg/ml, median (range) | 131 (40–275) | 106 (28–229) | 163 (82–288) | 237 (84–398) | 382 (269–522) | 3.8E−41 | 2.9E−04 | 3.4E−07 | 6.9E−21 | 3.4E−07 | 8.3E−16 | 4.5E−24 | 3.4E−07 | 3.8E−15 | 3.2E−07 | 1.6E−05 |
NRGN in pg/ml, median (range) | 262 (73–498) | 250 (56–501) | 431 (188–752) | 657 (353–1268) | 1060 (754–1915) | 3.4E−63 | 0.735 | 9.3E−25 | 3.9E−30 | 8.1E−08 | 4.4E−25 | 9.2E−30 | 8.1E−08 | 4.3E−23 | 5.6E−08 | 1.2E−06 |
P-tau subgroups associated with amyloid production and synaptic biomarkers in AD
Protein (Z-score) | Controls (n = 98) | Protein level per p-tau group: mean ± standard error of the mean (SE) | Contrasts between p-tau subgroups | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Differences between p-tau subgroups: mean ± SE | p-values of contrasts | ||||||||||||||||||
Subgroup 1: p-tau ≤ 56 pg/ml (n = 94) | Subgroup 2: p-tau 57–96 pg/ml (n = 147) | Subgroup 3: p-tau 97–159 pg/ml (n = 89) | Subgroup 4: p-tau > 159 pg/ml (n = 11) | 1 vs control | 2 vs 1 | 3 vs 1 | 4 vs 1 | 3 vs 2 | 4 vs 2 | 4 vs 3 | 1 vs control | 2 vs 1 | 3 vs 1 | 4 vs 1 | 3 vs 2 | 4 vs 2 | 4 vs 3 | ||
BACE1 (n = 439) | 0.11 ± 0.1 | -0.46 ± 0.09 | 0.58 ± 0.07 | 1.44 ± 0.1 | 2.58 ± 0.27 | − 0.57 ± 0.13 | 1.05 ± 0.12 | 1.9 ± 0.13 | 3.04 ± 0.29 | 0.85 ± 0.12 | 1.99 ± 0.28 | 1.14 ± 0.28 | 1.1E−04 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 4.1E−11 | 2.6E−11 | 4.6E−04 |
Aβ40 (n = 439) | 0.18 ± 0.1 | -0.82 ± 0.1 | 0.32 ± 0.08 | 1.16 ± 0.1 | 1.67 ± 0.29 | − 0.99 ± 0.14 | 1.14 ± 0.13 | 1.98 ± 0.15 | 2.49 ± 0.31 | 0.84 ± 0.13 | 1.35 ± 0.3 | 0.51 ± 0.31 | 9.6E−11 | 0.0E+00 | 0.0E+00 | 8.3E−14 | 3.5E−09 | 8.2E−05 | 0.513 |
NfL (n = 436) | 0.13 ± 0.09 | 0.76 ± 0.09 | 1.22 ± 0.07 | 1.83 ± 0.09 | 2.36 ± 0.25 | 0.63 ± 0.12 | 0.47 ± 0.11 | 1.07 ± 0.12 | 1.6 ± 0.26 | 0.61 ± 0.11 | 1.14 ± 0.26 | 0.53 ± 0.26 | 2.8E−06 | 1.6E−04 | 7.8E−16 | 1.6E−08 | 4.9E−07 | 8.2E−05 | 0.262 |
VAMP2 (n = 396) | 0.12 ± 0.1 | -0.62 ± 0.1 | 0.67 ± 0.08 | 1.64 ± 0.1 | 2.9 ± 0.29 | − 0.74 ± 0.14 | 1.29 ± 0.13 | 2.25 ± 0.15 | 3.52 ± 0.31 | 0.97 ± 0.13 | 2.23 ± 0.3 | 1.27 ± 0.31 | 2.3E−06 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 5.7E−12 | 6.6E−12 | 3.1E−04 |
