Longitudinal modeling of cognitive aging and the TOMM40 effect

Caselli, Richard J.; Dueck, Amylou C.; Huentelman, Matthew J.; Lutz, Michael W.; Saunders, Ann M.; Reiman, Eric M.; Roses, Allen D.

doi:10.1016/j.jalz.2011.11.006

Cited by 69Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMitochondrial Function and Pathology

Longitudinal modeling of cognitive aging and the TOMM40 effect

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Caselli, Richard J., Dueck, Amylou C., Huentelman, Matthew J., Lutz, Michael W., Saunders, Ann M., Reiman, Eric M., Roses, Allen D.·2012·Alzheimer's & Dementia

DOI 10.1016/j.jalz.2011.11.006PMC PMC3483561

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Abstract

BACKGROUND: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. METHODS: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. RESULTS: There were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. CONCLUSION: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.

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The TOMM40 gene, and by extension its protein product, could potentially impact LOAD.
“from a strict association perspective it does appear that the TOMM40 gene, and by extension its protein product, could potentially impact LOAD.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [144]

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“This “non-effect” of the VL allele on accelerated memory decline accords well with the recent clinical series by Cruchaga et al, who found an association between age of AD onset and the S, but not the VL, TOMM40 allele, even though we were unable to identify accelerated memory decline in association with the S allele,…”
Result
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“Correlations between age of symptomatic AD onset in a clinical series of 34 APOE e3/4 heterozygotes as well as in an autopsy series of 22 APOE e3/3 individuals have showed that those with a “long-long” TOMM40 genotype (in which L and VL variants were grouped together) had a younger age of onset than those with an SL o…”
Background
Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes
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“To compare the cognitive change between TOMM40 S/S and VL/VL variants within the APOE e3/3 group and to compare cognitive change between APOE e4/ 4 subjects with the TOMM40 L/L variant with the TOMM40 VL/VL group, a previously described mixed model [21] was applied without modification.”
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“With FDR correction, all nominally signi ﬁ cant (uncorrected) effects attenuated to nonsigni ﬁ cance except for the main effect of TOMM40 523 S/L* versus L*/L* on left ventral cingulum FA in APOE ε 3/ ε 4 carriers (models 1, 2, and 3; FDR-adjusted p -values all ¼ 0.017).”
MethodInfluential
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“Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38were related tomitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D.”
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“The VL variants were associated with lower memory performance (Caselli et al., 2012; Hayden et al., 2012; Johnson et al., 2011), reduced gray matter volume in the posterior cingulate cortex, and greater age-related differences in gray matter volume of the right anterior medial temporal lobe (Johnson et al.”
BackgroundResult
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“To attempt to control for this, in Steps 2 and 3, the L and VL alleles were pooled into an ‘L*’ group; participants with the S/S genotype were compared with those carrying only one S allele (pooled S/L and S/VL; hereinafter S/L*), and also against participants carrying no S alleles (pooled L/L, L/VL and VL/VL; hereina…”
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“Furthermore, according to caselli et al (16) and Roses et al (17), TOMM40 also influences the performance of age-related memory, which indicates the potential of TOMM40 as a promising therapeutic target for cognitive dysfunction (18).”
African‐American TOMM40'523‐APOE haplotypes are admixture of West African and Caucasian alleles
Roses, A. D., Lutz, M. W., Saunders, A. M., Goldgaber, D., Saul, R., Sundseth, S. S., Akkari, P. A., Roses, S. M., Gottschalk, W. K., Whitfield, K. E., et al. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.06.009 · Cited by 35 · see citing works
“Our data would suggest a single structural variation located in a TOMM40 intron may affect the expression of TOMM40, APOE, and possibly other nearby genes or structural variants to influence the metabolism leading to agedependent expression of early metabolic imaging studies and expression of clinical disease [13-15].”
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“Another group, Caselli et al. , found that both TOMM40 and APOE signiﬁcantly inﬂuence age-related memory performance, but that they function independent of each other (Caselli et al. , 2012).”
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Association and interaction of TOMM40 and PVRL2 with plasma amyloid-β and Alzheimer's disease among Chinese older adults: a population-based study
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“APOE-independent effects of TOMM400523 are also reported in studies of episodic memory [15,33,34] and brain imaging changes associated with early AD expression [35].”
BackgroundMethod
Neuropathologic features of TOMM40 '523 variant on late‐life cognitive decline
Yu, L., Lutz, M. W., Farfel, J. M., Wilson, R. S., Burns, D. K., Saunders, A. M., Jager, P. L. D., Barnes, L. L., Schneider, J. A., & Bennett, D. A. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.05.002 · Cited by 29 · see citing works
“Previous studies show that the risk of clinical diagnosis of AD and age at onset differ by these ’523 genotypes, though findings are inconsistent [10,11,20,39,40].”
The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes
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“…intron 6 of the TOMM40 gene (chr19:45,403,049-45,403,083, human genome reference assembly GRCh37/hg19), was reported to be associated with cognitive decline, AD susceptibility and age at onset (Caselli et al., 2012; Hayden et al., 2012; Johnson et al., 2011; Li et al., 2013; Roses et al., 2010).”
BackgroundMethodResultInfluential
Factors Influencing Alzheimer’s Disease Risk: Whether and How They are Related to the APOE Genotype
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Hippocampal thinning linked to longer TOMM40 poly‐T variant lengths in the absence of the APOE ε4 variant
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“one S allele (pooled S/L and S/VL, hereinafter S/L*) and also compared with participants carrying no S alleles (pooled L/L, L/VL, and VL/VL, hereinafter L*/L* [9]).”
BackgroundInfluential
Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?
Lyall, D. M., Harris, S. E., Bastin, M. E., Maniega, S. M., Murray, C. L., Lutz, M. W., Saunders, A. M., Roses, A. D., Hernández, M. D. C. V., Royle, N. A., et al. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.89 · Cited by 26 · see citing works
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APOE/TOMM40 Genetic Loci, White Matter Hyperintensities, and Cerebral Microbleeds
