Local ancestry on chromosome 19 and age at amyloid onset

T. Castel November 03, 2026

Cohort FLARE chr19 VCF present Analyzed Reason
A4 yes yes Amyloid PET and local ancestry both available
ACT yes no No amyloid PET in the ADSP PHC dataset
ADNI yes yes Amyloid PET and local ancestry both available
EFIGA yes no No amyloid PET in the ADSP PHC dataset
NACC yes yes Amyloid PET and local ancestry both available
ROSMAP yes no No amyloid PET in the ADSP PHC dataset
WASHU yes no No amyloid PET in the ADSP PHC dataset
WHICAP yes no No amyloid PET in the ADSP PHC dataset
WRAP yes yes Amyloid PET and local ancestry both available

Participants

Participant flow

Cohort A: amyloid PET B: genotyped (SILA) B: events C: Cox sample C: events Analyzed
A4 4445 123 31 123 31 yes
ADNI 2187 22 9 22 9 yes
NACC 3654 137 32 137 32 yes
WRAP 588 16 1 16 1 yes
HABS-HD 2837 0 0 0 0 no
KBASE 602 0 0 0 0 no
WASHU 1027 0 0 0 0 no
Total 15340 298 73 298 73

Note: Cohorts with amyloid PET but no FLARE chromosome 19 output in the analysis: HABS-HD, KBASE.

All ADSP participants with amyloid PET

Characteristic Overall A4 ADNI HABS-HD KBASE NACC WASHU WRAP
N 15340 4445 2187 2837 602 3654 1027 588
Sex: 1 6391 (41.7%) 1806 (40.6%) 1063 (48.6%) 1051 (37.0%) 253 (42.0%) 1560 (42.7%) 472 (46.0%) 186 (31.6%)
Sex: 2 8949 (58.3%) 2639 (59.4%) 1124 (51.4%) 1786 (63.0%) 349 (58.0%) 2094 (57.3%) 555 (54.0%) 402 (68.4%)
Race: 1 66 (0.4%) 9 (0.2%) 6 (0.3%) 2 (0.1%) 0 (0.0%) 49 (1.3%) 0 (0.0%) 0 (0.0%)
Race: 2 949 (6.2%) 170 (3.8%) 85 (3.9%) 0 (0.0%) 602 (100.0%) 83 (2.3%) 8 (0.8%) 1 (0.2%)
Race: 3 2041 (13.3%) 159 (3.6%) 241 (11.0%) 1007 (35.5%) 0 (0.0%) 448 (12.3%) 142 (13.8%) 44 (7.5%)
Race: 4 8 (0.1%) 2 (0.0%) 3 (0.1%) 0 (0.0%) 0 (0.0%) 3 (0.1%) 0 (0.0%) 0 (0.0%)
Race: 5 12074 (78.7%) 4054 (91.2%) 1783 (81.5%) 1793 (63.2%) 0 (0.0%) 3030 (82.9%) 872 (84.9%) 542 (92.2%)
Race: 6 202 (1.3%) 51 (1.1%) 69 (3.2%) 35 (1.2%) 0 (0.0%) 41 (1.1%) 5 (0.5%) 1 (0.2%)
Ethnicity: 1 1413 (9.2%) 141 (3.2%) 153 (7.0%) 879 (31.0%) 0 (0.0%) 235 (6.4%) 3 (0.3%) 2 (0.3%)
Ethnicity: 2 13927 (90.8%) 4304 (96.8%) 2034 (93.0%) 1958 (69.0%) 602 (100.0%) 3419 (93.6%) 1024 (99.7%) 586 (99.7%)
Education (years), mean (SD) 15.7 (3.3) 16.6 (2.8) 16.3 (2.6) 13.9 (3.8) 11.5 (4.8) 16.3 (2.7) 16.1 (2.6) 16.4 (2.8)
Age at first amyloid PET, mean (SD) 69.8 (8.2) 71.3 (4.7) 72.2 (7.8) 65.5 (8.7) 66.9 (13.4) 71.0 (8.7) 70.7 (8.1) 65.3 (7.7)
Age at last amyloid PET, mean (SD) 70.8 (8.4) 71.3 (4.7) 74.9 (8.4) 66.1 (8.9) 69.2 (13.7) 71.3 (8.7) 73.3 (8.1) 68.9 (7.2)
PET follow-up (years), median [IQR] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1.9 [0.0, 4.1] 0.0 [0.0, 2.0] 2.0 [0.0, 4.0] 0.0 [0.0, 0.0] 0.0 [0.0, 4.4] 2.0 [0.0, 7.0]
Amyloid PET scans per person, median [IQR] 1.0 [1.0, 1.0] 1.0 [1.0, 1.0] 2.0 [1.0, 3.0] 1.0 [1.0, 2.0] 2.0 [1.0, 3.0] 1.0 [1.0, 1.0] 1.0 [1.0, 2.0] 2.0 [1.0, 3.0]
Baseline Centiloid, median [IQR] 6.0 [-5.0, 37.0] 9.0 [-4.0, 31.0] 14.0 [-2.0, 62.0] 0.0 [-9.0, 12.0] 0.0 [-5.0, 39.8] 8.0 [-3.0, 60.0] 4.0 [-5.0, 41.0] 3.0 [-2.0, 12.0]
Amyloid-positive at first scan (>= 21 CL), n (%) 5078 (33.1%) 1510 (34.0%) 999 (45.7%) 507 (17.9%) 178 (29.6%) 1433 (39.2%) 337 (32.8%) 114 (19.4%)

