Translocase Of Outer Mitochondrial Membrane 40 Research Articles

On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.

Genome-wide association studies have identified numerous disease susceptibility loci (DSLs) for Alzheimer's disease (AD). However, only a limited number of studies have investigated the dependence of the genetic effect size of established DSLs on genetic ancestry. We utilized the whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) including 35,569 participants. A total of 25,459 subjects in four distinct populations (African ancestry, non-Hispanic White, admixed Hispanic, and Asian) were analyzed. We found that nine DSLs showed significant heterogeneity across populations. Single nucleotide polymorphism (SNP) rs2075650 in translocase of outer mitochondrial membrane 40 (TOMM40) showed the largest heterogeneity (Cochran's Q=0.00, I2=90.08), followed by other SNPs in apolipoprotein C1 (APOC1) and apolipoprotein E (APOE). Two additional loci, signal-induced proliferation-associated 1 like 2 (SIPA1L2) and solute carrier 24 member 4 (SLC24A4), showed significant heterogeneity across populations. We observed substantial heterogeneity for the APOE-harboring 19q13.32 region with TOMM40/APOE/APOC1 genes. The largest risk effect was seen among African Americans, while Asians showed a surprisingly small risk effect.

TOMM40 Correlates with Cholesterol and is Predictive of a Favorable Prognosis in Endometrial Carcinoma.

A link between cholesterol and endometrial cancer has been established, but current studies have been limited in their findings. We aimed to elucidate the causal relationship between cholesterol and endometrial cancer and to find prognostic genes for endometrial cancer. We first explored the causal relationship between total cholesterol and endometrial cancer using two-sample Mendelian randomization and then obtained differential genes to screen for prognosis-related genes in endometrial cancer. Then, we utilized pan-cancer analysis based on RNA sequencing data to evaluate the expression pattern and immunological role of the Translocase of Outer Mitochondrial Membrane 40 (TOMM40). Through multiple transcriptome datasets and multi-omics in-depth analysis, we comprehensively explore the relationship of TOMM40 expression with clinicopathologic characteristics, clinical outcomes and mutations in endometrial cancer. Lastly, we systematically associated the TOMM40 with different cancers from immunological properties from numerous perspectives, such as immune cell infiltration, immune checkpoint inhibitors, immunotherapy, gene mutation load and microsatellite instability. We found a negative association between cholesterol and endometrial cancer. A total of 78 genes were enriched by relevant single nucleotide polymorphisms (SNPs), of which 12 upregulated genes and 5 downregulated genes in endometrial cancer. TOMM40 was found to be a prognostic gene associated with endometrial cancer by prognostic analysis. TOMM40 was found to be positively correlated with the infiltration of most immune cells and immunization checkpoints in a subsequent study. Meanwhile, TOMM40 also was an oncogene in many cancer types. High TOMM40 was associated with lower genome stability. The findings of our study indicate that the maintenance of normal total cholesterol metabolism is associated with a decreased risk of developing endometrial cancer. Moreover, TOMM40 may have potential as a prognostic indicator for endometrial cancer.

APOE Independent Associations of TOMM40 rs2075650 Genotype on Hippocampal Volume

Apolipoprotein E ε4 (APOE ε4) confers the greatest genetic risk for late-onset Alzheimer's disease (AD). The adjacent Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene may increase risk through APOE ε4 independent associations with AD- sensitive brain regions like the hippocampus. ANOVA and multiple linear regression tested TOMM40 rs2075650 ('650) G vs. A genotype on total hippocampal volume using UK Biobank data (n=10,130), across all participants and by APOE haplotype groups. Age and sex interactions with TOMM40 '650 were also tested. Across participants, having both APOE ε4 and TOMM40 '650 G carriage was related to hippocampal atrophy. Among non-APOE ε4 adults, age and sex jointly modulated '650 G carriage effects. Compared to younger middle- aged adults, older women and men respectively showed modest protective and markedly detrimental associations. TOMM40 '650 G carriage may have APOE ε4-independent associations with hippocampal volume based on age and sex.

