Hippocampal Thinning Linked to Longer TOMM40 Poly-T Variant Lengths in the Absence of the APOE &Epsi

Alzheimer’s & Dementia - (2017) 1-10 Featured Article Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant Alison C. Burggrena,b,c,*, Zanjbeel Mahmoodb, Theresa M. Harrisona,b,d, Prabha Siddarthb,c,e, Karen J. Millerb,c,e, Gary W. Smallb,c,e, David A. Merrillb,c,e, Susan Y. Bookheimera,b,c,f aCenter for Cognitive Neurosciences, University of California, Los Angeles, CA, USA bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA cSemel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA dInterdepartmental Graduate Program in Neuroscience, University of California, Los Angeles, CA, USA eDivision of Geriatric Psychiatry, Longevity Center, University of California, Los Angeles, CA, USA fDepartment of Psychology, University of California, Los Angeles, CA, USA Abstract Introduction: The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a prom- ising gene in Alzheimer’s disease (AD) risk. 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. Methods: In this study, we examined the effects of TOMM40 using high-resolution magnetic reso- nance imaging in 65 healthy, older subjects with and without the APOE ε4 AD-risk variant. Results: Examining individual subregions within the MTL, we found a significant relationship between increasing poly-T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE ε4 allele. Discussion: Our data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE ε4. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. Keywords: APOE; TOMM40; Hippocampus; Alzheimer’s disease; MRI; Entorhinal cortex 1. Introduction progression remain unidentified or uncharacterized for their role in AD [5]. Possession of the ε4 variant of the APOE APOE For more than two decades, the apolipoprotein E ( ) gene does not provide sufficient sensitivity, selectivity, or gene has been consistently identified as the primary risk power to be used as a predictive tool for AD diagnosis [6], gene for late-onset Alzheimer’s disease, accounting for and much of the last decade of genetics research in AD approximately 50% of the genetic risk for AD [1–3]. has focused on identifying other genetic markers related to Despite the strength of the APOE ε4 risk variant in disease risk and age of onset in the hopes of identifying those predicting AD, population studies of APOE allele more likely to experience future cognitive decline. frequency among AD patients indicate that 36%–50% of Several studies implicate APOE’s neighbor on chromo- patients do not carry the ε4 variant [4], and that other signif- some 19, the translocase of outer mitochondrial membrane icant genetic contributions to disease risk and pathological 40 (TOMM40) homolog gene, in risk for AD [4–7]. The variant (rs10524523, “523”) in intron 6 of the TOMM40 gene is a variable length poly-T sequence with lengths clas- *Corresponding author. Tel.: (310) 794-1021; Fax: (310) 825-8334. sified as short (14–20 repeats; i.e., “S”), long (21–29 repeats, E-mail address: [email protected] i.e., “L”), or very long (.29 repeats, i.e., “VL”). The number http://dx.doi.org/10.1016/j.jalz.2016.12.009 1552-5260/Published by Elsevier Inc. on behalf of the Alzheimer’s Association. 2 A.C. Burggren et al. / Alzheimer’s& Dementia - (2017) 1-10 of T residues in the homopolymer, “N,” is 35, and the spe- (MTL), especially in ERC, can be more sensitive to possible cific variation described by rs10524523 is a 19-base pair preclinical morphology differences in both nondemented deletion, making the homopolymer T16 (N 5 16 T residues) APOE ε4 subjects [25] and MCI patients [26] than volu- the variant allele [8,9]. One of the earliest studies of this metric measures. Our group [27–29] and others [30,31] variant concluded that the longer length poly-T allele in- have used high-resolution MRI combined with a cortical un- creases risk for AD and decreases age of onset [10]; this folding technique that improves visibility of the MTL to finding was replicated in an independent study a few years investigate subregional changes in this area, even in nonde- later [11]. Linkage disequilibrium between TOMM40 and mented, cognitively intact subjects who carry the at-risk ε4 APOE genes ensures that the L poly-T repeat in the variant [25]. TOMM40 gene is almost always (with rare exceptions) in- The aim of the present study was to use high-resolution herited with the APOE ε4 allele. However, the ε3 allele is imaging combined with subregional data analysis tech- most commonly with either a VL or an S poly-T