Alzheimer’s disease cortical morphological phenotypes are associated with TOMM40′523-APOE haplotypes
Year: 2023
Type: article
Study design: Observational Study
Abstract: Background and Objectives: Both the APOE ε4 and TOMM40 rs10524523 (‘523’) genes have been associated with risk for Alzheimer’s disease (AD) as well as with neuroimaging biomarkers of AD. To date, no studies have investigated the relationship of TOMM40’523-APOE ε4 on the structural complexity of the brain in MCI/AD individuals. We hypothesized that the TOMM40’523 very-long allele may contribute to early AD neural phenotypes in CU individuals, and that in MCI and AD individuals, the APOE ε4-TOMM40 L haplotype would be related to more brain degeneration.Methods: We studied 242 individuals from the University of Kansas Alzheimer’s Disease Research Center cohort study who underwent clinical, neuropsychological, genetic and neuroimaging analysis. We used a comprehensive approach to quantify brain morphology and multiple cortical attributes in our sample of individuals with mild cognitive impairment (MCI) and AD (n=94), then tested whether APOE ε4 or TOMM40 poly-T genotypes were related to AD morphological biomarkers in cognitively unimpaired individuals (CU, n=148) and MCI/AD individuals. We generated indices of cortical thickness (which reflects gray matter atrophy), white matter convexity (or sulcal depth, which reflects surface area changes), fractal dimension and gyrification index, which each provide a phenotype of unique complexity into the small changes that occur with dementia and aging.Results: We identified several AD-specific phenotypes in brain morphology and found that, contrary to our hypothesis, TOMM40 poly-T short alleles are associated with early, AD-specific brain morphological changes in healthy aging. We observed decreased cortical thickness in the fusiform and decreased sulcal depth and fractal dimension in the posterior cingulate and superior parietal cortices compared to the long-linked APOE ε4 allele and TOMM40 very-long alleles. Moreover, in MCI/AD subjects, the APOE ε4 (TOMM40 L) individuals had a higher rate of gene-related significant morphological markers indicative of AD.Discussion: Our data contribute to a growing literature supporting the role of TOMM40 variant repeat length on brain structure in limbic and metabolically sensitive regions, independent of APOE. TOMM40’523 is associated with early changes in metabolically complex regions of the brain while the APOE ε is associated with brain degeneration later in the disease process.
Source: Neurobiology of Aging
Institutions: University of Kansas, University of Kansas Medical Center
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
Awards: Relationship of Energetics and Cognitive Trajectory’, Longitudial Study of Cardiorespiratory Fitness in Alzheimer's Disease, Dementia Risk and Dynamic Response to Exercise, G3118785633, G3876327265, Energy Metabolism and Brain Changes with Age and Alzheimer's Disease, G4924162002, Cardiorespiratory Fitness in Alzheimer's Disease, Acute exercise and the cerebral metabolic response in aging and Alzheimer's Disease, Aerobic Fitness in Slowing the Progression of Alzheimer's Disease, G5900277370, Dose-Response Study of Exercise in Older Adults, University of Kansas Alzheimer's Disease Core Centers, Heartland Institute for Clinical and Translational Research, Siemens Magnetom Verio MRI Scanner, Frontiers Clinical and Translational Science Institute at the University of Kansas, University of Kansas Alzheimer's Disease Research Center (KU ADRC)
OpenAlex ID: W4386608419