Background
Methods
Ethics
Registration
Study design
Subject disposition
Study material
β-hydroxybutyrate testing
Genotyping
Cognitive Testing
Statistical Methods
Results and Discussion
Single Nucleotide Polymorphisms (SNPs) effects on ADAS-Cog
gene | SNP | AC-1202 | Placebo | |||
---|---|---|---|---|---|---|
Allele | Count | Frequency | Count | Frequency | ||
IL1B
| rs1143627 | C | 6 | 0.098 | 9 | 0.173 |
Het | 27 | 0.443 | 17 | 0.327 | ||
T | 28 | 0.459 | 26 | 0.500 | ||
Total | 61 | 1 | 52 | 1 | ||
IL1B
| rs16944 | C | 28 | 0.459 | 26 | 0.500 |
Het | 27 | 0.443 | 17 | 0.327 | ||
T | 6 | 0.098 | 9 | 0.173 | ||
Total | 61 | 1 | 52 | 1 | ||
IDE
| rs2251101 | C | 9 | 0.138 | 7 | 0.127 |
Het | 21 | 0.323 | 25 | 0.454 | ||
T | 35 | 0.538 | 23 | 0.418 | ||
Total | 65 | 1 | 55 | 1 |
Day 45 Change from Baseline | ||||||||
---|---|---|---|---|---|---|---|---|
Gene | SNP/Allele | Genotype | AC1202 | n | Placebo | n | p-value* | Difference (CI) |
APOE
|
APOE
| 3/2 | -1.222 | 3 | 5.167 | 2 | 0.182 | 6.389(-3.050, 15.828) |
APOE
|
APOE
| 3/3 | -2.317 | 20 | 2.999 | 23 |
0.001
| 5.315(2.154, 8.476) |
APOE
|
APOE
| 4/2 | 2.778 | 3 | . | 0 | na | na |
APOE
|
APOE
| 4/3 | 1.107 | 28 | 2.175 | 19 | 0.492 | 1.068(-2.005, 4.142) |
APOE
|
APOE
| 4/4 | -1.667 | 3 | -1.167 | 10 | 0.884 | 0.500(-6.306, 7.306) |
IDE
| rs2251101 | C | 2.375 | 8 | -0.905 | 7 | 0.138 | 3.280(-1.076, 7.635) |
IDE
| rs2251101 | Het | -1.647 | 17 | 2.317 | 23 |
0.004
| 3.964(1.273, 6.656) |
IDE
| rs2251101 | T | -0.711 | 30 | 1.290 | 23 | 0.092 | 2.001(-0.331, 4.333) |
IDE c/c |
IDE c/c (-) |
IDE - | -1.050 | 47 | 1.804 | 46 |
0.002
| 2.853(1.100, 4.606) |
IDE c/c |
IDE c/c (+) |
IDE + | 2.375 | 8 | -0.905 | 7 | 0.140 | 3.280(-1.094, 7.654) |
IL1B
| rs1143627 | C | 1.000 | 5 | 2.481 | 9 | 0.545 | 1.481(-3.365, 6.328) |
IL1B
| rs1143627 | Het | -1.097 | 24 | -0.020 | 17 | 0.439 | 1.078(-1.677, 3.832) |
IL1B
| rs1143627 | T | -0.768 | 23 | 2.026 | 24 |
0.031
| 2.795(0.259, 5.330) |
IL1B
| rs16944 | C | -0.768 | 23 | 2.026 | 24 |
0.031
| 2.795(0.259, 5.330) |
IL1B
| rs16944 | Het | -1.097 | 24 | -0.020 | 17 | 0.439 | 1.078(-1.677, 3.832) |
IL1B
| rs16944 | T | 1.000 | 5 | 2.481 | 9 | 0.545 | 1.481(-3.365, 6.328) |
Day 90 Change from Baseline | ||||||||
APOE
|
APOE
| 3/2 | 3.667 | 1 | 6.333 | 1 | 0.737 | 2.667(-13.098, 18.431) |
APOE
|
APOE
| 3/3 | -2.579 | 19 | 1.398 | 20 |
0.029
| 3.977(0.406, 7.548) |
APOE
|
APOE
| 4/2 | -3.667 | 2 | . | 0 | na | na |
APOE
|
APOE