variant, niques in nondemented, older subjects to investigate the again, with rare exceptions [10,12]. In individuals impact of rs10524523 poly-T alleles on the MTL in vivo, homozygous for the ε3 variant, the VL variant was found which is the site of the very earliest structural changes in to be associated with a higher risk and earlier age of onset AD [32]. We focused analyses on subjects who did not carry for AD, whereas S variant carriers had a later age of onset the ε4 risk variant of APOE, to investigate the contribution of [10]. A review of the APOE-TOMM40 phylogenetic field the poly-T variant length in the absence of other known suggests that the discovery of the polymorphism in genetic risk attributable to the APOE gene. TOMM40 may improve AD-risk prediction [13]. Recent results suggest that the protein encoded by the 2. Methods TOMM40 gene may affect the development of AD via mitochondrial function [12,14]. The protein that TOMM40 2.1. Participants encodes, TOM40, is a mitochondrial import channel protein The study was conducted with the approval of the Univer- b that facilitates the transport of amyloid- protein precursor sity of California, Los Angeles Institutional Review Board; b b (APP) and amyloid- (A ) transport to the mitochondria all subjects signed informed consent forms before participa- [15,16]. The TOM40 protein acts as a chaperone, tion. Participants were drawn from a larger study of predic- expediting the movement of preproteins through the tors of cognitive decline by the UCLA Longevity Center channel and assembling them posttranslationally in the [33,34]. Briefly, volunteers from the local community were ε b mitochondrion [16]. Because APOE 4, A , and APP have recruited through local advertisements. Subjects were been found to influence function and motility of mitochon- screened over the phone by research staff of the Longevity dria, it has been postulated that APOE and TOMM40 genes Center. However, subjects meeting criteria for AD or any might mediate disease risk, and lower age of onset, through other dementia were excluded from the study [35]. Subjects mitochondrial dysfunction [10,17–19]. Mitochondrial were also excluded for any history of substance abuse, head dysfunction is a well-documented factor in the pathogenesis trauma or other major systemic disease affecting brain func- of several age-related diseases, including Parkinson’s disease, tion, a history of neurological or psychiatric disorders, and amyotrophic lateral sclerosis, Huntington’s disease, and AD hypertension or cardiovascular disease. [20–23]. During their visit to the Longevity Center, subjects under- ε ε In homozygous APOE 3/ 3 subjects, a phylogenetic went neuropsychological testing and a clinical interview, in experiment suggested that possession of the VL poly-T addition to a medical examination and laboratory screening repeat was associated with increased disease risk and earlier including blood tests, to rule out medical conditions that age of onset [10]. A separate study revealed similar findings; could affect cognitive performance. The present study was possession of the VL poly-T variant in subjects homozygous conducted on a subset of 65 of these participants (see ε for 3 was linked to developing AD at a higher rate when Table 1) who had successfully completed genotyping for they were 79 years old [11]. The authors conclude that both APOE and TOMM40 and cognitive and imaging pro- ε in the absence of 4, longer poly-T variants increase the like- cedures. lihood of developing AD, where the ε3 allele may be linked to either an S or a VL poly-T repeat [10]. 2.2. Neuropsychological testing To pinpoint the biologically relevant endophenotypes that relate to the TOMM40 gene, it is crucial to investigate Neuropsychiatric test scores were divided into the healthy individuals using sensitive metrics to assess the following domains of cognitive function: processing speed very earliest manifestations of pathophysiological changes (trail making test, part A; Stroop test, word reading speed; in the brain, before the onset of clinical symptoms. Although Weschler adult intelligence scale-III digit symbol), memory hippocampal volume is a hallmark brain imaging phenotype encoding (Buschke-Fuld selective reminding test, consistent in AD, substantial work has shown that the first brain long-term retrieval; Weschler memory scale-II, logical changes in AD begin in entorhinal cortex (ERC) [24]. Addi- memory I and verbal paired associates I), delayed memory tionally, subregional

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