Updated APOE and TOMM40 rs2075650 genotype effects on cognition: a UK Biobank study

AbstractBackground58‐79% of late‐onset Alzheimer’s disease (AD) is due to genetic heritability. The epsilon 4 (ε4) variant of Apolipoprotein E (APOE) is the strongest genetic risk factor for AD, yet only accounts for 20% of AD heritability. In addition, the APOE ε2 or ε3 variants appear to have either a protective or neutral effect on AD risk respectively. Translocase of Outer Mitochondrial Membrane 40 (TOMM40) is next to APOE and may modulate different APOE variant effects, such as with the Single Nucleotide Polymorphism (SNP) at rs2075650. Thus, we explored main and interaction effects of TOMM40 and APOE on longitudinal measures of executive function and memory.Method10,347 adults (40‐70y) in the UK Biobank were genotyped for APOE and TOMM40 ‘650. Executive function and memory were tested at baseline and twice over a period of 6‐10 years. Main effects within APOE haplotypes and TOMM40 SNP genotypes (A,G) were analyzed, as well as interactions between these genetic markers.ResultHaving the TOMM40 ‘650 G risk variant was related to better baseline cognitive scores regardless of APOE haplotype (ps <.05), but a greater decline over time in APOE4 carriers (ps <.05) The effects of the APOE haplotype were strongly modulated by sex. Men vs. women had less protective or more detrimental effects based on APOE2 or APOE4 haplotype respectively.ConclusionThe data suggests that TOMM40 modulates APOE, regardless of its haplotype. Future studies should stratify APOE by haplotype to re‐test our findings. In addition, more research needs to be done on the effect of having what we term a “mixed” APOE haplotype (carrying a copy of both the protective and risk gene variants).

TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer's Disease.

Translocase of outer mitochondrial membrane 40 (TOMM40) is located in the outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer's disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines.

An AS-qPCR-based method for the detection of Alzheimer's disease-related SNPs.

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases in the world and has a strong genetic predisposition. At present, there is still no effective method for the early diagnosis and prevention of AD. Accumulating evidence shows the association of several loci with AD risk, such as apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 (TOMM40). However, for routine disease diagnosis in clinics, genotype detection methods based on gene sequencing technology are time-consuming and excessively costly. Thus, in this study, we developed a high-sensitivity, low-cost, and convenient single nucleotide polymorphism(SNP) detection assay method based on allele-specific quantitative polymerase chain reaction (AS-qPCR) technology, which can be used to determine the SNP genotype in APOE and TOMM40. A total of 40 patients were recruited from the outpatient department of the memory clinic of Dongzhimen Hospital, Beijing University of Chinese Medicine. The SNP detection assay method includes three steps. First, positive plasmids with different genotypes (TT/CC/TC) in APOE rs429358, rs7412, and TOMM40 rs11556505 were prepared. Second, 3'-T/3'-C primers were designed to amplify these positive plasmids for each SNP site. Finally, we calculated the log10 of the copy number ratio for each positive plasmid, and the genotype interpretation interval was established. Based on this method, we investigated whether the SNPs in 40 patients could be accurately calculated using AS-qPCR technology. The accuracy of SNP detection was verified by PCR-Pooling sequencing. The results showed that SNP genotypes assessed by AS-qPCR technology corresponded perfectly to the results obtained by conventional DNA sequencing. We have developed a genotype detection method for AD based on AS-qPCR, which can be performed easily, rapidly, accurately, and at low cost. The method will contribute to the early diagnosis of patients with late-onset Alzheimer's and the detection of large clinical samples in the future.

APOE, TOMM40, and Sex Interactions on Neural Network Connectivity

AbstractBackgroundThe Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The Translocase of Outer Mitochondrial Membrane‐40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. MethodWe examined 21 orthogonal neural networks among 8,222 middle‐aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderatorsResultAPOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G‐carriage led to less network strength with increasing age, while in non G‐carriers this was only seen in women but not men.ConclusionTOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

APOE, TOMM40, and sex interactions on neural network connectivity

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while '650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

TOMM40\u2018523\u2019 poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson\u2019s disease

The translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

Outer and inner mitochondrial membrane proteins TOMM40 and TIMM50 are intensively concentrated and localized at Purkinje and pyramidal neurons in the New Zealand white rabbit brain.

Mitochondria are involved in a variety of developmental processes and neurodegenerative diseases. The translocase complexes of the outer and inner mitochondrial membranes (TOM and TIM) are protein complexes involved in transporting protein precursors across mitochondrial membranes. Although rabbits are important animal models for neurodegenerative diseases, the expression of TOM and TIM complexes has yet to be examined in the rabbit brain. In the present study, we quantitatively evaluated the protein expression of the translocase of outer mitochondrial membrane 40 (TOMM40) and inner mitochondrial membrane 50 (TIMM50) complexes, two of the TOM/TIM complexes, in the cerebral, cerebellar, and hippocampal cortices of the New Zealand white rabbit brain, using immunohistochemistry. Sections from brain specimens were initially stained for cytochrome c oxidase (COX), a well-known mitochondrial marker, which was found to be homogeneously expressed in the cerebrum, but localized to the Purkinje and pyramidal neurons of the cerebellum and hippocampus, respectively. TOMM40 and TIMM50 proteins consistently revealed a similar expression pattern, although at different ratios. In the cerebrum, TOMM40 and TIMM50 immunoreactions were homogeneously distributed within the cytoplasm of various neurons. Meanwhile, Purkinje cells in the cerebellum and pyramidal neurons in the hippocampus displayed higher intensities in their cytoplasm. The specific cellular localization of TOMM40 and TIMM50 proteins in various regions of the rabbit brain suggests a distinct function of each protein in these regions. Further analysis will be required to evaluate the molecular functions of these proteins.