| 4/3 | 1.302 | 21 | 0.471 | 17 | 0.651 | 0.831(-2.806, 4.468,) |
APOE
|
APOE
| 4/4 | 1.667 | 2 | 0.867 | 10 | 0.854 | 0.800(-7.835, 9.435) |
IDE
| rs2251101 | C | 3.905 | 7 | -1.857 | 7 |
0.047
| 5.762(0.074, 11.450) |
IDE
| rs2251101 | Het | -2.769 | 13 | 2.944 | 19 |
0.004
| 5.713(1.883, 9.543) |
IDE
| rs2251101 | T | -0.931 | 24 | 0.446 | 21 | 0.392 | 1.377(-1.803, 4.556) |
IDE c/c |
IDE c/c (-) |
IDE - | -1.577 | 37 | 1.633 | 40 |
0.011
| 3.209(0.766, 5.652) |
IDE c/c |
IDE c/c (+) |
IDE + | 3.905 | 7 | -1.857 | 7 |
0.049
| 5.762(0.038, 11.486) |
IL1B
| rs1143627 | C | -1.083 | 4 | 1.815 | 9 | 0.396 | 2.898(-3.859, 9.656) |
IL1B
| rs1143627 | Het | -0.193 | 19 | -0.044 | 15 | 0.940 | 0.149(-3.735, 4.033) |
IL1B
| rs1143627 | T | -1.947 | 19 | 1.748 | 20 |
0.044
| 3.696(0.093, 7.298) |
IL1B
| rs16944 | C | -1.947 | 19 | 1.748 | 20 |
0.044
| 3.696(0.093, 7.298) |
IL1B
| rs16944 | Het | -0.193 | 19 | -0.044 | 15 | 0.940 | 0.149(-3.735, 4.033) |
IL1B
| rs16944 | T | -1.083 | 4 | 1.815 | 9 | 0.396 | 2.898(-3.859, 9.656) |
Day 104 Change from Baseline | ||||||||
APOE
|
APOE
| 3/2 | -1.333 | 3 | 2.333 | 2 | 0.474 | 3.667(-6.443, 13.776) |
APOE
|
APOE
| 3/3 | -0.812 | 23 | 1.384 | 21 | 0.196 | 2.196(-1.147, 5.538) |
APOE
|
APOE
| 4/2 | 0.889 | 3 | . | 0 | na | na |
APOE
|
APOE
| 4/3 | 0.821 | 26 | -0.722 | 18 | 0.370 | 1.543(-1.853, 4.938) |
APOE
|
APOE
| 4/4 | -1.083 | 4 | 0.933 | 10 | 0.543 | 2.017(-4.535, 8.568) |
IDE
| rs2251101 | C | 3.762 | 7 | 0.952 | 7 | 0.331 | 2.810(-2.895, 8.514) |
IDE
| rs2251101 | Het | -2.169 | 18 | 0.317 | 20 | 0.158 | 2.485(-0.982, 5.953) |
IDE
| rs2251101 | T | -0.029 | 33 | 0.867 | 22 | 0.547 | 0.896(-2.042, 3.834) |
IDE c/c |
IDE c/c (-) |
IDE - | -0.784 | 51 | 0.605 | 42 | 0.217 | 1.389(-0.828, 3.606) |
IDE c/c |
IDE c/c (+) |
IDE + | 3.762 | 7 | 0.952 | 7 | 0.330 | 2.810(-2.878, 8.497) |
IL1B
| rs1143627 | C | 0.778 | 6 | 0.407 | 9 | 0.898 | 0.370(-5.373, 6.114) |
IL1B
| rs1143627 | Het | -0.376 | 24 | 0.524 | 14 | 0.627 | 0.900(-2.765, 4.565) |
IL1B
| rs1143627 | T | -0.720 | 25 | 0.380 | 23 | 0.490 | 1.100(-2.049, 4.248) |
IL1B
| rs16944 | C | -0.720 | 25 | 0.380 | 23 | 0.490 | 1.100(-2.049, 4.248) |
IL1B
| rs16944 | Het | -0.376 | 24 | 0.524 | 14 | 0.627 | 0.900(-2.765, 4.565) |
IL1B
| rs16944 | T | 0.778 | 6 | 0.407 | 9 | 0.898 | 0.370(-5.373, 6.114) |
APOEgenotype effects on ADAS-Cog
Interactions with APOE4
Day 45 Change from Baseline | ||||||||
---|---|---|---|---|---|---|---|---|
gene | SNP | Allele | AC1202 | n | Placebo | n | p-value* | Difference(CI) |