Genotyped participants (SILA input)

Characteristic Overall A4 ADNI NACC WRAP
N 298 123 22 137 16
Sex: 1 88 (29.5%) 38 (30.9%) 6 (27.3%) 37 (27.0%) 7 (43.8%)
Sex: 2 210 (70.5%) 85 (69.1%) 16 (72.7%) 100 (73.0%) 9 (56.2%)
Race: 1 2 (0.7%) 1 (0.8%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Race: 3 287 (96.3%) 115 (93.5%) 22 (100.0%) 134 (97.8%) 16 (100.0%)
Race: 5 3 (1.0%) 2 (1.6%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Race: 6 6 (2.0%) 5 (4.1%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Ethnicity: 1 1 (0.3%) 1 (0.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Ethnicity: 2 297 (99.7%) 122 (99.2%) 22 (100.0%) 137 (100.0%) 16 (100.0%)
Education (years), mean (SD) 15.9 (2.7) 16.3 (3.0) 16.0 (2.7) 15.7 (2.5) 15.6 (2.2)
Age at first amyloid PET, mean (SD) 70.8 (7.3) 70.3 (4.7) 69.5 (7.7) 72.2 (8.5) 65.4 (10.0)
Age at last amyloid PET, mean (SD) 71.6 (7.3) 70.3 (4.7) 75.0 (9.3) 72.6 (8.5) 68.1 (8.2)
PET follow-up (years), median [IQR] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 4.5 [0.0, 9.2] 0.0 [0.0, 0.0] 0.0 [0.0, 6.2]
Amyloid PET scans per person, median [IQR] 1.0 [1.0, 1.0] 1.0 [1.0, 1.0] 3.0 [1.0, 5.0] 1.0 [1.0, 1.0] 1.0 [1.0, 3.0]
Baseline Centiloid, median [IQR] 3.0 [-6.0, 19.0] 6.0 [-6.0, 20.5] 11.5 [2.2, 31.8] 1.0 [-7.0, 15.0] -1.5 [-7.5, 3.0]
Amyloid-positive at first scan (>= 21 CL), n (%) 72 (24.2%) 31 (25.2%) 9 (40.9%) 32 (23.4%) 0 (0.0%)
SILA-defined amyloid onset observed (event), n (%) 73 (24.5%) 31 (25.2%) 9 (40.9%) 32 (23.4%) 1 (6.2%)
Estimated age at amyloid onset among events, mean (SD) 66.8 (8.2) 65.7 (5.7) 67.1 (11.2) 68.2 (9.0) 51.2 (NA)