Associations of Vascular Risk Factors, APOE and TOMM40 Polymorphisms With Cognitive Function in Dementia-Free Chinese Older Adults: A Community-Based Study.

Objective: The associations of vascular risk factors (VRFs), apolipoprotein E (APOE), and translocase of outer mitochondrial membrane 40 (TOMM40) with cognitive function have been investigated mostly in western societies. In the present study, we sought to examine the associations of VRFs [i.e., current smoking, current drinking, physical inactivity, obesity, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), diabetes, and hypertension] and variants located in APOE (ε2/3/4) and TOMM40 (rs2075650) with global cognitive function in Chinese older adults, with a focus on their potential interactions.Methods: This is a cross-sectional study that included 422 permanent residents (mean age 69.2 years, 54.3% female) living in Beijing, who were free of dementia. Data were collected through interviews, clinical examinations, and laboratory tests. The two genetic polymorphisms were genotyped, and participants were dichotomized as carriers vs. non-carriers of APOE ε4 or TOMM40 G. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Data were analyzed with multivariable linear regression models.Results: Physical inactivity and diabetes were independently associated with a lower MMSE score (all p < 0.05). When four putative VRFs (i.e., current smoking, physical inactivity, high LDL-C, and diabetes) were aggregated, an increasing number of having these factors was associated with a decreasing MMSE score in a dose–response manner (p = 0.001). TOMM40 polymorphisms, independent of the APOE ε4 allele, interacted with aggregated VRFs to influence cognitive performance, such that having one or more of these VRFs was particularly detrimental to the cognition of TOMM40 carriers. Further analyses revealed interactions of the TOMM40 polymorphism with (i) physical inactivity and (ii) diabetes, such that having either physical inactivity or diabetes in combination with carrying a TOMM40 G allele, compared to having neither, was significantly associated with a markedly lower MMSE score (all p < 0.05).Conclusion: This study provides some evidence supporting the association of vascular risk factors with poor cognitive performance among dementia-free Chinese older adults and further revealed their interactions with the TOMM40 polymorphism. The results underscore the vulnerability of global cognitive function to VRFs, which could be reinforced by carrying the TOMM40 rs2075650 G allele. These findings have potential implications for developing tailored intervention programs to maintain cognitive function.

A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk

BackgroundAlthough the human chromosome 19q13 loci are reported to be associated with hyper-LDL-cholesterolemia, the haplotype of single nucleotide polymorphism (SNP) has not been studied. Therefore, the association of the haplotype in 19q13 loci with hyper-LDL-cholesterolemia was determined and their interactions with lifestyles and nutrient intakes were evaluated in 28,445 Koreans aged > 40 years.MethodsSNPs were selected from 19q13 loci that had an association with hyper-LDL-cholesterolemia with the adjustment of confounders (age, gender, area of residence, and body mass index). Haplotype was constructed from the selected SNPs. An adjusted odds ratio of the haplotype for hyper-LDL-cholesterolemia and the interaction between haplotype and lifestyles was analyzed after adjusting for covariates.ResultsHyper-LDL-cholesterolemia had an association with apolipoprotein E (APOE)_ rs7259620, translocase of outer mitochondrial membrane 40(TOMM40)_rs157581, poliovirus receptor-related 2(PVRL2)_rs403155, exocyst complex component 3-like 2(EXOC3L2)_ rs10406604 and CD3e molecule-associated protein (CD3EAP)_rs3212986 in 19q13. The haplotype of these SNPs had a negative association with hyper-total-cholesterolemia and hyper-LDL-cholesterolemia by 0.669 and 0.684 times, respectively, after adjusting for covariates. The incidence of cardiovascular diseases, especially myocardial infarction, had a negative association with the minor alleles. The balanced diet pattern (BD) and protein intake had a significant interaction with the haplotype: the major-allele of the haplotype exhibited a positive association with hyper-LDL-cholesterolemia, compared to the minor allele, only when combined with a high intake of BD. The participants with the minor allele exhibited a lower hyper-LDL-cholesterolemia risk compared to those with the major allele only with high protein intake.ConclusionThe minor allele of haplotype located in 19q13 loci protected against hyper-LDL-cholesterolemia, especially with BD and high protein intake. The minor allele also had a negative association with myocardial infarction events.