IDE
|
IDE- |
IDE c/c (-) | -2.772 | 19 | 2.071 | 23 |
0.000
| 4.843(2.568, 7.118) |
IDE
|
IDE+ |
IDE c/c (+) | 0.667 | 4 | -0.667 | 1 | 0.745 | 1.333(-6.870, 9.536) |
IDE
| rs2251101 | C | 0.667 | 4 | -0.667 | 1 | 0.744 | 1.333(-6.867, 9.534) |
IDE
| rs2251101 | Het | -4.500 | 6 | 1.775 | 12 |
0.001
| 6.275(2.608, 9.942) |
IDE
| rs2251101 | T | -1.974 | 13 | 2.394 | 11 |
0.005
| 4.368(1.364, 7.373) |
IL1B
| rs1143627 | C | 0.333 | 3 | 4.333 | 3 | 0.192 | 4.000(-2.103, 10.103) |
IL1B
| rs1143627 | Het | -2.083 | 8 | 0.524 | 7 | 0.180 | 2.607(-1.261, 6.476) |
IL1B
| rs1143627 | T | -3.633 | 10 | 1.997 | 13 |
0.001
| 5.631(2.487, 8.775) |
IL1B
| rs16944 | C | -3.633 | 10 | 1.997 | 13 |
0.001
| 5.631(2.487, 8.775) |
IL1B
| rs16944 | Het | -2.083 | 8 | 0.524 | 7 | 0.180 | 2.607(-1.261, 6.476) |
IL1B
| rs16944 | T | 0.333 | 3 | 4.333 | 3 | 0.192 | 4.000(-2.103, 10.103) |
Day 90 Change from Baseline | ||||||||
IDE
|
IDE- |
IDE c/c (-) | -3.729 | 16 | 2.156 | 19 |
0.003
| 5.885(2.192, 9.578) |
IDE
|
IDE+ |
IDE c/c (+) | 3.583 | 4 | -5.333 | 1 | 0.146 | 8.917(-3.252, 21.086) |
IDE
| rs2251101 | C | 3.583 | 4 | -5.333 | 1 | 0.132 | 8.917(-2.834, 20.667) |
IDE
| rs2251101 | Het | -7.733 | 5 | 2.956 | 9 |
0.001
| 10.689(4.827, 16.551) |
IDE
| rs2251101 | T | -1.909 | 11 | 1.437 | 10 | 0.148 | 3.346(-1.246, 7.938) |
IL1B
| rs1143627 | C | -1.000 | 3 | 3.222 | 3 | 0.370 | 4.222(-5.241, 13.685) |
IL1B
| rs1143627 | Het | -0.250 | 8 | -0.389 | 6 | 0.964 | 0.139(-6.120, 6.398) |
IL1B
| rs1143627 | T | -5.667 | 8 | 2.463 | 10 |
0.005
| 8.130(2.633, 13.627) |
IL1B
| rs16944 | C | -5.667 | 8 | 2.463 | 10 |
0.005
| 8.130(2.633, 13.627) |
IL1B
| rs16944 | Het | -0.250 | 8 | -0.389 | 6 | 0.964 | 0.139(-6.120, 6.398) |
IL1B
| rs16944 | T | -1.000 | 3 | 3.222 | 3 | 0.370 | 4.222(-5.241, 13.685) |
Day 104 Change from Baseline | ||||||||
IDE
|
IDE- |
IDE c/c (-) | -1.909 | 22 | 1.686 | 21 |
0.026
| 3.595(0.451, 6.739) |
IDE
|
IDE+ |
IDE c/c (+) | 4.833 | 4 | -3.333 | 1 | 0.160 | 8.167(-3.356, 19.690) |
IDE
| rs2251101 | C | 4.833 | 4 | -3.333 | 1 | 0.152 | 8.167(-3.117, 19.451) |
IDE
| rs2251101 | Het | -4.546 | 8 | 0.867 | 10 |
0.028
| 5.413(0.625, 10.200) |
IDE
| rs2251101 | T | -0.402 | 14 | 2.430 | 11 | 0.167 | 2.833(-1.234, 6.899) |
IL1B
| rs1143627 | C | 1.444 | 3 | -0.333 | 3 | 0.670 | 1.778(-6.598, 10.153) |
IL1B
| rs1143627 | Het | 0.478 | 9 | 1.611 | 6 | 0.674 | 1.133(-4.273, 6.540) |
IL1B
| rs1143627 | T | -3.333 | 12 | 0.894 | 12 |
0.048