Cox analytic samples

Characteristic Overall A4 ADNI NACC WRAP
N 298 123 22 137 16
Sex: 1 88 (29.5%) 38 (30.9%) 6 (27.3%) 37 (27.0%) 7 (43.8%)
Sex: 2 210 (70.5%) 85 (69.1%) 16 (72.7%) 100 (73.0%) 9 (56.2%)
Race: 1 2 (0.7%) 1 (0.8%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Race: 3 287 (96.3%) 115 (93.5%) 22 (100.0%) 134 (97.8%) 16 (100.0%)
Race: 5 3 (1.0%) 2 (1.6%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Race: 6 6 (2.0%) 5 (4.1%) 0 (0.0%) 1 (0.7%) 0 (0.0%)
Ethnicity: 1 1 (0.3%) 1 (0.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Ethnicity: 2 297 (99.7%) 122 (99.2%) 22 (100.0%) 137 (100.0%) 16 (100.0%)
Education (years), mean (SD) 15.9 (2.7) 16.3 (3.0) 16.0 (2.7) 15.7 (2.5) 15.6 (2.2)
Age at first amyloid PET, mean (SD) 70.8 (7.3) 70.3 (4.7) 69.5 (7.7) 72.2 (8.5) 65.4 (10.0)
Age at last amyloid PET, mean (SD) 71.6 (7.3) 70.3 (4.7) 75.0 (9.3) 72.6 (8.5) 68.1 (8.2)
PET follow-up (years), median [IQR] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 4.5 [0.0, 9.2] 0.0 [0.0, 0.0] 0.0 [0.0, 6.2]
Amyloid PET scans per person, median [IQR] 1.0 [1.0, 1.0] 1.0 [1.0, 1.0] 3.0 [1.0, 5.0] 1.0 [1.0, 1.0] 1.0 [1.0, 3.0]
Baseline Centiloid, median [IQR] 3.0 [-6.0, 19.0] 6.0 [-6.0, 20.5] 11.5 [2.2, 31.8] 1.0 [-7.0, 15.0] -1.5 [-7.5, 3.0]
Amyloid-positive at first scan (>= 21 CL), n (%) 72 (24.2%) 31 (25.2%) 9 (40.9%) 32 (23.4%) 0 (0.0%)
SILA-defined amyloid onset observed (event), n (%) 73 (24.5%) 31 (25.2%) 9 (40.9%) 32 (23.4%) 1 (6.2%)
Estimated age at amyloid onset among events, mean (SD) 66.8 (8.2) 65.7 (5.7) 67.1 (11.2) 68.2 (9.0) 51.2 (NA)

Reconstruction check against the Cox jobs’ own sample summaries

Cohort n (this report) events (this report) n (Cox job) events (Cox job) Match
A4 123 31 123 31 yes
ADNI 22 9 22 9 yes
NACC 137 32 137 32 yes
WRAP 16 1 16 1 yes

How the sample changes across stages

Stage N Cohorts Age at first PET, mean Follow-up yrs, median Scans, median Baseline CL, median Positive at baseline, %
A: amyloid PET 15340 7 69.8 0 1 6 33.1
B: genotyped 298 4 70.8 0 1 3 24.2
C: Cox samples 298 4 70.8 0 1 3 24.2

Sex and race distribution by stage (codes as in the ADSP file)

Variable Level A B C
Race 1 66 (0.4%) 2 (0.7%) 2 (0.7%)
Race 2 66 (0.4%) 0 (0.0%) 0 (0.0%)
Race 3 66 (0.4%) 2 (0.7%) 2 (0.7%)
Race 4 66 (0.4%) 0 (0.0%) 0 (0.0%)
Race 5 66 (0.4%) 2 (0.7%) 2 (0.7%)
Race 6 66 (0.4%) 2 (0.7%) 2 (0.7%)
Sex 1 6391 (41.7%) 88 (29.5%) 88 (29.5%)
Sex 2 6391 (41.7%) 88 (29.5%) 88 (29.5%)