TOMM40 and APOE variants synergistically increase the risk of Alzheimer's disease in a Chinese population.

The apolipoprotein E (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) in Caucasian and African American populations. It suggests that other genetic factors may modulate AD pathogenesis in Chinese populations, among which the frequency of this allele is reduced but the AD prevalence is maintained. The translocase of outer mitochondrial membrane 40 (TOMM40), which is located adjacent to APOE, may play an APOE-dependent role in modulating AD pathogenesis. This work aimed to investigate whether TOMM40 polymorphisms modulate AD risk independently of, or in conjunction with APOE polymorphisms in Chinese populations. We conducted a case-control study including 834 patients with AD recruited from the Memory Clinic and 643 cognitively normal participants recruited from the community. The Taqman SNP method was used for APOE genotyping, while TOMM40 polymorphism genotyping was conducted via a polymerase chain reaction-ligase detection reaction. The TOMM40 rs10119 and rs71352238 alleles were associated with AD independently of the patient APOE status. The rs10119 AA genotype and rs71352238 CC genotype were risk genotypes of AD. Individuals carrying a TOMM40 rs10119 GG/APOE ε4+ (OR, 3.73; 95% CI 1.49-9.37; P = 0.005), TOMM40 rs10119 AG/APOE ε4+ (OR, 4.16; 95% CI 3.30-5.24; P < 0.001), or TOMM40 rs10119 AA/APOE ε4+ (OR, 14.78; 95% CI 8.56-25.54; P < 0.001) genotype exhibited a significantly higher AD risk. Those carrying a TOMM40 rs71352238 TT/APOE ε4+ (OR, 3.82; 95% CI 2.32-6.29; P < 0.001), TOMM40 rs71352238 CT/APOE ε4+ (OR, 4.40; 95% CI 3.46-5.56; P < 0.001), or TOMM40 rs71352238 CC/APOE ε4+ (OR, 14.02; 95% CI 7.81-25.17; P < 0.001) genotype also exhibited a significantly increased AD risk. This study provides invaluable insights into the mechanisms underlying the prevalence of AD in Chinese populations, and supports that simultaneous TOMM40 and APOE genotyping in the clinical setting may identify individuals at high risk of developing AD.

TOMM40 polymorphism is associated with resting-state functional MRI results in patients with Alzheimer's disease.

Translocase of outer mitochondrial membrane 40 (TOMM40) encodes translocase of the outer mitochondrial membrane (TOM), which is associated with mitochondrial dysfunction in Alzheimer's disease (AD). TOMM40 rs157581-G has been reported to increase susceptibility to AD. However, the effect of TOMM40 rs157581-G in resting-state functional MRI (rs-fMRI) on AD has not been studied. Therefore, we aimed to investigate the role of TOMM40 rs157581-G on rs-fMRI results in AD patients. Twenty-four AD patients were divided into two groups based on TOMM40 rs157581-G status, and clinical and imaging data were compared between the groups. TOMM40 rs157581-G carriers of AD showed decreased regional homogeneity in the left precuneus and decreased amplitude of low-frequency fluctuations in the bilateral temporal poles compared with noncarriers of AD. TOMM40 rs157581-G carriers of AD also showed increased functional connectivity between the right middle occipital gyrus and the left supramarginal gyrus and decreased connectivity between the left superior occipital gyrus and the right transverse temporal gyrus in comparison with TOMM40 rs157581-G noncarriers. We analyzed rs-fMRI characteristics of TOMM40 rs157581-G carriers of AD for the first time, which suggest that TOMM40 rs157581-G plays a harmful role in AD patients.

Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding.

BackgroundThe 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.MethodsA 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.ResultsData 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.ConclusionsThis 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.

'Governor vessel-unblocking and mind-regulating' acupuncture therapy ameliorates cognitive dysfunction in a rat model of middle cerebral artery occlusion.