| 4.228(0.040, 8.415) |
IL1B
| rs16944 | C | -3.333 | 12 | 0.894 | 12 |
0.048
| 4.228(0.040, 8.415) |
IL1B
| rs16944 | Het | 0.478 | 9 | 1.611 | 6 | 0.674 | 1.133(-4.273, 6.540) |
IL1B
| rs16944 | T | 1.444 | 3 | -0.333 | 3 | 0.670 | 1.778(-6.598, 10.153) |
Day 45 Change from Baseline | ||||||||
---|---|---|---|---|---|---|---|---|
gene | SNP | Allele | AC1202 | n | Placebo | n | p-value | Difference(CI) |
IDE
|
IDE- |
IDE c/c (-) | 0.119 | 28 | 1.536 | 23 | 0.276 | 1.417(-1.163, 3.998) |
IDE
|
IDE+ |
IDE c/c (+) | 4.083 | 4 | -0.944 | 6 | 0.094 | 5.028(-0.892, 10.947) |
IDE
| rs2251101 | C | 4.083 | 4 | -0.944 | 6 | 0.091 | 5.028(-0.827, 10.883) |
IDE
| rs2251101 | Het | -0.091 | 11 | 2.909 | 11 | 0.126 | 3.000(-0.868, 6.868) |
IDE
| rs2251101 | T | 0.255 | 17 | 0.278 | 12 | 0.989 | 0.023(-3.397, 3.443) |
IL1B
| rs1143627 | C | 2.000 | 2 | 1.556 | 6 | 0.908 | 0.444(-7.234, 8.123) |
IL1B
| rs1143627 | Het | -0.604 | 16 | -0.400 | 10 | 0.914 | 0.204(-3.587, 3.995) |
IL1B
| rs1143627 | T | 1.436 | 13 | 2.061 | 11 | 0.746 | 0.625(-3.228, 4.477) |
IL1B
| rs16944 | C | 1.436 | 13 | 2.061 | 11 | 0.746 | 0.625(-3.228, 4.477) |
IL1B
| rs16944 | Het | -0.604 | 16 | -0.400 | 10 | 0.914 | 0.204(-3.587, 3.995) |
IL1B
| rs16944 | T | 2.000 | 2 | 1.556 | 6 | 0.908 | 0.444(-7.234, 8.123) |
Day 90 Change from Baseline | ||||||||
IDE
|
IDE- |
IDE c/c (-) | 0.063 | 21 | 1.159 | 21 | 0.508 | 1.095(-2.211, 4.402) |
IDE
|
IDE+ |
IDE c/c (+) | 4.333 | 3 | -1.278 | 6 | 0.143 | 5.611(-1.965, 13.187) |
IDE
| rs2251101 | C | 4.333 | 3 | -1.278 | 6 | 0.143 | 5.611(-1.961, 13.183) |
IDE
| rs2251101 | Het | 0.333 | 8 | 2.933 | 10 | 0.308 | 2.600(-2.479, 7.679) |
IDE
| rs2251101 | T | -0.103 | 13 | -0.455 | 11 | 0.872 | 0.352(-4.035, 4.739) |
IL1B
| rs1143627 | C | -1.333 | 1 | 1.111 | 6 | 0.687 | 2.444(-9.715, 14.603) |
IL1B
| rs1143627 | Het | -0.152 | 11 | 0.185 | 9 | 0.894 | 0.337(-4.723, 5.396) |
IL1B
| rs1143627 | T | 0.758 | 11 | 1.033 | 10 | 0.910 | 0.276(-4.643, 5.194) |
IL1B
| rs16944 | C | 0.758 | 11 | 1.033 | 10 | 0.910 | 0.276(-4.643, 5.194) |
IL1B
| rs16944 | Het | -0.152 | 11 | 0.185 | 9 | 0.894 | 0.337(-4.723, 5.396) |
IL1B
| rs16944 | T | -1.333 | 1 | 1.111 | 6 | 0.687 | 2.444(-9.715, 14.603) |
Day 104 Change from Baseline | ||||||||
IDE
|
IDE- |
IDE c/c (-) | 0.069 | 29 | -0.476 | 21 | 0.733 | 0.545(-2.646, 3.737) |
IDE
|
IDE+ |
IDE c/c (+) | 2.333 | 3 | 1.667 | 6 | 0.866 | 0.667(-7.210, 8.543) |
IDE
| rs2251101 | C | 2.333 | 3 | 1.667 | 6 | 0.868 | 0.667(-7.357, 8.690) |
