![]() Cognitive performance was assessed once every roughly 2 years over 4 Waves, from baseline to approximately 7–10 years later for a given participant.ĭata on aged subjects (92.7% Caucasian, non-Hispanic) was obtained from the ADNI database (). There were 912 non- APOE4 (129 APOE ε2/ε2 or ε2/ε3 783 APOE ε3/ε3) participants with TOMM40 ‘523 and neuropsychological data. Participants were originally recruited from 40–65 years of age. Late middle-aged subjects (91.3% Caucasian, non-Hispanic) were recruited from the WRAP study. APOE4 subjects were not considered for this report, as their in-phase TOMM40 genotype (“Long”, or L) is different and could confound effects of S and VL genotypes in APOE ε3/ε4 subjects. AST, also called glutamic oxaloacetate transaminase, differs in CSF levels among AD patients and related dementias, and shows higher concentrations in AD frontal and parietal cortices. Cytosol AST is an enzyme that facilitates catabolism of glucogenic amino acids through the malate-aspartate shuttle by a final conversion step of aspartate to oxaloacetate, helping to maximize ATP production through glycolysis. To establish that FH and TOMM40 meaningfully interacted to affect mitochondrial processes, CSF levels of a cytosolic aspartate aminotransferase (AST) peptide were gauged. ![]() Previous WRAP and ADNI reports either focused on cross-sectional cognition with fewer subjects or age of onset but not cognitive or mitochondrial outcomes. The primary outcomes were longitudinal memory decline in both cohorts and global decline in the aged cohort. Our objective was to explore FH and TOMM40 interactions separately in non- APOE4 late middle-aged or aged subjects from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study or Alzheimer’s Disease Neuroimaging Initiative (ADNI) respectively, to see if FH or FHM modulated TOMM40 effects in middle-age and along the AD spectrum in old age. As neurons in hippocampus and other medial temporal lobe (MTL) areas have high ATP requirements, FH and TOMM40 might interact to affect mitochondrial dysfunction and contribute to memory and global cognitive decline, as well as cognitive impairment risk. To link FH and TOMM40 with AD, the mitochondrial cascade hypothesis posits that multiple factors determine baseline and age-related decline in mitochondrial function. ![]() Like TOMM40, FH can increase AD risk independent of APOE. For example, maternal FH (FHM) is related to reduced cytochrome oxidase activity, leading to electron transport chain dysfunction, lower ATP production, and neuronal damage. Both FH and TOMM40 influence mitochondrial bioenergetic processes needed for adenosine triphosphate (ATP) synthesis. AD FH is typically defined as maternal or paternal LOAD onset between ages 65 to 80. It may be important to account for other factors that can modulate mitochondrial function, such as AD family history (FH). However, other reports with large samples have found no effect or a benefit of TOMM40 VL on age of onset and memory decline. To date, several studies have also found that TOMM40 VL in non- APOE4’s or APOE ε3/ε4’s predicts memory deficits or earlier age of AD onset. ![]() Some studies find that subjects with the VL allele have worse memory and executive function scores in middle-aged and aged cohorts. Among non- APOE4’s, the phase-in haplotypes are APOE ε3-linked to either a TOMM40 ‘523 “short” (S) or “very long” (VL) poly-T length. In addition, a TOMM40 variable length deoxythymidine-homopolymer (poly-T) at rs10524523 (‘523) within intron 6 has sometimes been shown to associate with LOAD risk. Genome-wide association studies (GWAS) have implicated several TOMM40 single nucleotide polymorphisms (SNPs) in increased LOAD risk, cognitive decline, and brain atrophy, particularly SNP rs2075650 that has consistently shown such associations. TOMM40 constitutes the central channel of the outer mitochondrial membrane, through which mitochondria-specific ribosomal pre-proteins enter for post-translational modification in the inner matrix. TOMM40 shares strong linkage disequilibrium (LD) with APOE on chromosome 19. As mitochondrial dysfunction is associated with LOAD, several groups have investigated gene loci that impact mitochondrial bioenergetics, such as Translocase of Outer Mitochondrial Membrane-40kD ( TOMM40). ![]() Subjects without the ε4 allele (non- APOE4s) are considered at neutral risk but show substantial variability for developing AD, where there is tremendous interest in finding genetic risk factors for non- APOE4’s that strongly predict memory, global decline, and cognitive impairment risk. The Apolipoprotein E ( APOE) gene is the most replicated genetic risk factor for late-onset Alzheimer’s disease (LOAD). ![]()
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