TOMM40 intron 6 poly‐T length, age at onset, and neuropathology of AD in individuals with APOE ɛ3/ɛ3

Background This study investigates the association between TOMM40 poly‐T length, age at onset, and neuropathology in individuals with Alzheimer's disease (AD) with the apolipoprotein E ( APOE ) ɛ3/ɛ3 allele. Methods Thirty‐two presenilin 1 ( PSEN1 ) mutation carriers with AD, 27 presenilin 2 ( PSEN2 ) mutation carriers with AD, 59 participants with late‐onset AD (LOAD), and 168 autopsied subjects from a community‐based cohort were genotyped for TOMM40 intron 6 poly‐T (rs10524523) length using short tandem repeat assays. Results Among AD individuals with PSEN2 mutations, the presence of a long poly‐T was associated with an earlier age at onset, whereas there were no such associations for subjects with PSEN1 mutations or LOAD. In community‐based participants, the presence of a long poly‐T was associated with increased neuritic tangles and a greater likelihood of pathologically diagnosed AD. Conclusion TOMM40 intron 6 poly‐T length may explain some of the variation in age at onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ɛ3/ɛ3.