Browsing by Subject "APOE"

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    Genotypic Effects of the TOMM40′523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study
    (Journal of Prevention of Alzheimer's Disease, 2023-01-01) Zou, H; Luo, S; Liu, H; Lutz, MW; Bennett, DA; Plassman, BL; Welsh-Bohmer, KA
    Background: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. Objectives: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. Design: A phase 3, double-blind, placebo-controlled, randomized clinical trial. Setting: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. Participants: Cognitively normal older adults aged 65 to 83. Intervention: Pioglitazone tablet. Measurements: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40′523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40′523 genotypes. Results: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40′523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40′523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. Conclusions: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.
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    Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank.
    (Alzheimer's & dementia (New York, N. Y.), 2020-01) Vitek, Michael P; Araujo, Joseph A; Fossel, Michael; Greenberg, Barry D; Howell, Gareth R; Rizzo, Stacey J Sukoff; Seyfried, Nicholas T; Tenner, Andrea J; Territo, Paul R; Windisch, Manfred; Bain, Lisa J; Ross, April; Carrillo, Maria C; Lamb, Bruce T; Edelmayer, Rebecca M
    Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic.