Genotypic Effects of the TOMM40′523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study

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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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Zou, H, S Luo, H Liu, MW Lutz, DA Bennett, BL Plassman and KA Welsh-Bohmer (2023). 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. 10.14283/jpad.2023.115 Retrieved from

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Haotian Zou

Postdoctoral Associate

Sheng Luo

Professor of Biostatistics & Bioinformatics

Michael William Lutz

Professor in Neurology

Developing and using computational biology methods to understand the genetic basis of disease with a focus on Alzheimer’s Disease.   Recent work has focused on identification and validation of clinically-relevant biomarkers for Alzheimer’s disease and Alzheimer’s disease with Lewy bodies.


Brenda Lee Plassman

Professor in Psychiatry and Behavioral Sciences

My research interests include the following areas:
1) Epidemiological studies to examine the prevalence and incidence of dementia and cognitive impairment, not dementia (CIND)
2) Studies examining risk and protective factors for dementia and CIND
3) Behavioral genetics of aging and dementia with an emphasis on twin studies
4) Long term outcomes of traumatic brain injury
5) Oral health and cognition in later life


Kathleen Anne Welsh-Bohmer

Professor in Psychiatry and Behavioral Sciences

Dr. Kathleen Welsh-Bohmer is a Professor of Psychiatry with a secondary appointment in the Department of Neurology.   

Clinically trained as a neuropsychologist, Dr. Welsh-Bohmer's research activities have been focused around developing effective prevention and treatment strategies to delay the onset of cognitive disorders occurring in later life.  From 2006 through 2018 she directed the Joseph and Kathleen Bryan Alzheimer’s Center in the Department of Neurology. She also oversaw the neuropsychology scientific operations of a ground-breaking Phase III global clinical trial to delay the onset of early clinical symptoms of Alzheimer’s disease entitled the “TOMMORROW” study (Takeda Pharmaceutical Company funded) which concluded in 2018.

Currently, she directs the Alzheimer's disease therapeutic area within the Duke Clinical Research Institute and she collaborates actively with VeraSci, a Durham based company, to develop reliable digital cognitive and functional assessment tools of early Alzheimer's disease and related dementias.  The methods her team is developing are informed by advances in neuroscience and technology and fill an information void in early pre-clinical Alzheimer's disease. Her work has implications for clinical practice and for the acceleration of global clinical trials aimed at the prevention of Alzheimer’s disease and related dementias.

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