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“However, mitochondrial function is partly maintained by the outer mitochondria membrane 40 homolog (TOMM40) productions which mediate the transmission of nuclear-encoded mitochondrial proteins from the cytoplasm to mitochondria [4].”
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Meta-analysis of the rs2075650 polymorphism and risk of Alzheimer disease
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“mitochondrial membrane pore subunit through which cytoplasmic proteins pass, which can induce oxidative stress, vascular endothelial dysfunction, hypoxia, glucose deprivation, and mitochondrial dysfunction of brain to increase the risk of AD [11].”
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Association Analysis of Polymorphisms in TOMM40, CR1, PVRL2, SORL1, PICALM, and 14q32.13 Regions in Colombian Alzheimer Disease Patients
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“Genetic risk factors for AD such as APOE e4 may also modify cognitive trajectories in healthy aging [Caselli et al., 2007, 2012; Sweet et al., 2012].”
Background
TOMM40‐APOE haplotypes are associated with cognitive decline in non‐demented Blacks
Deters, K., Mormino, E. C., Yu, L., Lutz, M. W., Bennett, D. A., & Barnes, L. L. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12295 · Cited by 18 · see citing works
APOE-TOMM40 in the Pharmacogenomics of Dementia
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“Several reports suggest that both APOE and TOMM40 influence memory performance in normal [53] and pathological conditions [54,80].”
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An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients
Lamparello, A. J., Namas, R. A., Schimunek, L., Cohen, M., El-Dehaibi, F., Yin, J., Barclay, D. A., Zamora, R., Billiar, T. R., & Yoram Vodovotz, B. (2019) · Shock · doi:10.1097/shk.0000000000001411 · Cited by 15 · see citing works
A TOMM40/APOE allele encoding APOE‐E3 predicts high likelihood of late‐onset Alzheimer’s disease in autopsy cases
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Cross-Sectional and Longitudinal Effects of CREB1 Genotypes on Individual Differences in Memory and Executive Function: Findings from the BLSA
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“Other genes, besides being implicated in AD, are suspected to be linked with age-related cognitive decline in healthy aging, e.g., APP and TOMM40 (Caselli et al., 2012; Jonsson et al., 2012; Davies et al., 2015; Payton et al., 2016) also may be regulated by CREB (Ge et al., 2004; Zhang et al., 2005; Tanis et al., 2008…”
Background
Characterization of APOE and TOMM40 allele frequencies in the Japanese population
Nishimura, A., Nonomura, H., Tanaka, S., Yoshida, M., Maruyama, Y., Aritomi, Y., Saunders, A. M., Burns, D. K., Lutz, M. W., Runyan, G., et al. (2017) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.07.003 · Cited by 13 · see citing works
Alzheimer’s disease cortical morphological phenotypes are associated with TOMM40′523-APOE haplotypes
Honea, R. A., Hunt, S. L., Lepping, R. J., Vidoni, E. D., Morris, J. K., Watts, A. S., Michaelis, E. K., Burns, J. M., & Swerdlow, R. H. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.09.001 · Cited by 13 · see citing works
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“According to [82], the most significant APOE effect on the onset of dementia may be observed in patients over the age of 60 (p = 0.”
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Willette, A. A., Webb, J. L., Lutz, M. W., Bendlin, B. B., Wennberg, A. M. V., Oh, J. M., Roses, A. D., Koscik, R. L., Hermann, B. P., Dowling, N. M., et al. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.03.009 · Cited by 12 · see citing works
“[10] noted that non-APOE 34 S/S versus VL/VL subjects showed less RAVLT decline in middle-age, but a flat slope after age 60 years, indicating that initial differences in cognitive performance abated over time.”
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TOMM40 ‘523 Associations with Baseline and Longitudinal Cognition in APOE ɛ 3 Homozygotes
Watts, A. S., Wilkins, H., Michaelis, E. K., & Swerdlow, R. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190293 · Cited by 11 · see citing works
APOE and aging-related cognitive change in a longitudinal cohort of men
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“It has been suggested that the APOE genetic effects on normal cognitive aging may be mediated by mechanisms that are at least partly independent of its effect on AD (Caselli et al., 2012; Deary et al., 2002).”
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Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding
Siddarth, P., Burggren, A. C., Merrill, D. A., Ercoli, L. M., Mahmood, Z., Barrio, J. R., & Small, G. W. (2018) · PLoS ONE · doi:10.1371/journal.pone.0208358 · Cited by 10 · see citing works
TOMM40 may mediate GFAP, neurofilament light Protein, pTau181, and brain morphometry in aging
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TOMM40 ‘523 Genotype Distinguishes Patterns of Cognitive Improvement for Executive Function in APOE ɛ3 Homozygotes
Watts, A. S., Haneline, S. A., Welsh-Bohmer, K. A., Wu, J., Alexander, R., Swerdlow, R. H., Burns, D. K., & Saunders, A. M. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230066 · Cited by 3 · see citing works
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“The linkage disequilibrium of the TOMM40 gene with the APOE gene indicated similar expression patterns (Caselli et al. 2012).”
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Featured Article A genetics-based biomarker risk algorithm for predicting risk of Alzheimer's disease
Lutz, M. W., Sundseth, S. S., Burns, D. K., Saunders, A. M., Hayden, K. M., Burke, J. R., Welsh-Bohmer, K. A., & Roses, A. D. (2016)
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O2‐03‐01: TOMM40, APOE and preclinical memory decline
Caselli, R. J., Dueck, A. C., Lutz, M. W., Huentelman, M. J., Saunders, A. M., Locke, D. E. C., Reiman, E. M., & Roses, A. D. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.05.850
P4‐009: EVIDENCE FOR LINKAGE BETWEEN COGNITIVE DECLINE AND APOE‐ ɛ4 AND TOMM40 POLYMORPHISMS
Michaelis, E. K., Mahnken, J. D., Wang, X., Florez, M. A., Burns, J. M., Michaelis, M. L., Swerdlow, R. H., & Michaelis, E. K. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.05.1523
P2‐075: Alzheimer's Disease Family History Modulates Effects of '523 TOMM40 on Memory Decline and Medial Temporal Pathology
Willette, A. A., Webb, J. L., Lutz, M. W., Wennberg, A. M. V., Roses, A. D., Johnson, S. C., Bendlin, B. B., & Initiative, A. D. N. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.1280
TOMM40 ‘523 Associations with Baseline and Longitudinal Cognition in APOE ɛ 3 Homozygotes
Watts, A. S., Wilkins, H., Michaelis, E. K., & Swerdlow, R. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190293 · Cited by 11 · see citing works
IC‐P‐065: AD Family History in Non‐APOE4S Modulates The Effects of '523 TOMM40 on Neuropathology and Memory Decline
Willette, A. A., Webb, J. L., Lutz, M. W., Wennberg, A. M. V., Roses, A. D., Johnson, S. C., Bendlin, B. B., & Initiative, T. A. D. N. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.095

Authors: Caselli, R. J., Dueck, A. C., Huentelman, M. J., Lutz, M. W., Saunders, A. M., Reiman, E. M., & Roses, A. D.
Affiliations: Mayo Clinic in Arizona (US)
Translational Genomics Research Institute (US)
Duke University (US)
Corresponding author: Caselli, Richard J.
ORCID: Caselli, Richard J.
Dueck, Amylou C.
Huentelman, Matthew J.
Lutz, Michael W.
Saunders, Ann M.
Reiman, Eric M.
Venue: Alzheimer's & Dementia
Publisher: Wiley
Published: 2012-11
Volume: 8
Issue: 6
Pages: 490-495
ISSN: 1552-5260 (ISSN-L)
1552-5279
DOI: 10.1016/j.jalz.2011.11.006
PMC: PMC3483561
OpenAlex: W2011563517
Cited by: 69
References: 26
Citations by year: 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 13 · 2016: 6 · 2015: 4 · 2014: 10 · 2013: 8 · 2012: 1
FWCI: 5.17
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Alzheimer s & Dementia (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Duke University (P30AG19610, R01AG6031581)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords: TOMM40, apolipoprotein E
MeSH terms: Mitochondrial Precursor Protein Import Complex Proteins, Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Middle Aged, Neuropsychological Tests, Genetic Predisposition to Disease, Membrane Transport Proteins, Young Adult

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Longitudinal modeling of cognitive aging and the TOMM40 effect

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