Membership in high-risk genetic groups predicts Alzheimer’s disease and age-at-onset Elizabeth CorderDuke University Shirley PodusloMedical College of.

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Membership in high-risk genetic groups predicts Alzheimer’s disease and age-at-onset Elizabeth CorderDuke University Shirley PodusloMedical College of Georgia

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

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

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 ( g ik ): estimate the degree to which a subject belongs to a pure type P ij   g ik 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

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

Table 1. Probabilities representing GoM groups I to V.* Attribute I II III IV V H AD case Age (years) < <

Group V: Long life without AD Permissive promotion of the APOE gene Several genotypes:  23,  33 and even  34! Heterozygosity for the LDL receptor for APOE

Table 1.cont I II III IV V H I II III IV V HAPOE           APOE – 491 AA AA AT AT TT TT APOE-427 TT TT TC TC CC CC APOCI AA n/a AA n/a AB n/a AB n/a BB n/a BB n/a I II III IV V H I II III IV V HLDLr8 GG GG AG AG AA AA LDLr13 TT TT TC TC CC CC CST3 GG GG GA GA AA AA CTSD CC CC CT CT

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

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

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

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% % 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%)

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)