P1‐245: TOMM40 Poly‐T Length Variant and Age‐At‐Onset in Familial AD Caused by PSEN1 and PSEN2 Mutation

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Our previous study showed that familial Alzheimer's disease (AD) caused by apresenilin 2 (PSEN2) mutation (N141I) has similar neuropathology but a wide variation in age-at-onset. A recent study found that the length of a poly-T nucleotide repeat (rs10524523) within intron 6 of the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene, which is adjacent to apolipoprotein E (APOE), is associated with age-at-onset in late-onset AD. In this study, we examine associations between TOMM40 poly-T length and age-at-onset in AD patients carrying either presenilin 1 (PSEN1 on chromosome 14) or PSEN2 mutations. Thirty-two PSEN1 mutation carriers and 27 PSEN2 mutation carriers with AD and APOE e3/e3 genotype were recruited from the University of Washington ADRC. AD diagnosis and age-at-onset were determined based on history and clinical evaluation. The rs10524523 poly-T length was genotyped using a short tandem repeats genotyping assay developed in Dr. Yu's laboratory. Poly-T length was dichotomized into the short (< 20) and long (= 20). The age-at-onset was compared between those with and without long poly-T variants. To account for this intra-family correlation of age-at-onset, standard error was estimated using robust linear regression. In AD patients with PSEN2 mutations, the age-at-onset was an average of 7 years earlier for patients with long poly-T variants than patients with short/short variants (p = 0.036). After accounting for the intra-family correlation, the significance of the difference dropped slightly to p = 0.06. In patients with PSEN1 mutations, age-at-onset did not differ by presence of long poly-T variants (Table 1, p = 0.82). PSEN2 carriers with at least one copy of the long poly-T have on average an AD age-at-onset 7 years earlier than those without the long poly-T. This finding is consistent with previous report in late-onset AD. Further study is needed to determine whether the lack of association between TOMM40 poly-T and age-at-onset in persons with PSEN1 mutation is due to heterogeneity of PSEN1 mutations or a different mechanism of TOMM40 in AD.

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