NRGN (n = 439) | 0.1 ± 0.09 | 0.03 ± 0.08 | 1.41 ± 0.07 | 2.43 ± 0.09 | 3.92 ± 0.24 | − 0.07 ± 0.12 | 1.37 ± 0.11 | 2.4 ± 0.12 | 3.89 ± 0.26 | 1.02 ± 0.11 | 2.51 ± 0.25 | 1.49 ± 0.26 | 0.997 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 7.1E−08 |
Protein (n) | Protein level per group: estimate ± SE | Differences between p-tau subgroups: mean ± SE | p-values of contrasts | |||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Controls (n = 98) | Subgroup 1: p-tau ≤ 56 pg/ml (total n = 94) | Subgroup 2: p-tau 57–96 pg/ml (total n = 147) | Subgroup 3: p-tau 97–159 pg/ml (total n = 89) | Subgroup 4: p-tau > 159 pg/ml (total n = 11) | Interaction with cognitive stage: p-value | 1 vs controls | 2 vs 1 | 3 vs 1 | 4 vs 1 | 3 vs 2 | 4 vs 2 | 4 vs 3 | 1 vs controls | 2 vs 1 | 3 vs 1 | 4 vs 1 | 3 vs 2 | 4 vs 2 | 4 vs 3 | |
Preclinical AD | ||||||||||||||||||||
BACE1 (n = 51) | 0.1 ± 0.09 | − 0.27 ± 0.19 | 1.23 ± 0.19 | 1.86 ± 0.29 | 3.14 ± 0.86 | 0.381 | − 0.37 ± 0.21 | 1.5 ± 0.27 | 2.13 ± 0.34 | 3.41 ± 0.89 | 0.64 ± 0.34 | 1.92 ± 0.88 | 1.28 ± 0.91 | 0.788 | 9.0E−07 | 2.2E−08 | 2.8E−03 | 0.755 | 0.481 | 0.975 |
Aβ40 (n = 51) | 0.17 ± 0.1 | − 0.39 ± 0.2 | 0.96 ± 0.21 | 1.38 ± 0.31 | 2.78 ± 0.94 | 0.831 | − 0.55 ± 0.22 | 1.35 ± 0.29 | 1.77 ± 0.37 | 3.17 ± 0.96 | 0.42 ± 0.37 | 1.82 ± 0.96 | 1.4 ± 0.99 | 0.267 | 1.0E−04 | 5.5E−05 | 2.3E−02 | 0.998 | 0.721 | 0.973 |
NfL (n=50) | 0.15 ± 0.09 | 0.37 ± 0.17 | 0.92 ± 0.17 | 2.14 ± 0.26 | 2.05 ± 0.79 | 0.123 | 0.22 ± 0.19 | 0.56 ± 0.25 | 1.78 ± 0.31 | 1.69 ± 0.81 | 1.22 ± 0.31 | 1.13 ± 0.8 | − 0.09 ± 0.83 | 0.998 | 0.412 | 5.2E−07 | 0.549 | 2.3E−03 | 0.975 | 1.000 |
VAMP2 (n = 48) | 0.11 ± 0.1 | − 0.42 ± 0.21 | 1.09 ± 0.2 | 1.91 ± 0.3 | 2.96 ± 0.91 | 0.764 | − 0.53 ± 0.23 | 1.51 ± 0.29 | 2.32 ± 0.37 | 3.38 ± 0.93 | 0.81 ± 0.36 | 1.87 ± 0.93 | 1.06 ± 0.96 | 0.383 | 8.0E−06 | 1.5E−08 | 7.0E−03 | 0.414 | 0.620 | 0.999 |
