Supplemental Table 1. Age of symptom onset and disease course for ADAD mutation types. (sd=standard deviation, se=standard error, n=number of affected individuals, f=number of families). Mutation types which met strict criteria for definitely pathogenic ADAD mutations on individual review by the DIAN study Genetics and Clinical Cores are indicated with asterisks (*).
Gene / Mutation / * / Onset.mean / Onset.sd / Onset.se / n / f / Course.mean / Course.sd / Course.se / ReferencesAPP / K670N / * / 52.25 / 5.74 / 2.87 / 4 / 1 / 8.50 / 4.95 / 3.50 / 1
APP / D678N / * / 58.83 / 1.26 / 0.73 / 3 / 1 / 11.50 / NA / NA / 2
APP / K687N / 56.33 / 14.01 / 8.09 / 3 / 1 / 12.00 / 12.12 / 7.00 / 3
APP / A692G / * / 47.00 / 3.37 / 1.68 / 4 / 2 / 11.00 / NA / NA / 1,4
APP / E693del / 52.50 / 8.96 / 4.48 / 4 / 1 / 7.00 / 3.61 / 2.08 / 5
APP / E693N / 51.50 / 1.29 / 0.65 / 4 / 1 / 6.25 / 6.55 / 3.28 / 1
APP / D694N / 56.50 / 4.37 / 1.78 / 6 / 1 / 11.00 / 7.04 / 2.88 / 6
APP / A713T / * / 64.90 / 10.96 / 3.47 / 10 / 5 / 6.00 / 3.42 / 1.21 / 7–9
APP / T714A / * / 49.33 / 5.20 / 2.12 / 6 / 3 / 2.00 / NA / NA / 10–12
APP / V715A / * / 50.00 / 5.43 / 2.43 / 5 / 2 / NA / NA / NA / 11,13
APP / V715M / * / 47.80 / 8.17 / 3.65 / 5 / 2 / 8.00 / 2.83 / 2.00 / 14,15
APP / I716F / * / 32.33 / 2.31 / 1.33 / 3 / 2 / 4.33 / 2.08 / 1.20 / 16,17
APP / I716V / * / 52.67 / 0.58 / 0.33 / 3 / 1 / NA / NA / NA / 18
APP / V717F / * / 42.07 / 4.29 / 1.15 / 14 / 4 / 5.8 / 3.2 / 1.78 / 1,19,20
APP / V717G / * / 50.00 / 6.00 / 2.68 / 5 / 1 / 10.67 / 3.79 / 2.19 / 21
APP / V717I / * / 50.25 / 8.6 / 1.18 / 53 / 18 / 11.86 / 4.64 / 0.99 / 1,22–26
APP / V717L / * / 45.28 / 6.59 / 1.32 / 25 / 6 / 9.33 / 4.74 / 1.58 / 1,19,27–29
APP / L723P / * / 44.00 / NA / NA / 1 / 1 / 9.00 / NA / NA / 1
APP / L723R / 45.50 / 3.54 / 2.50 / 2 / 1 / 12.50 / 0.71 / 0.50 / 1
APP / K724N / * / 53.50 / 2.12 / 1.50 / 2 / 1 / 4.00 / NA / NA / 30
APP / duplication (0.58Mb) / * / 47.00 / 2.83 / 2.00 / 2 / 1 / 10.50 / 4.95 / 3.50 / 31
APP / duplication (0.5Mb) / * / 52.60 / 5.81 / 2.60 / 5 / 1 / NA / NA / NA / 32
APP / duplication (0.78Mb) / * / 54.50 / 2.66 / 1.09 / 6 / 1 / 8.00 / 2.61 / 1.06 / 31
APP / duplication (1.98Mb) / * / 51.40 / 4.04 / 1.81 / 5 / 1 / 5.80 / 4.09 / 1.83 / 31
