Membership in high-risk genetic groups predicts Alzheimer’s disease and age-at-onset

1. Membership in high-risk genetic groups predicts Alzheimer’s disease and age-at-onset • Elizabeth Corder Duke University • Shirley Poduslo Medical College of Georgia

4. Background • Some degree of AD brain changes (plaques and tangles) is almost universal by age 80 • Extended longevity implies a strong! need to identify root causes and interventions • I believe that risk pertains to many genes that have biologic plausibility but have been difficult to verify from sample to sample due to wide variation in frequencies of high-risk combinations

5. Goal • Use GoM to define multilocus genotypes at high and low risk for AD • Demonstrate that persons with high resemblance to high-risk ‘pure types’ are affected while those with low membership are OK

6. Grade of Membership analysis(Woodbury et al., 1978) • Lambda coefficient (): probability that a specific variable outcome is associated with a particular pure type • Grade of membership coefficients (gik): estimate the degree to which a subject belongs to a pure type • Pij gikkj • k • Internal variables and external (validating) variables • The number of pure types that provide the best partition of the data matrix is determined by log likelihood tests

7. Data • Age/ AD status • APOE genotype • Genotypes for plausible candidate loci: • APOE promoter polymorphisms at –491 and –427 • Adjacent gene APOCI • LDL receptor for APOE • Cystatin C • Cathepsin D

8. Table 1. Probabilities representing GoM groups I to V.* Attribute I II III IV V H AD case 100 100 100 0 0 0.68 Age (years) < 65 31 17 12 0 0 0.90 65- 69 30 0 0 0 70 0 45 41 41 0 75 0 0 36 59 0 80+ 0 0 0 0 100

9. Group V: Long life without AD • Permissive promotion of the APOE gene • Several genotypes: e23, e33 and even e34! • Heterozygosity for the LDL receptor for APOE

10. Table 1.cont I II III IV V H APOE e23 40 0 4 0 48 1.17 e33 0 0 0 10024 e24 47 7 0 0 0 e34 0 0 96 0 28 e44 19 93 0 0 0 APOE –491 AA 0 100 100 100 0 0.90 AT 0 0 0 0 100 TT 100 0 0 0 0 APOE-427 TT 0 100 99 100 74 0.30 TC 100 0 0 0 25 CC 0 0 1 0 1 APOCI AA n/a 100 0 0 0 0.91 AB n/a 0 100 0 100 BB n/a 0 0 100 0 I II III IV V H LDLr8 GG 100 100 100 99 0 0.40 AG 0 0 0 0 100 AA 0 0 0 1 0 LDLr13 TT 0 100 0 0 0 0.82 TC 0 0 100 53 100 CC 100 0 0 47 0 CST3 GG 0 90 84 100 69 0.52 GA 100 0 0 0 0 AA 0 10 16 0 31 CTSD CC 0 100 100 100 100 0.41 CT 100 0 0 0 0

11. Group I: Affected before age 70 • Ultra-high expression of APOE • High-risk homozygous combinations of APOE & LDL receptor genotypes • Rare cathepsin D + cystatin C genotypes => that slow rate of amyloid degradation

12. Group II: Affected before age 75 • High-risk APOE44 in combination with an alternate homozygous LDL exon 13 receptor genotypes, I.e. several high-risk APOE-LDL combinations

13. Group III: Affected before age 80 • Common garden variety APOE34 • Unaffected group IV of similar age carried APOE33 not APOE34

14. Table 2. AD status according to membership in the high-risk groups (I+II+III) AD Membership 0-20% 20-40% 40-60% 60-80% 80-100% YES (n=180) 0(0%) 11(31%) 43(61%) 24(57%) 102(100%) NO (n=120) 50(100%) 24(69%) 28(39%) 18(43%) 0(0%) 50 35 71 42 102

15. Conclusions • Identification of high-risk combinations of gene variants jointly with the resemblance of study subjects to the to combinations may prove to be useful: • To predict the level of risk and likely age at onset of AD for individuals • Robust verification of candidate risk genes (the frequency of high-risk persons may vary from sample to sample while the risk groups rooted in biology are stable)