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• W2896684016 abstract "Alzheimer's disease (AD) is characterized by the aggregation of beta-amyloid and paired helical filament tau. However, TAR DNA binding protein 43 (TDP-43) has recently been associated with progressive hippocampal atrophy, a hallmark of AD. Therefore, it is important to identify risk factors for TDP-43. The APOE ε4 allele has been strongly associated with beta-amyloid aggregation and risk of AD, but its relationship with TDP-43 is not known. We conducted a cross-sectional genetic-histological study, analyzing post-mortem brain tissue from 738 participants with an AD spectrum pathological diagnosis enrolled in the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. TDP-43 (present versus absent) was measured. We additionally assessed participants APOE genotype, beta-amyloid status (positive versus negative), neurofibrillary tangle stage (B1=Braak stages 1 and 2; B2= 2< Braak stage ≤ 4; B3=Braak stage > 4), and hippocampal sclerosis (present versus absent). We fit structural equation models (SEMs) with probit link functions to map these associations. We report p-values, and regression estimates and their associated standard errors on the probit scale. The SEM with TDP-43 being downstream from beta-amyloid and tau fit the data well (Comparative fit index=0.988, acceptable threshold>0.95; Tucker-Lewis Index=0.964, acceptable threshold>0.95). After accounting for age, beta-amyloid, tau, and hippocampal sclerosis, we found APOE ε4 is directly associated with TDP-43 (estimate (SE) 0.23 (0.12), p=0.04) (Figure 1). Among 85 year olds with any level of tau, B1-B3, and without hippocampal sclerosis, ε4 carriers are approximately 10% more likely to have TDP-43 than non-carriers. The APOE ε4 allele had a greater effect on TDP-43 among those without hippocampal sclerosis. We also found an indirect association of APOE on TDP-4 via beta-amyloid (1.32 (0.16), p<0.001). Structural equation models (SEMs) path analyses. These pathways were tested in the SEMs. The arrow linking from APOE to TDP-43 represents a direct effect, and the arrows from APOE to amyloid to tau toTDP-43 represent an indirect effect (mediation by amyloid and tau). Their sum represents the total effect of APOE on TDP-43. Our findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele directly affects TDP-43 in the brains of AD patients." @default.
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• W2896684016 date "2018-07-01" @default.
• W2896684016 modified "2023-10-16" @default.
• W2896684016 title "P4‐236: STRUCTURAL EQUATION MODELLING REVEALS A DIRECT AND INDIRECT EFFECT OF APOE ε4 ON TAR DNA BINDING PROTEIN 43" @default.
• W2896684016 doi "https://doi.org/10.1016/j.jalz.2018.07.057" @default.
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