Trial news: woes, new approaches.

Tomm40 has created a stir in Alzheimer’s disease (AD) research with the recent proposal that variablelength polymorphisms of this gene, which lives near apolipoprotein E (ApoE) on chromosome 19, can help predict at what age a person may develop late-onset AD (LOAD) [1,2]. This finding came from analysis of several small cohorts in which ages of LOAD onset were determined retrospectively. Now, new work on Tomm40 (aka translocase of the outer mitochondrial membrane 40) confirms the age-of-onset connection in a small prospective study of cognitively normal adults who went on to develop mild cognitive impairment (MCI) or AD. Scientists reported the preliminary findings at the International Conference on Alzheimer’s Disease (ICAD) held 10-15 July in Honolulu, Hawaii, along with other data showing that the Tomm40 length variants also correlate with brain atrophy and cognition in asymptomatic middle-aged people. If the results hold up, they could explain why some ApoE3/E3 homozygotes, a supposedly risk-neutral group, have LOAD risk that parallels that of E4 carriers, and may improve stratification of participants in future clinical trials. Plowing through phylogenetic analyses, researchers led by Allen Roses and Michael Lutz of Duke University in Durham, North Carolina, and Eric Reiman of Banner Alzheimer’s Institute in Phoenix, Arizona, came upon a poly-T variant within intron 6 of Tomm40 that greatly improved predictions for when ApoE3 carriers might develop AD. In particular, among autopsyconfirmed ApoE3/4 patients, those with two copies of the long Tomm40 variant (more than 20 poly-T repeats) – aka the “long/longs” – developed AD about eight years earlier than the “short/longs,” who had a copy of the short Tomm40 variant (20 or fewer poly-T repeats) along with the long version [3]. In this earlier study, the researchers analyzed several independent cohorts of patients whose LOAD onset ages were documented in medical records. Because retrospective data can be unreliable, the scientists sought to reproduce those findings in prospective studies of people with known ApoE and Tomm40 status who are being followed with neuropsychological testing for future development of MCI or AD. On an ICAD poster, Richard Caselli of Mayo Clinic, Scottsdale, Arizona, and colleagues including Reiman and Roses, reported preliminary data from 30 participants in the first of several prospective studies in progress for five to 19 years. In short, the results came out as predicted: the “long/long” group developed incident MCI or AD about nine years earlier than the “short/longs” (onset age 73 versus 82). The cohort was too small to correct for ApoE genotype, Caselli noted, but the earlier age of onset in the long/longs did hold for both ApoE3/4 (n = 10) and ApoE3/3 (n = 11) subgroups. The Tomm40 length variants also seem to track with other defining measures of AD – namely, brain atrophy and cognition. These preliminary studies involved participants of a longitudinal cohort study called WRAP (Wisconsin Registration for Alzheimer’s Prevention) that started in 2001 under the leadership of Mark Sager at the University of Wisconsin in Madison. Participants around a mean age of 54 enter the study asymptomatic and get cognitive testing every few years. Some also receive brain imaging through ancillary studies