APP / duplication (3.4Mb) / * / 52.00 / 9.32 / 3.80 / 6 / 2 / NA / NA / NA / 29
APP / duplication (3.96Mb) / * / 50.50 / 7.23 / 3.62 / 4 / 1 / 9.00 / 6.00 / 3.00 / 31
APP / duplication (6.37Mb) / * / 54.67 / 2.52 / 1.45 / 3 / 1 / 5.33 / 4.16 / 2.40 / 31
PS1 / splice site (intron 4) / * / 36.00 / 1.73 / 1.00 / 3 / 1 / 6.00 / NA / NA / 34
PS1 / splice site (exon 10) / 45.50 / 0.71 / 0.50 / 2 / 1 / 17.00 / 2.83 / 2.00 / 35
PS1 / splice site (exon 4) / 39.00 / 4.24 / 3.00 / 2 / 1 / 9.00 / NA / NA / 1
PS1 / splice site (exon 9) / 45.27 / 6.26 / 0.90 / 48 / 6 / 8.57 / 4.09 / 0.75 / 1,36–38
PS1 / A79V / * / 62.50 / 10.64 / 2.01 / 28 / 9 / 13.00 / 4.93 / 1.86 / 1,25,39–41
PS1 / L85P / * / 23.00 / NA / NA / 1 / 1 / NA / NA / NA / 42
PS1 / V89L / * / 48.67 / 2.52 / 1.45 / 3 / 1 / 10.50 / 6.36 / 4.50 / 43
PS1 / C92S / * / 55.80 / 8.17 / 3.65 / 5 / 2 / 6.00 / NA / NA / 44
PS1 / V94M / * / 53.00 / NA / NA / 1 / 1 / NA / NA / NA / 45
PS1 / V96F / * / 45.00 / 4.24 / 3.00 / 2 / 1 / NA / NA / NA / 46
PS1 / V97L / 50.33 / 6.66 / 3.84 / 3 / 1 / NA / NA / NA / 47
PS1 / F105L / * / 51.20 / 8.87 / 3.97 / 5 / 2 / 10.00 / 1.73 / 1.00 / 1,25
PS1 / L113Q / * / 33.00 / NA / NA / 1 / 1 / 3.00 / NA / NA / 19
PS1 / Y115C / * / 43.25 / 6.52 / 1.88 / 12 / 3 / 11.00 / 0.00 / 0.00 / 1,39
PS1 / Y115H / * / 37.00 / 3.61 / 2.08 / 3 / 2 / 12.00 / NA / NA / 1,19
PS1 / T116I / * / 45.00 / NA / NA / 1 / 1 / NA / NA / NA / 48
PS1 / T116N / * / 37.80 / 2.17 / 0.97 / 5 / 2 / 5.67 / 2.08 / 1.20 / 17,49
PS1 / T116R / 35.00 / NA / NA / 1 / 1 / 8.00 / NA / NA / 50
PS1 / P117A / 30.83 / 3.76 / 1.54 / 6 / 2 / 8.50 / 3.54 / 2.50 / 51,52
PS1 / P117L / * / 30.56 / 3.75 / 1.25 / 9 / 3 / 4.25 / 1.28 / 0.45 / 53–55
PS1 / P117R / * / 36.33 / 1.37 / 0.56 / 6 / 2 / 3.67 / 1.15 / 0.67 / 11,56
PS1 / P117S / * / 31.00 / 2.00 / 1.15 / 3 / 1 / 4.33 / 0.58 / 0.33 / 54
PS1 / E120D / * / 44.80 / 7.05 / 3.15 / 5 / 3 / 11.33 / 4.93 / 2.85 / 50,57
PS1 / E120G / * / 37.75 / 2.50 / 1.25 / 4 / 2 / 3.00 / NA / NA / 56,58
PS1 / E120K / * / 36.00 / NA / NA / 1 / 1 / 8.00 / NA / NA / 50
PS1 / E123K / * / 59.00 / 4.24 / 3.00 / 2 / 1 / NA / NA / NA / 59
PS1 / S132A / 60.00 / NA / NA / 1 / 1 / 10.00 / NA / NA / 1