NRGN (n = 51) | 0.09 ± 0.09 | 0.09 ± 0.17 | 1.65 ± 0.18 | 2.86 ± 0.26 | 3.96 ± 0.79 | 0.403 | 0 ± 0.19 | 1.56 ± 0.25 | 2.77 ± 0.31 | 3.87 ± 0.81 | 1.21 ± 0.32 | 2.31 ± 0.81 | 1.1 ± 0.84 | 1.000 | 1.3E−08 | 0.0E+00 | 5.7E−05 | 3.0E−03 | 0.094 | 0.988 |
Prodromal AD | ||||||||||||||||||||
BACE1 (n = 102) | 0.1 ± 0.09 | − 0.14 ± 0.15 | 0.62 ± 0.13 | 1.73 ± 0.19 | 3.12 ± 0.5 | 0.381 | − 0.24 ± 0.18 | 0.76 ± 0.2 | 1.87 ± 0.24 | 3.26 ± 0.52 | 1.11 ± 0.23 | 2.5 ± 0.51 | 1.38 ± 0.53 | 0.980 | 2.9E−03 | 2.5E−12 | 2.1E−08 | 3.0E−05 | 3.4E−05 | 0.180 |
Aβ40 (n = 102) | 0.17 ± 0.1 | − 0.58 ± 0.17 | 0.52 ± 0.14 | 1.55 ± 0.21 | 2.12 ± 0.54 | 0.831 | − 0.75 ± 0.19 | 1.11 ± 0.21 | 2.13 ± 0.27 | 2.71 ± 0.57 | 1.03 ± 0.25 | 1.6 ± 0.56 | 0.57 ± 0.58 | 2.5E−03 | 8.2E−06 | 2.1E−13 | 5.1E−05 | 8.7E−04 | 0.088 | 1.000 |
NfL (n = 101) | 0.15 ± 0.09 | 0.65 ± 0.14 | 0.84 ± 0.12 | 1.28 ± 0.17 | 2.01 ± 0.45 | 0.123 | 0.51 ± 0.16 | 0.18 ± 0.18 | 0.63 ± 0.22 | 1.35 ± 0.47 | 0.44 ± 0.21 | 1.17 ± 0.47 | 0.73 ± 0.48 | 4.4E−02 | 1.000 | 0.102 | 0.091 | 0.506 | 0.235 | 0.950 |
VAMP2 (n = 90) | 0.11 ± 0.1 | − 0.35 ± 0.16 | 0.69 ± 0.15 | 1.91 ± 0.21 | 3.27 ± 0.52 | 0.764 | − 0.46 ± 0.19 | 1.05 ± 0.22 | 2.26 ± 0.27 | 3.62 ± 0.55 | 1.22 ± 0.26 | 2.57 ± 0.54 | 1.36 ± 0.56 | 0.278 | 5.7E−05 | 9.3E−15 | 2.8E−09 | 5.3E−05 | 6.3E−05 | 0.287 |
NRGN (n = 102) | 0.09 ± 0.09 | 0.19 ± 0.14 | 1.45 ± 0.12 | 2.75 ± 0.18 | 4.74 ± 0.46 | 0.403 | 0.1 ± 0.16 | 1.26 ± 0.18 | 2.56 ± 0.22 | 4.55 ± 0.48 | 1.3 ± 0.21 | 3.29 ± 0.47 | 1.99 ± 0.49 | 1.000 | 3.0E−10 | 0.0E+00 | 0.0E+00 | 2.5E−08 | 2.6E−10 | 1.1E−03 |
AD dementia | ||||||||||||||||||||
BACE1 (n = 188) | 0.1 ± 0.09 | − 0.81 ± 0.13 | 0.41 ± 0.1 | 1.27 ± 0.11 | 2.27 ± 0.32 | 0.381 | − 0.91 ± 0.16 | 1.22 ± 0.16 | 2.08 ± 0.18 | 3.08 ± 0.35 | 0.86 ± 0.15 | 1.86 ± 0.34 | 1 ± 0.34 | 6.9E−07 | 1.1E−11 | 0.0E+00 | 0.0E+00 | 2.5E−07 | 1.4E−06 | 0.074 |
Aβ40 (n = 188) | 0.17 ± 0.1 | − 1.22 ± 0.15 | 0.06 ± 0.1 | 0.99 ± 0.12 | 1.33 ± 0.35 | 0.831 | − 1.38 ± 0.18 | 1.28 ± 0.18 | 2.21 ± 0.19 | 2.55 ± 0.38 | 0.93 ± 0.16 | 1.27 ± 0.37 | 0.34 ± 0.37 | 7.2E−13 | 6.6E−11 | 0.0E+00 | 1.7E−09 | 2.6E−07 | 1.3E−02 | 1.000 |
