Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding
[1];
- Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine
- Univ. of California, Los Angeles, CA (United States); Univ. of Oregon, Eugene, OR (United States)
- San Diego State Univ./Univ. of California, San Diego Joint Doctoral Program in Clinical Psychology, CA (United States)
- Univ. of California, Los Angeles, CA (United States)
The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer’s disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL.A total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14–20 repeats; S), long (21–29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates. Data from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning. This is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.
- Research Organization:
- Univ. of California, San Diego, CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); Zegar Family Foundation Research Fund; Ahmanson Foundation; McComb Foundation; McMahan Foundation; Bob and Marion Wilson; Fran and Ray Stark Foundation Fund for Alzheimer’s Disease Research; Plott Professorship; Parlow-Solomon Professorship; National Institutes of Health (NIH)
- Grant/Contract Number:
- FC03-87ER60615; P01-AG025831; AG13308; P50 AG 16570; MH/AG58156; MH52453; AG10123; M01-RR00865
- OSTI ID:
- 1614562
- Journal Information:
- PLoS ONE, Vol. 13, Issue 12; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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