TOMM40 “523” Genotype Affects Age of Alzheimer’s Disease Onset Differentially by Race

Abstract

The TOMM40 gene encodes the translocase of the outer mitochondrial membrane pore subunit, and is in linkage disequilibrium with APOE. The length of a poly-T variant (“523”) within intron 6 of TOMM40 has been shown to predict the age of onset of late onset Alzheimer's Disease (LOAD). We present new data using Kaplan Meier (KM) survival curves showing the effect of “523” on LOAD within a large, well-characterized sample followed annually for up to five years. The Bryan ADRC Memory Health and Aging study is comprised of a diverse group of residents from the local community (28% African-American; AfrAmer) all of whom were independent in their daily function at baseline. They were visited in the home or in the clinic annually and evaluated on a number of measures including a neuropsychological test battery, health history, behavioral functional assessments, and neurological evaluation. Using a sample of n = 438 participants, cognitively normal at baseline, we produced empirical survival curves to estimate age-specific proportions of participants surviving for TOMM40 “523” genotypes based on poly-T length. Individuals were followed over time until death, dementia onset, including probable or possible AD, or their last visit. A total of 106 individuals were diagnosed with dementia at a mean age of 78 (SD 8.0) years. KM curves show an effect (p < 0.0001, log rank test) of “523” genotype on age of LOAD onset, with age at 50% affected ranging from 75 to 94 years and a 3-5 year separation between curves. Ethnicity has an effect (p = 0.004) on LOAD onset whereas gender and years of education were not statistically-significant covariates. Limiting analysis to individuals with the APOE 3 /3 genotype (n = 199) showed a significant effect (p < 0.02) of “523” on LOAD onset. “523” genotypes define characteristic age of onset curves for LOAD which provide additional temporal resolution to curves based on APOE genotype. Results suggest that the age of onset in AfrAmer in this cohort is earlier, across all “523” genotypes, however this needs to be studied further as there were few AfrAmer in the sample.