Diabetes is one of the leading causes of death in the U.S.1 The future projection of the diabetes epidemic in our growing, aging, and increasingly overweight population is even more alarming2. While mortality has been slowly improving in high income countries,3 the disease remains associated with significant morbidity and increased mortality.4 Underwriting diabetes might seem like a simple task, but this perception arises from our traditionally simplistic approach. Diabetes is a complex disease with a shifting landscape of complications.
Advances in treatment of diabetes have reduced adverse outcomes from some vascular, “traditional” complications including cardiovascular disease, but evidence shows an increased burden of a different set of “non-traditional” complications5, including cancer, infections, liver disease, heart failure or Dementia. Non-traditional complications further increase the complexity of diabetes and present underwriting challenges.
This article investigates the potential links between Dementia and Type 2 Diabetes and explores the possible insurance implications of recent advancements in Alzheimer’s research. Type 2 Diabetes and Alzheimer’s disease, the most common form of Dementia, are the most pressing epidemics of our time. Whether these two conditions are coincidental or parallel phenomena arising from similar overlapping risk factors or are synergistic diseases somehow linked, is still part of a debate.6
Dementia rates have been rising, mirroring the trend seen with Type 2 Diabetes. With our aging and growing population, Dementia cases worldwide are anticipated to surge dramatically. Dementia, characterized by progressive and irreversible cognitive decline, affects various brain functions. Alzheimer’s Dementia is the most common type of Dementia. Currently Alzheimer’s Dementia is the sixth leading cause of death in the United States. (Figure 1).1 Around 6.7 million Americans aged 65 or older have Alzheimer’s Dementia, a figure that is projected to nearly double in the coming decades.7-8 Globally, the affected population is expected to reach 100 -150 million.
Leading underlying causes of death – National Vital Statistics System, United States, 2023
Figure 1: Source: CDC National Center for Health Statistics, “Mortality in the United States – Provisional Data, 2023”, https://www.cdc.gov/mmwr/volumes/73/wr/mm7331a1.htm 1
There are numerous risk factors of Alzheimer’s Dementia, including Type 2 Diabetes. Type 2 Diabetes substantially increases risk of not only cerebrovascular disease, but also late life Alzheimer’s disease. A significant portion of people with Dementia also have diabetes, suggesting overlapping risk factors with Type 2 Diabetes. Alzheimer’s Dementia and diabetes are emerging as the most pressing epidemics of our time.
Alzheimer’s disease is a progressive neurodegenerative disorder that ultimately destroys various cognitive functions and abilities secondary to brain cell loss. The neurons damaged first are those in parts of the brain responsible for memory, language and perception, judgments with more severe deterioration in later stages. Despite being discovered over a century ago, the root cause remains elusive.
The disease is marked by toxic protein deposits (beta-amyloid plaques and protein tau neurofibrillary tangles), leading to cell death and brain atrophy.8 These hallmarks drive and signal the disease but likely do not directly cause it. Research reveals important contributing roles of genetics and inflammation in Alzheimer’s disease development, both of which are discussed in this article.
Recent research (on several genes) has identified a strong genetic risk factor and a novel link between the late onset Alzheimer’s disease and the APOE ε4 isoform – a variant of the apolipoprotein E (APOE) gene, which provides the blueprint for a protein that transports blood cholesterol but also has pleiotropic effects.8
About 55% of Alzheimer’s disease patients carry at least one copy of this gene. Having one or two copies of the gene multiplies the likelihood and risk of Alzheimer’s disease, however, carrying the APOE ε4 isoform does not mean that an individual will inevitably develop Dementia. Notably, 25% of the general population carries at least one allele,8 but without necessarily developing the condition – indicating the importance of gene-environment interactions.
Alzheimer’s Dementia typically progresses over several years before noticeable symptoms present (Figure 2).8 Currently, overt symptoms prompt the investigations which result with the medical diagnosis. There is no cure for the disease, only disease-modifying therapies are available to slow progression.
The long latent phase of 15-20 years (silent stage) could offer a window for timely intervention, not only with potential future medications but with preventive and proactive lifestyle changes, with the “eat well, move more, stress less and love more” approaches.9
Silent Alzheimer’s Disease could be detected from a single drop of blood.
As a result of breakthrough research, it is not science fiction that preclinical Alzheimer’s Disease could be detected from a single drop of blood, using biomarkers – before its debilitating effects take hold.10-13 Digital biomarkers (i.e., wearable technology) or artificial intelligence in disease prediction (i.e., brain-imaging, voice recognition, etc.) could also play role in early detection or prediction of cognitive decline.14-15 The recent success of anti-amyloid immunotherapy trials in symptomatic Alzheimer’s Disease has increased the enthusiasm for testing this strategy.
The benefits of the significant advancement in timely detection of the disease are obvious. However, it can raise important and relevant concerns – including ethical, psychological, and discriminatory worries.