NfL (n = 188) | 0.15 ± 0.09 | 1.02 ± 0.12 | 1.5 ± 0.09 | 1.97 ± 0.1 | 2.54 ± 0.29 | 0.123 | 0.87 ± 0.15 | 0.48 ± 0.15 | 0.95 ± 0.16 | 1.52 ± 0.32 | 0.47 ± 0.13 | 1.04 ± 0.31 | 0.57 ± 0.31 | 1.4E−07 | 2.9E−02 | 1.2E−07 | 5.6E−05 | 1.1E−02 | 1.6E−02 | 0.762 |
VAMP2 (n = 167) | 0.11 ± 0.1 | − 0.95 ± 0.15 | 0.55 ± 0.11 | 1.5 ± 0.12 | 2.71 ± 0.37 | 0.764 | − 1.07 ± 0.18 | 1.5 ± 0.18 | 2.45 ± 0.2 | 3.67 ± 0.4 | 0.95 ± 0.16 | 2.17 ± 0.38 | 1.22 ± 0.39 | 2.0E−07 | 1.4E−13 | 0.0E+00 | 0.0E+00 | 2.8E−07 | 6.9E−07 | 3.7E−02 |
NRGN (n = 188) | 0.09 ± 0.09 | − 0.13 ± 0.12 | 1.32 ± 0.09 | 2.25 ± 0.1 | 3.57 ± 0.3 | 0.403 | − 0.22 ± 0.15 | 1.45 ± 0.15 | 2.38 ± 0.16 | 3.69 ± 0.32 | 0.93 ± 0.14 | 2.24 ± 0.31 | 1.32 ± 0.31 | 0.961 | 0.0E+00 | 0.0E+00 | 0.0E+00 | 5.4E−10 | 4.9E−11 | 7.1E−04 |
Associations of p-tau subgroups with protein levels in CN amyloid-negative individuals
Protein (n) | Protein level per group: estimate ± standard error of the mean (SE) | Differences between p-tau subgroups: mean ± SE | p-values of contrasts | ||||||
---|---|---|---|---|---|---|---|---|---|
Subgroup 1: p-tau ≤ 56 pg/ml (n = 103) | Subgroup 2: p-tau 57–96 pg/ml (n = 7) | Subgroup 3: p-tau 97–159 pg/ml (n = 2) | 2 vs 1 | 3 vs 1 | 3 vs 2 | 2 vs 1 | 3 vs 1 | 3 vs 2 | |
Core AD biomarker | |||||||||
Aβ42 (n = 112) | 0.04 ± 0.11 | 0.61 ± 0.39 | − 0.01 ± 0.74 | 0.56 ± 0.41 | − 0.05 ± 0.74 | − 0.62 ± 0.83 | 0.427 | 1.000 | 0.843 |
Analytes | |||||||||
BACE1 (n = 112) | 0.03 ± 0.1 | 1.44 ± 0.37 | 2.71 ± 0.69 | 1.4 ± 0.38 | 2.68 ± 0.69 | 1.28 ± 0.78 | 1.02E−03 | 5.61E−04 | 0.276 |
Aβ40 (n = 112) | 0.1 ± 0.1 | 1.55 ± 0.36 | 2.3 ± 0.69 | 1.45 ± 0.38 | 2.2 ± 0.69 | 0.75 ± 0.77 | 6.24E−04 | 5.54E−03 | 0.701 |
NfL (n = 111) | − 0.07 ± 0.09 | 0.36 ± 0.31 | 0.34 ± 0.59 | 0.42 ± 0.32 | 0.41 ± 0.59 | − 0.02 ± 0.66 | 0.470 | 0.869 | 1.000 |
VAMP2 (n = 105) | 0.07 ± 0.11 | 1.4 ± 0.38 | 2.3 ± 0.72 | 1.33 ± 0.39 | 2.23 ± 0.72 | 0.9 ± 0.8 | 3.16E−03 | 7.51E−03 | 0.604 |
NRGN (n = 112) | 0.09 ± 0.1 | 1.37 ± 0.38 | 2.88 ± 0.71 | 1.29 ± 0.39 | 2.79 ± 0.72 | 1.5 ± 0.8 | 4.25E−03 | 5.29E−04 | 0.180 |