Acupuncture is a traditional Chinese medicinal therapy, which is used for the amelioration of cognitive dysfunction. The aim of this study was to investigate the effectiveness and relevancy mechanisms of ‘governor vessel-unblocking and mind-regulating’ acupuncture therapy for cognitive dysfunction in rats with ischemia. For this purpose, we used the middle cerebral artery occlusion (MCAO) method to induce cognitive dysfunction in rats. The behavioral changes in the rats were examined using the Morris water maze (MWM) test. The effects of the treatment on oxidative stress response and the function of the mitochondria in brain tissues were also assessed. The results revealed that ‘governor vessel-unblocking and mind-regulating’ acupuncture therapy markedly improved the cognitive ability of the rats with cognitive dysfunction. The production of pro-oxidative stress factors, including nitric oxide (NO) and inducible nitric oxide synthase (iNOS), was also blocked along with the amelioration of cognitive function, while the production of adenosine triphosphate (ATP), superoxide dismutase (SOD) and cyclooxygenase (COX) was restored. At the molecular level, the accumulation of amyloid β (Aβ) in the mitochondria was suppressed by ‘governor vessel-unblocking and mind-regulating’ acupuncture therapy, which may be attributed to the inhibition of the function of translocase of outer mitochondrial membrane 40 (TOMM40) and translocase of inner mitochondrial membrane 17A (TIMM17A). On the whole, the findings of the present study confirm the effects of ‘governor vessel-unblocking and mind-regulating’ acupuncture therapy on cognitive dysfunction induced by brain ischemia in rats, and that the mechanisms underlying the effects of this treatment might be mediated through the inhibition of TOMM40 and TIMM17A synthesis, which can relieve mitochondrial dysfunction from the accumulation of Aβ.

Characterization of APOE and TOMM40 allele frequencies in the Japanese population

IntroductionDementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E (APOE) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 (TOMM40) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known. MethodsWhole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes. ResultsOur results indicated that the APOE ε3–TOMM40′523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE ε3–TOMM40′523 long and APOE ε3–TOMM40′523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE ε4–TOMM40′523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population. DiscussionA biomarker risk assignment algorithm, using a combination of APOE, TOMM40′523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan.

Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant

IntroductionThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising 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. MethodsIn this study, we examined the effects of TOMM40 using high-resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE ε4 AD-risk variant. ResultsExamining 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. DiscussionOur data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE ε4.

CHARACTERIZATION OF THE SCREENED POPULATION FOR THE TOMMORROW STUDY: A PHARMACOGENETICS-SUPPORTED CLINICAL TRIAL TO DELAY THE ONSET OF MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE

In order to address the unmet burden of Alzheimer’s disease (AD), there is a growing interest in delaying symptom onset by initiating treatment in individuals at risk for disease but without overt evidence of cognitive deficits. To identify asymptomatic individuals at risk for disease, a biomarker risk assignment algorithm (BRAA) that includes the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 (TOMM40) genotypes [polyT homopolymer, rs10524523] and age has been developed. The TOMMORROW study will simultaneously qualify the BRAA for assigning risk of developing mild cognitive impairment (MCI) due to AD and evaluate the efficacy of low-dose pioglitazone (0.8 mg SR) for delaying the onset of MCI due to AD in individuals identified by the BRAA to be high-risk. A global, phase 3, double-blind, placebo-controlled trial was initiated in 2013 and has now been fully enrolled. The time-to-onset study operationalizes the core clinical diagnostic criteria (Albert et al. 2011) for MCI due to AD as the primary endpoint event. The study will be completed when 202 events in the high risk subjects have been reached; the treatment period is anticipated to be approximately 5 years. The TOMMORROW study (NCT01931566 clinicaltrials.gov) completed enrollment in December 2015 with 3494 subjects randomized. Screening was carried out on >24,000 individuals between ages 65–83 years (inclusive) at 59 study sites in five countries. At screening, <3% of the subjects self-identified as cognitively normal primarily failed due to not meeting the cognitive threshold for inclusion (age- and education-adjusted MMSE ≥25). The regional composition was 67% US, 20% UK, 11% AU, and 2% Germany and Switzerland. The gender split was approximately 56% female and 44% male. Genetic data for APOE and TOMM40’523were generated on >22,000 subjects. The demographic description, genetic characteristics (including APOE distribution of genotype status), and screening characteristics for this screening cohort of elderly, cognitively normal subjects will be presented. The experience of recruiting this study cohort provides valuable insights into the characteristics of healthy adults interested in clinical trials to delay symptomatic AD. The results may facilitate recruitment efforts for subsequent studies along the AD continuum.

The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age

Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 60–87 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 × 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r2 = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE ε4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R2 = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R2 = 0.08) “risk” alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE ε4 carriers with additional TOMM40 “risk” alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60.