PS1 / N135D / 35.40 / 1.34 / 0.60 / 5 / 1 / 14.33 / 3.06 / 1.76 / 60
PS1 / N135S / * / 34.33 / 2.45 / 0.82 / 9 / 3 / 6.50 / 3.00 / 1.50 / 19,61
PS1 / M139I / * / 36.43 / 2.23 / 0.84 / 7 / 2 / 7.75 / 3.95 / 1.97 / 1,62
PS1 / M139K / * / 37.00 / NA / NA / 1 / 1 / NA / NA / NA / 63
PS1 / M139V / * / 39.95 / 4.06 / 0.91 / 20 / 7 / 8.08 / 3.23 / 0.93 / 1,11,25,64,65
PS1 / I143F / * / 55.00 / 2.00 / 1.15 / 3 / 1 / 11.00 / 2.83 / 2.00 / 66
PS1 / I143M / * / 47.50 / 0.71 / 0.50 / 2 / 1 / NA / NA / NA / 67
PS1 / I143T / * / 30.00 / NA / NA / 1 / 1 / NA / NA / NA / 45
PS1 / I143V / * / 51.00 / 3.61 / 2.08 / 3 / 1 / 14.00 / 6.00 / 3.46 / 68
PS1 / M146I / * / 45.06 / 5.74 / 1.35 / 18 / 5 / 9.65 / 4.46 / 1.08 / 1,69,70
PS1 / M146L / * / 39.29 / 3.47 / 0.93 / 14 / 5 / 5.88 / 3.09 / 1.09 / 1,19,71–73
PS1 / M146V / * / 39.00 / NA / NA / 1 / 1 / 4.00 / NA / NA / 50
PS1 / L153V / * / 35.33 / 0.58 / 0.33 / 3 / 1 / 7.00 / NA / NA / 74
PS1 / Y154N / * / 37.00 / NA / NA / 1 / 1 / NA / NA / NA / 75
PS1 / H163R / * / 46.41 / 4.37 / 0.75 / 34 / 10 / 12.14 / 3.44 / 1.30 / 1,11,56,76
PS1 / H163Y / * / 54.17 / 7.20 / 1.70 / 18 / 1 / 11.67 / 4.47 / 1.15 / 77
PS1 / L166R / * / 38.00 / 8.49 / 6.00 / 2 / 1 / 4.00 / NA / NA / 78
PS1 / S169 deletion / * / 44.75 / 3.77 / 1.89 / 4 / 1 / 9.00 / 1.41 / 1.00 / 79
PS1 / S169L / * / 30.63 / 2.56 / 0.91 / 8 / 4 / 6.2 / 2.95 / 1.32 / 1,80,81
PS1 / S169P / * / 33.25 / 1.71 / 0.85 / 4 / 1 / 7.00 / NA / NA / 82
PS1 / S170F / * / 30.33 / 5.35 / 2.19 / 6 / 3 / 9.20 / 4.87 / 2.18 / 1,83,84
PS1 / L171P / * / 41.33 / 1.15 / 0.67 / 3 / 1 / 12.00 / 5.66 / 4.00 / 1
PS1 / L173F / * / 42.33 / 4.04 / 2.33 / 3 / 1 / NA / NA / NA / 85
PS1 / L174M / * / 58.27 / 7.68 / 1.98 / 15 / 2 / 9.17 / 3.79 / 1.09 / 44,86
PS1 / L174R / * / 48.25 / 5.32 / 2.66 / 4 / 1 / 7.00 / 5.66 / 4.00 / 87
PS1 / F177S / * / 29.75 / 0.5 / 0.25 / 4 / 1 / 7.5 / 0.58 / 0.29 / 88
PS1 / G183V / 51.00 / 4.58 / 2.65 / 3 / 1 / 13.67 / 7.23 / 4.18 / 89
PS1 / E184D / * / 39.80 / 3.91 / 1.24 / 10 / 4 / 9.33 / 3.56 / 1.45 / 1,90
PS1 / I202F / * / 52.00 / 5.29 / 2.65 / 4 / 2 / NA / NA / NA / 1,91
PS1 / G206A / * / 53.53 / 7.63 / 1.09 / 49 / 18 / 11.60 / 6.90 / 2.18 / 1,92
PS1 / G206D / * / 38.00 / 1.41 / 1.00 / 2 / 1 / NA / NA / NA / 93
PS1 / G206S / * / 37.50 / 3.54 / 2.50 / 2 / 1 / 4.00 / NA / NA / 14
PS1 / G206V / * / 32.00 / NA / NA / 1 / 1 / NA / NA / NA / 1
PS1 / G209R / * / 49.00 / 3.61 / 2.08 / 3 / 1 / NA / NA / NA / 94
PS1 / G209V / * / 41.16 / 4.51 / 1.04 / 19 / 1 / NA / NA / NA / 76
PS1 / E210D / 46.44 / 4.42 / 1.47 / 9 / 1 / NA / NA / NA / 76
PS1 / S212Y / * / 45.38 / 6.50 / 2.30 / 8 / 2 / 14.50 / 5.17 / 2.11 / 1,95
PS1 / I213F / * / 33.00 / NA / NA / 1 / 1 / NA / NA / NA / 11
PS1 / I213T / * / 50.00 / 1.00 / 0.58 / 3 / 1 / NA / NA / NA / 46
PS1 / H214D / * / 55.00 / NA / NA / 1 / 1 / NA / NA / NA / 17
PS1 / G217D / 40.00 / 2.83 / 2.00 / 2 / 1 / NA / NA / NA / 96
PS1 / G217R / * / 44.42 / 2.50 / 0.72 / 12 / 2 / 12.18 / 7.26 / 2.19 / 1,97
PS1 / L219P / * / 51.40 / 7.67 / 3.43 / 5 / 1 / 14.20 / 8.76 / 3.92 / 1
PS1 / Q222H / * / 39.67 / 4.16 / 2.40 / 3 / 2 / 11.50 / 4.95 / 3.50 / 1,98
PS1 / Q223R / * / 34.75 / 2.99 / 1.49 / 4 / 1 / 4.00 / 0.00 / 0.00 / 99
PS1 / L226F / 34.50 / 2.12 / 1.50 / 2 / 1 / 6.00 / NA / NA / 56
PS1 / L226R / * / 47.00 / 3.00 / 1.73 / 3 / 1 / 8.67 / 2.08 / 1.20 / 1
PS1 / I229F / * / 39.00 / 5.00 / 2.89 / 3 / 1 / 18.00 / NA / NA / 1
PS1 / A231V / * / 58.00 / 3.56 / 1.78 / 4 / 1 / NA / NA / NA / 39
PS1 / M233L / * / 33.50 / 7.78 / 5.50 / 2 / 2 / 8.00 / NA / NA / 100,101
PS1 / M233T / * / 33.67 / 3.27 / 1.33 / 6 / 4 / 9.00 / 2.83 / 2.00 / 1,14,17,102
PS1 / L235P / * / 32.50 / 0.71 / 0.50 / 2 / 1 / 1.00 / NA / NA / 19
PS1 / L235R / 51.50 / 6.91 / 2.44 / 8 / 1 / NA / NA / NA / 103
PS1 / L235V / * / 41.50 / 11.39 / 5.69 / 4 / 1 / NA / NA / NA / 1
PS1 / F237I / * / 31.00 / NA / NA / 1 / 1 / NA / NA / NA / 104
PS1 / I238M / 54.00 / 8.49 / 6.00 / 2 / 1 / 6.00 / NA / NA / 1
PS1 / K239N / * / 54.14 / 8.71 / 3.29 / 7 / 1 / NA / NA / NA / 105
PS1 / T245P / * / 42.00 / 2.00 / 1.00 / 4 / 1 / 25.00 / NA / NA / 1
PS1 / A246E / * / 50.14 / 4.30 / 1.62 / 7 / 6 / 13.17 / 6.43 / 2.63 / 1,50
PS1 / L250S / * / 52.50 / 4.95 / 3.50 / 2 / 2 / 6.50 / 0.71 / 0.50 / 50
PS1 / L250V / * / 50.50 / 0.71 / 0.50 / 2 / 1 / NA / NA / NA / 106
PS1 / Y256S / * / 27.50 / 3.54 / 2.50 / 2 / 1 / 2.50 / 0.71 / 0.50 / 98
PS1 / A260G / 53.00 / 9.91 / 3.51 / 8 / 1 / 13.00 / 5.35 / 2.68 / 1
PS1 / A260V / * / 30.00 / NA / NA / 1 / 1 / NA / NA / NA / 17