Stages of Alzheimer’s Disease
Figure 2. Continuum shows components, are not representative of duration. Source: Alzheimer’s Association. 2024 Alzheimer’s Disease Facts and Figures. (modified picture) https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf
Alzheimer’s Disease and Type 2 Diabetes share several pathophysiological features (Figure 3)16 most importantly, the insulin resistance (IR).6, 17
Peripheral IR is well known feature of Type 2 diabetes. Brain IR is age related, but in diabetes – especially with longer duration and with suboptimal control – fuels the development of brain IR.
Insulin resistance can be defined as the failure of cells to respond to insulin as they normally would – utilization of glucose as primary energy source. Brain cells are highly dependent on insulin and glucose. IR leads to cellular “starvation” and eventually impairment in specific brain functions.
The toxic protein clumps, characteristics of Alzheimer’s Disease, enhance the brain insulin resistance. This effect is further intensified in the presence of APOE ε4. The variant has also been reported as an independent risk factor for the development of Type 2 Diabetes Mellitus in certain populations.18
The close connection between Type 2 Diabetes and Alzheimer’s Dementia has led to Alzheimer’s Disease being referred to as ‘Type 3 Diabetes’.
The link between these two conditions has led to Alzheimer’s Disease being referred to as “Type 3 Diabetes.”17 The term, however, is not a medical diagnosis, but rather a research expression highlighting the relationship between metabolic dysfunction and brain health.
Shared Links Between Alzheimer’s Disease and Diabetes
Figure 3: Source: Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impact on Cognitive Decline https://www.mdpi.com/2072-6643/7/9/5341
Another important element that links Alzheimer’s Disease and Type 2 Diabetes is inflammation. The role of inflammation in Alzheimer’s Disease pathogenesis and the role of the blood brain barrier in the inflammation have been recently recognized. The chronic neuroinflammation accelerates the development of brain insulin resistance (IR), leading to progression of Alzheimer’s Disease. The presence of the APOE ε4 genotype escalates this inflammatory process.
In Type 2 Diabetes, high blood sugar and associated blood products can damage the blood-brain-barrier, which normally protects the brain from harmful substances. When the blood brain barrier is disrupted, toxic blood products can enter the brain triggering immune responses and chronic inflammation. This leads to increased brain insulin resistance and enhanced neurodegeneration.19
The connection between Type 2 Diabetes and Alzheimer’s Disease raises the question: can anti-diabetic medications be effective in combating Alzheimer’s Disease? There are two main groups:
Another superpower of Diabetes and Obesity drugs: suppressing inflammation.
Early research shows promising results.20-23 Clinical trials suggest these medications may protect the brain, improve cognitive function, and reduce the incidence of Dementia, extending beyond just glucose control or weight loss. Additionally, their positive effects on Dementia are linked to improved vascular protection, overall cardiovascular improvement, and reduced IR. A key underlying factor in these benefits is the reduction of inflammation.
Type 2 Diabetes and Alzheimer’s disease are leading epidemics of our time with overlapping risk factors and mechanisms. The root cause of Alzheimer’s cases is still mostly unknown, but recent discovery about the APOE ε4 gene and the inflammation offer new insights. Timely identification of the Alzheimer’s disease is paramount for effective management and prevention. Detecting Alzheimer disease in its preclinical (silent) stage is a promising screening opportunity, but it also brings controversies. The strong link between Type 2 diabetes and Alzheimer’s disease serves as the basis to investigate whether newer diabetic treatments (i.e., GLP1RA, SGLT2i) can slow Dementia progression. In this is exciting new area of research with substantiated early hopes, further studies are necessary to confirm their full potential.
A significant portion of life-insurance applicants suffer from diabetes, and this number continues to rise. The combination of decreasing mortality and increasing prevalence has increased the average years lived with diabetes. New factors, impact of Alzheimer’s Dementia on morbidity and mortality, are influencing diabetes outcomes. Novel treatments of disease modifying strategies like GLP1RA and SGLT2i therapy may mitigate some concerns, however their therapeutic potential is yet to be determined.
Impacts could be anticipated across various business domains, including underwriting, pricing, product development, claims, and underwriting manuals.
Awareness of the shifting landscape of diabetes complications can assist in refined pricing prediction and in risk assessment. It can facilitate to depict early signs or signals and identify individuals who are at an increased risk for cognitive decline (i.e., clients older than 65, with long history and sub-optimally controlled diabetes and with multiple risk factors, and/or carrying the APOE ε4 gene, and/or who are, for example, recently forgetting important dates, etc.).
Carriers could leverage the benefits of the predictive power of various biomarker testing and artificial intelligence, opening opportunities for specific new insurance products. However, in addition to clear benefits of the early detection of Alzheimer’s dementia in asymptomatic stage, this could potentially bring controversy to the table with ethical and discriminatory concerns.
As a global life reinsurer, we continuously monitor research and developments around these topics to provide insights and impacts with carriers. For more insights about the trends in diabetes and its impact on the life insurance industry, see our recent article, A New Dawn for Diabetes Management.
Contact us
Please contact us if you would like to find out more about developments in diabetes and Alzheimer’s and/or to discuss the mortality and morbidity impacts or resulting new product initiatives. We would be happy to set up a meeting with you.
Contributor
Emoke Posan, Chief Medical Officer, Life & Health North America
References