Variants

Variants entering and leaving the analysis

Cohort People in model Events Variants seen Variants fit % fit Model rows Rows: EUR/AFR Rows: AFR/AFR Rows with warning Rows with NA estimate Variants with rsID
A4 123 31 180611 180611 100.0 361222 180611 180611 5300 0 180611
ADNI 22 9 147419 39199 26.6 78398 39199 39199 540 0 147419
NACC 137 32 151893 151893 100.0 303786 151893 151893 3046 0 151893
WRAP 16 1 165515 49138 29.7 98276 49138 49138 98276 0 165515

Overlap of fitted variants across cohorts

Cohorts with estimate (k) AFR/AFR EUR/AFR
4 12180 12180
3 47873 47873
2 100452 100452
1 25851 25851

Which cohort combinations each variant was fit in (TRUE = fit in that cohort)

variants
186418

Estimating age at amyloid onset with SILA

Person-level outcome

Quantity Value
People with an onset estimate 298
Onset observed (event = 1) 73 (24.5%)
Censored at last scan 225 (75.5%)
Events with onset estimated before first scan (prevalent at entry) 69 (94.5%)
People whose per-scan onset estimate varied (latest used) 0 (0.0%)
Estimated onset age among events, mean (SD) 66.8 (8.2)
Estimated onset age among events, median [IQR] 67.0 [60.5, 73.1]
Censoring age among censored, median [IQR] 69.9 [66.0, 76.0]
Projected onset age among censored, median [IQR] 113.5 [106.2, 120.3]

Survival model

Model specification

At each variant position, within each cohort, the model is a Cox proportional-hazards regression of time to amyloid onset (age scale, as defined under Person-level outcome) on local-ancestry genotype, adjusted for sex:

hazard(age) = baseline hazard(age) × exp(β₁·[EUR/AFR] + β₂·[AFR/AFR] + β₃·Sex)

EUR/EUR is the reference. β₁ is the log hazard ratio for people with one African and one European haplotype at that position; β₂ is for two African haplotypes. Phase is ignored. Participants with an Amerindigenous haplotype at the position are excluded from that position’s model only. If only one of the two non-reference genotypes is present in the cohort at that position, the model contains that single contrast. Sex is dropped from the model only if the cohort has a single sex.

Data entering each cohort’s model

A4

Participants in model: 123; events: 31; variants fit: 180611.

People per local-ancestry genotype across all fitted variants

Genotype group Median per variant Min Max
EUR/EUR 9 5 15
EUR/AFR 42 27 56
AFR/AFR 70 61 81
AMR carriers dropped 1 0 4

ADNI

Participants in model: 22; events: 9; variants fit: 39199.

People per local-ancestry genotype across all fitted variants

Genotype group Median per variant Min Max
EUR/EUR 1 1 3
EUR/AFR 4 2 8
AFR/AFR 16 13 18
AMR carriers dropped 0 0 1

NACC

Participants in model: 137; events: 32; variants fit: 151893.

People per local-ancestry genotype across all fitted variants

Genotype group Median per variant Min Max
EUR/EUR 8 5 13
EUR/AFR 42 33 57
AFR/AFR 84 70 93
AMR carriers dropped 2 0 5

WRAP

Participants in model: 16; events: 1; variants fit: 49138.

People per local-ancestry genotype across all fitted variants

Genotype group Median per variant Min Max
EUR/EUR 1 1 3
EUR/AFR 4 2 8
AFR/AFR 11 7 13
AMR carriers dropped 0 0 1

Per-cohort results

A4

Tests with a finite p-value: 358572. Passing Bonferroni: 0. Passing FDR < 0.05: 0. Smallest p-value: 0.0021.

ADNI

Tests with a finite p-value: 78398. Passing Bonferroni: 0. Passing FDR < 0.05: 0. Smallest p-value: 0.0059.

NACC

Tests with a finite p-value: 302263. Passing Bonferroni: 0. Passing FDR < 0.05: 0. Smallest p-value: 0.0005.

WRAP

Tests with a finite p-value: 94250. Passing Bonferroni: 0. Passing FDR < 0.05: 0. Smallest p-value: 0.0651.