PS1 / V261F / * / 34.00 / 2.00 / 1.15 / 3 / 1 / 15.00 / 2.83 / 2.00 / 1
PS1 / V261I / 42.50 / 7.78 / 5.50 / 2 / 1 / 7.00 / NA / NA / 1
PS1 / V261L / * / 40.33 / 0.58 / 0.33 / 3 / 2 / NA / NA / NA / 56,107
PS1 / L262F / * / 50.33 / 4.93 / 2.85 / 3 / 1 / NA / NA / NA / 108
PS1 / P264L / * / 47.08 / 4.33 / 1.20 / 13 / 5 / 10.80 / 5.17 / 2.31 / 1,76,109
PS1 / G266S / * / 37.67 / 2.52 / 1.45 / 3 / 1 / 10.00 / 0.00 / 0.00 / 110
PS1 / R269G / * / 48.33 / 1.15 / 0.67 / 3 / 2 / NA / NA / NA / 111
PS1 / R269H / * / 51.00 / 4.58 / 2.65 / 3 / 2 / 10.00 / 1.41 / 1.00 / 1,50
PS1 / L271V / * / 52.29 / 5.25 / 1.98 / 7 / 2 / 10.20 / 6.14 / 2.75 / 1
PS1 / V272A / 29.00 / 2.65 / 1.53 / 3 / 1 / 12.00 / 2.83 / 2.00 / 56
PS1 / A275V / 49.00 / 0.00 / 0.00 / 2 / 1 / 10.00 / 0.00 / 0.00 / 1
PS1 / R278I / * / 54.50 / 3.11 / 1.55 / 4 / 1 / 10.00 / 2.83 / 2.00 / 1
PS1 / R278K / * / 44.67 / 3.51 / 2.03 / 3 / 1 / 12.00 / NA / NA / 112
PS1 / R278S / * / 39.00 / NA / NA / 1 / 1 / NA / NA / NA / 113
PS1 / E280A / * / 38.45 / 8.63 / 0.67 / 164 / 19 / 12.79 / 3.75 / 0.86 / 1,45,114
PS1 / E280G / * / 40.43 / 2.64 / 1.00 / 7 / 3 / 13.25 / 9.25 / 4.63 / 1,115
PS1 / L282F / * / 51.00 / 2.83 / 2.00 / 2 / 1 / NA / NA / NA / 116
PS1 / L282R / * / 43.75 / 6.75 / 3.38 / 4 / 1 / 7.00 / 1.00 / 0.58 / 56
PS1 / L282V / * / 46.50 / 5.00 / 2.50 / 4 / 1 / 7.00 / 2.16 / 1.08 / 117
PS1 / P284L / * / 32.00 / NA / NA / 1 / 1 / 22.00 / NA / NA / 35
PS1 / P284S / 37.50 / 5.57 / 2.78 / 4 / 1 / NA / NA / NA / 118
PS1 / L286P / * / 39.57 / 2.37 / 0.90 / 7 / 1 / 11.80 / 7.05 / 3.15 / 119
PS1 / L286V / * / 45.59 / 4.96 / 0.95 / 27 / 3 / 8.57 / 4.11 / 0.90 / 50,120
PS1 / Y288H / * / 45.75 / 2.75 / 1.38 / 4 / 1 / 17.00 / NA / NA / 1
PS1 / S290C / * / 41.21 / 3.66 / 0.98 / 14 / 2 / 8.10 / 2.23 / 0.71 / 1
PS1 / E318G / 56.83 / 7.78 / 3.18 / 6 / 4 / NA / NA / NA / 39,45,64,108
PS1 / S365A / * / 55.00 / NA / NA / 1 / 1 / NA / NA / NA / 17
PS1 / G378E / * / 40.50 / 4.95 / 3.50 / 2 / 1 / 5.00 / NA / NA / 1
PS1 / L381V / * / 45.67 / 17.21 / 9.94 / 3 / 1 / 5.67 / 2.08 / 1.20 / 121
PS1 / G384A / * / 36.00 / NA / NA / 1 / 1 / 12.00 / NA / NA / 50
PS1 / C410Y / * / 49.25 / 4.11 / 1.19 / 12 / 7 / 9.88 / 6.96 / 2.46 / 1,50
