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Reassessing Diabetes and APOE Genotype as Potential Interacting Risk Factors for Alzheimer’s disease

Original author: Ravipati K, Chen Y, Manns JR. et al. American Journal of Alzheimer’s Disease & Other Dementias® (2022) (DOI: 10.1177/15333175211070912)



Content writer – Clinical

November 2, 2022


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that affect a person's ability to function independently. Out of the approximately 50 million people worldwide with dementia, between 60% and 70% are estimated to have Alzheimer's disease. Approximately 5.8 million people in the United States aged 65 years and older live with Alzheimer's disease. The early signs of the disease include forgetting recent events or conversations. As the disease progresses, a person with Alzheimer's disease will develop severe memory impairment and lose the ability to carry out everyday tasks along with difficulty concentrating and thinking, especially about abstract concepts such as numbers. Hence, there is a need for a better early diagnosis of AD.

There are various/multiple risk factors associated with AD. Accurate assessment of risk factors is the key focus for early diagnosis of AD.  Researchers believe that genetics play a major role in the development of Alzheimer's disease. One of the best-characterized genetic risk factors for AD is the Apolipoprotein E (APOE) ε4 allele, one of three polymorphisms of the apolipoprotein E gene. Diabetes has also been proposed to be another risk factor for AD, and several recent studies have attempted to characterize the physiological relationship between diabetes and AD. However, an important unanswered question is an extent to which diabetes alone or in combination with APOE ε4 carriage predicts AD diagnosis.


The present study assessed the interaction between APOE ε4 and diabetes in the context of AD diagnosis by analyzing a large and diverse participant population. A retrospective cohort study was conducted on participants from the NIA-funded National Alzheimer’s Coordinating Center (NACC) database, which included data (n = 33456) collected (longitudinally for many participants) from 2005 to 2016 at 29 Alzheimer’s disease Centers (ADCs). A standardized clinical evaluation that included neuropsychological tests was used to diagnose participants into three categories: AD, cognitive impairment without AD, and cognitively unimpaired. Data were also collected regarding health, cognition, and demographics. Diagnosis of diabetes was based on patient self-reporting. No other confirmatory testing, including biomarkers or medication history, was available regarding diabetic status. APOE genotype was available for 24336 participants and was presented as 0, 1, or 2 APOE ε4 alleles in the NACC database. Of the 4204 who self-reported diabetes, 2803 (66.6%) had APOE genotype information.


All the data collected were tabulated and multiple statistical analysis models were used to assess the relationship between APOE genotype, diabetes, and AD diagnosis. All statistical analyses were performed using R software, version 3.4.1. Multinomial Logistic Regression Models were used to assess the participant’s first and last Alzheimer’s disease center (ADC) visit, as well as the association between the APOE 4 genotype and AD along with the association of diabetes and AD. A mixed effects model, was used to assess the risk of being diagnosed with AD at any visit. Structural Equation Modelling (SEM) was used to model how various factors mediated the influence of APOE genotype and diabetes on conversion to AD diagnosis in individuals not diagnosed with AD on their first visit.

In the present study, APOE 4 genotype showed a strong association with AD diagnosis and was significant whereas the association between diabetes and AD diagnosis was weak and non-significant.


In conclusion, the present study reported that the APOE ε4 genotype was strongly associated with AD risk and the finding that the APOE ε4 genotype correlates with impairment of long-term memory (LTM) loss provides clinicians with additional insight to make the most accurate diagnosis possible. Also, it was suggested that diabetes was not a potential risk factor for AD, and associating diabetes with working memory (WM) rather than LTM impairments will aid to distinguish AD from other types of dementia.

Impact of the research

  1. The identification of risk factors associated with AD may help in better and early diagnosis.

  2. It helps to differentiate different types of dementia to a certain extent.

  3. It also paves the way to unveil the pathophysiological link between APOE 4 genotype, diabetes, and AD pathology.

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