Pre-specified chromosome 19 variants

Meta-analysis estimates for the pre-specified variants (fixed effect; k = cohorts pooled)

SNP Gene Term k Cohorts HR (95% CI) p Q p I2 (%)
rs7412 APOE AFR/AFR 2 A4,NACC 0.60 (0.27, 1.30) 0.1953 0.7950 0.0
rs7412 APOE EUR/AFR 2 A4,NACC 0.69 (0.30, 1.58) 0.3744 0.9177 0.0
rs3764650 ABCA7 AFR/AFR 4 A4,ADNI,NACC,WRAP 0.32 (0.13, 0.84) 0.0198 0.3736 3.8
rs3764650 ABCA7 EUR/AFR 4 A4,ADNI,NACC,WRAP 0.24 (0.08, 0.77) 0.0160 0.1701 40.3
rs115550680 ABCA7 AFR/AFR 2 A4,NACC 0.30 (0.11, 0.82) 0.0192 0.1457 52.8
rs115550680 ABCA7 EUR/AFR 2 A4,NACC 0.20 (0.06, 0.68) 0.0098 0.0456 75.0
rs4147929 ABCA7 AFR/AFR 3 A4,ADNI,NACC 0.33 (0.13, 0.86) 0.0227 0.2330 31.4
rs4147929 ABCA7 EUR/AFR 3 A4,ADNI,NACC 0.23 (0.07, 0.75) 0.0142 0.0748 61.4
rs115882880 GRIN3B AFR/AFR 4 A4,ADNI,NACC,WRAP 0.31 (0.12, 0.81) 0.0161 0.3586 6.9
rs115882880 GRIN3B EUR/AFR 4 A4,ADNI,NACC,WRAP 0.23 (0.07, 0.74) 0.0134 0.1587 42.2
rs3865444 CD33 AFR/AFR 2 A4,ADNI 0.39 (0.14, 1.08) 0.0700 0.7450 0.0
rs3865444 CD33 EUR/AFR 2 A4,ADNI 0.26 (0.08, 0.80) 0.0192 0.8576 0.0
rs17685286 ZNF554 AFR/AFR 3 A4,NACC,WRAP 0.36 (0.16, 0.85) 0.0190 0.3225 11.6
rs17685286 ZNF554 EUR/AFR 3 A4,NACC,WRAP 0.38 (0.15, 0.95) 0.0392 0.4720 0.0
rs3852863 EMC10 AFR/AFR 3 A4,ADNI,NACC 0.60 (0.29, 1.26) 0.1756 0.9873 0.0
rs3852863 EMC10 EUR/AFR 3 A4,ADNI,NACC 0.40 (0.17, 0.90) 0.0279 0.9908 0.0

Meta-analysis

Results

Variant–contrast pairs pooled, by number of contributing cohorts

k (cohorts) AFR/AFR EUR/AFR
4 12180 12180
3 47873 47873
2 100452 100452

Primary (k = 4) analysis

term Tests FDR < 0.05 Bonferroni < 0.05 Smallest p Heterogeneous (Q p < 0.05) Median I2 (%)
AFR/AFR 12180 512 0 0.0008 0 0
EUR/AFR 12180 1723 0 0.0012 0 0

Top 10 pooled hits (k = 4)

SNP Position Term HR (95% CI) p FDR Bonferroni Q p I2 (%) Cohorts
rs1205318 54330126 AFR/AFR 0.27 (0.13, 0.58) 0.0008 0.0481 1.0000 0.4941 0 A4,ADNI,NACC,WRAP
rs7255023 54329235 AFR/AFR 0.27 (0.13, 0.58) 0.0008 0.0481 1.0000 0.4941 0 A4,ADNI,NACC,WRAP
rs198973 50877269 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs198974 50877346 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs198975 50877559 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs198976 50877870 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs34964828 50877108 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs8105211 50877345 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs8105275 50877189 EUR/AFR 0.28 (0.13, 0.60) 0.0012 0.0481 1.0000 0.8036 0 A4,ADNI,NACC,WRAP
rs10408670 50890575 EUR/AFR 0.28 (0.13, 0.61) 0.0014 0.0481 1.0000 0.7957 0 A4,ADNI,NACC,WRAP