IDE
| rs2251101 | Het | -0.267 | 10 | -0.233 | 10 | 0.990 | 0.033(-5.041, 5.108) |
IDE
| rs2251101 | T | 0.246 | 19 | -0.697 | 11 | 0.662 | 0.943(-3.356, 5.242) |
IL1B
| rs1143627 | C | 0.111 | 3 | 0.778 | 6 | 0.871 | 0.667(-7.534, 8.868) |
IL1B
| rs1143627 | Het | -0.889 | 15 | -0.292 | 8 | 0.814 | 0.597(-4.480, 5.675) |
IL1B
| rs1143627 | T | 1.692 | 13 | -0.182 | 11 | 0.432 | 1.874(-2.877, 6.625) |
IL1B
| rs16944 | C | 1.692 | 13 | -0.182 | 11 | 0.432 | 1.874(-2.877, 6.625) |
IL1B
| rs16944 | Het | -0.889 | 15 | -0.292 | 8 | 0.814 | 0.597(-4.480, 5.675) |
IL1B
| rs16944 | T | 0.111 | 3 | 0.778 | 6 | 0.871 | 0.667(-7.534, 8.868) |
Changes in serum β-hydroxybutyrate levels
APOE4 status | SNP | Genotype | N | Mean BHB mM | Std Error | Lower 95% | Upper 95% | p-value* |
---|---|---|---|---|---|---|---|---|
Baseline Post-dose (1/2 dose) | ||||||||
E4- | 29 | 0.121 | 0.014 | 0.093 | 0.148 | |||
E4+ | 38 | 0.161 | 0.012 | 0.137 | 0.185 | 0.030 | ||
E4-
|
IL1B
rs1143627
|
C/C
|
3
|
0.103
|
0.032
|
0.037
|
0.170
| |
E4-
|
IL1B
rs1143627
|
C/T
|
9
|
0.126
|
0.019
|
0.087
|
0.164
| |
E4-
|
IL1B
rs1143627
|
T/T
|
14
|
0.120
|
0.015
|
0.089
|
0.151
|
0.838
|
E4- |
IDE rs2251101 | C/C | 5 | 0.096 | 0.025 | 0.045 | 0.147 | |
E4- |
IDE rs2251101 | C/T | 9 | 0.134 | 0.018 | 0.097 | 0.172 | |
E4- |
IDE rs2251101 | T/T | 15 | 0.121 | 0.014 | 0.091 | 0.150 | 0.471 |
Day 45 Post-dose (full dose) | ||||||||
E4- | 23 | 0.334 | 0.047 | 0.240 | 0.428 | |||
E4+ | 33 | 0.355 | 0.039 | 0.276 | 0.434 | 0.730 | ||
E4-
|
IL1B
rs1143627
|
C/C
|
3
|
0.227
|
0.102
|
0.013
|
0.441
| |
E4-
|
IL1B
rs1143627
|
C/T
|
8
|
0.431
|
0.062
|
0.300
|
0.562
| |
E4-
|
IL1B
rs1143627
|
T/T
|
10
|
0.278
|
0.056
|
0.161
|
0.395
|
0.132
|
E4- |
IDE rs2251101 | C/C | 4 | 0.470 | 0.099 | 0.263 | 0.677 | |
E4- |
IDE rs2251101 | C/T | 6 | 0.315 | 0.081 | 0.146 | 0.484 | |
E4- |
IDE rs2251101 | T/T | 13 | 0.301 | 0.055 | 0.186 | 0.416 | 0.338 |
Day 90 Post-dose(full dose) | ||||||||
E4- | 20 | 0.301 | 0.076 | 0.147 | 0.454 | |||
E4+ | 22 | 0.471 | 0.072 | 0.325 | 0.617 | 0.111 | ||
E4-
|
IL1B
rs1143627
|
C/C
|
3
|
0.193
|
0.144
|
-0.111
|
0.498
| |
E4-
|
IL1B
rs1143627
|
C/T
|
8
|
0.378
|
0.088
|
0.191
|
0.564
| |
E4-
|
IL1B
rs1143627
|
T/T
|
8
|
0.296
|
0.088
|
0.110
|
0.483
|
0.544
|
E4- |
IDE rs2251101 | C/C | 4 | 0.123 | 0.113 | -0.116 | 0.361 | |
E4- |
IDE rs2251101 | C/T | 5 | 0.470 | 0.101 | 0.257 | 0.683 | |
E4- |
IDE rs2251101 | T/T | 11 | 0.288 | 0.068 | 0.144 | 0.432 | 0.099 |