PS1 / L424V / 26.00 / NA / NA / 1 / 1 / NA / NA / NA / 123
PS1 / A426E / 49.00 / NA / NA / 1 / 1 / 9.00 / NA / NA / 1
PS1 / A426P / * / 46.00 / 3.85 / 1.57 / 6 / 1 / NA / NA / NA / 76
PS1 / A431E / * / 39.98 / 4.68 / 0.67 / 49 / 29 / 9.00 / 2.71 / 0.86 / 1,124,125
PS1 / A434C / 30.33 / 4.16 / 2.40 / 3 / 1 / 24.00 / NA / NA / 126
PS1 / P436S / * / 47.00 / 4.24 / 3.00 / 2 / 1 / NA / NA / NA / 127
PS1 / I439S / * / 55.00 / NA / NA / 1 / 1 / NA / NA / NA / 56
PS1 / I439V / 65.50 / 16.26 / 11.50 / 2 / 1 / 4.00 / NA / NA / 1
PS1 / T440 deletion / 34.50 / 0.71 / 0.50 / 2 / 1 / 15.50 / 3.54 / 2.50 / 128
PS2 / R71W / 53.00 / NA / NA / 1 / 1 / NA / NA / NA / 17,129
PS2 / A85V / * / 66.00 / 6.98 / 3.49 / 4 / 1 / 23.50 / 2.12 / 1.50 / 130
PS2 / T122P / * / 46.75 / 2.22 / 1.11 / 4 / 2 / 4.00 / 1.00 / 0.58 / 19,25
PS2 / T122R / * / 57.25 / 5.56 / 2.78 / 4 / 1 / 6.25 / 2.99 / 1.49 / 131
PS2 / S130L / 65.00 / 0.00 / 0.00 / 3 / 1 / 16.33 / 2.31 / 1.33 / 44
PS2 / N141I / * / 54.27 / 7.46 / 0.67 / 125 / 12 / 10.23 / 4.52 / 0.44 / 1,132,133
PS2 / V148I / 71.00 / NA / NA / 1 / 1 / NA / NA / NA / 134
PS2 / M174V / * / 54.00 / NA / NA / 1 / 1 / NA / NA / NA / 17
PS2 / Q228L / 60.00 / NA / NA / 1 / 1 / NA / NA / NA / 11
PS2 / Y231C / 58.50 / 9.19 / 6.50 / 2 / 1 / 18.00 / NA / NA / 135
PS2 / M239I / * / 50.67 / 6.28 / 2.56 / 6 / 3 / 7.67 / 2.08 / 1.20 / 25,136
PS2 / M239V / * / 64.86 / 17.76 / 6.71 / 7 / 1 / NA / NA / NA / 137
PS2 / T430M / * / 55.33 / 9.61 / 5.55 / 3 / 1 / 11.00 / NA / NA / 138
PS2 / D439A / * / 56.00 / 5.66 / 4.00 / 2 / 1 / 20.00 / NA / NA / 139
References
1. Morris JC, Aisen PS, Bateman RJ, et al. Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network. Clin Investig (Lond) 2012;2:975–84.
2. Wakutani Y, Watanabe K, Adachi Y, et al. Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75:1039–42.
3. Kaden D, Harmeier A, Weise C, et al. Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. EMBO Mol Med 2012;4:647–59.
4. Kumar-Singh S, Cras P, Wang R, et al. Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol 2002;161:507–20.
5. Tomiyama T, Nagata T, Shimada H, et al. A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol 2008;63:377–87.
6. Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 2001;49:697–705.