Exploring the link between prediabetes and dementia 

A new study reported in Diabetologia shows that the association between prediabetes and dementia can be explained by the development of clinical diabetes. Preventing or delaying the progression of prediabetes to diabetes could help reduce the burden of dementia. Dr Susan Aldridge reports.

Prediabetes carries a high risk of progression to diabetes and is also independently associated with other clinical outcomes. Previous research has shown that prediabetes is a risk factor for cognitive decline and dementia, but few studies have looked at the impact of the transition from prediabetes to clinical diabetes upon the subsequent risk of dementia. It’s therefore not clear whether the intervening development of diabetes accounts for the excess risk of dementia in people with prediabetes. 

The risk of diabetes complications also depends on the age at which someone is diagnosed. Earlier onset diabetes generally means a more severe course of diabetes with a higher risk of complications compared with later onset diabetes. The age of onset is thus crucial in evaluating the risk of long-term outcomes such as dementia.

Elizabeth Selvin of Johns Hopkins University and colleagues elsewhere in the US used data from a large population-based cohort to look at the link between prediabetes and dementia. Their study examines how far the intervening development of diabetes can explain this association. They also looked at the link between dementia risk and incident diabetes according to age at diabetes onset.  

The Atherosclerosis Risk in Communities (ARIC) study is a prospective study of 15,792 participants aged 45 to 64 from four US counties within different states, recruited between 1987 and 1989. Baseline for the dementia study was the second visit, in which cognitive function and HbA1c were measured. There were 11,656 participants in the final analytical sample. Prediabetes was defined as HbA1c between 39 and 46 mmol/mol. Incident diabetes was self-reported or diabetes medication-use reported during a regular study visit or phone call. Dementia was diagnosed through hospital reports or cognitive function assessments during study visits. 

Prediabetes, diabetes – then dementia

It was found that 20% of the study group had prediabetes and during nearly 16 years of follow-up, 3143 participants developed diabetes. Those with prediabetes were, as expected, more likely to be diagnosed with diabetes than those without – 44.6% versus 22.5%. A total of 2247 participants developed dementia over a follow-up time of nearly 25 years. 

Among those with prediabetes, the cumulative incidence of dementia was 16.6% higher in those who went on to develop diabetes compared with those who did not. The cumulative incidence of dementia in those with prediabetes was 15%, and 10% among those without prediabetes by the age of 80 years and 63% and 53%, respectively, by the age of 90. Analysis showed that after adjusting for incident diabetes, the association of prediabetes and dementia was no longer significant. In other words, developing diabetes is the key transitional link between prediabetes and dementia. 

The cumulative incidence of dementia was highest among those who developed diabetes at an earlier age. The strength of the association between incident diabetes and dementia decreased with older age at diabetes onset. Those who were diagnosed with diabetes younger than 60 years of age were at the highest risk of dementia. Those diagnosed at age 80 or older did not have a significantly increased risk of dementia compared with those who did not go on to develop diabetes.

Therefore, prediabetes is associated with dementia, but this can be explained by its progression to clinical diabetes. This study shines a light on the link between prediabetes and dementia, showing that prediabetes in itself is not a risk factor in the absence of a subsequent diagnosis of diabetes.

Prevention is key

In the US, up to 96 million adults have prediabetes – 38% of the adult population. We know that structured lifestyle intervention programmes, such as the National Diabetes Prevention Program, can effectively prevent diabetes progression. However, fewer than 5% of those with prediabetes are receiving referrals to such programmes from their healthcare providers. And more than 80% of adults are unaware that they even have prediabetes. These new findings make an urgent case for pushing prediabetes higher up the public health agenda in the US and elsewhere. 

There are a few other studies in line with this new evidence. For instance, the Whitehall II study has shown that every five-year earlier onset of diabetes is significantly associated with a higher risk of dementia. And the Swedish Twin Registry study reported a greater risk of dementia among people whose age of diabetes onset was less than 65. 

Possible mechanisms by which prediabetes and diabetes lead to dementia include acute and chronic hyperglycaemia, glucose toxicity, insulin resistance and microvascular dysfunction of the central nervous system. Glucose toxicity and microvascular dysfunction are associated with increased inflammatory and oxidative stress, which lead to increased blood-brain permeability.

A combination of all these mechanisms has been proposed to explain the link between diabetes and both vascular and Alzheimer’s dementia. However, further studies are needed to clarify the underlying pathophysiology of prediabetes followed by diabetes and dementia.  

In conclusion, this new study underlines the importance of early detection of prediabetes and engagement in prevention of its progression to clinical diabetes as an approach to the prevention of dementia in later life.  

To read this study, go to: Hu J, Fang M, Pike JR, Lutsey PL, Richey Sharrett A, Wagenknecht LE, Hughes TM, Seegmiller JC, Gottesman RF, Mosley TH, Coresh J, Selvin E. et al. Prediabetes, intervening diabetes and subsequent risk of dementia: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 24 May 2023. https://doi.org/10.1007/s00125-023-05930-7

To learn more about conditions that are associated with diabetes, enrol on the EASD e-Learning course ‘Multimorbidity and diabetes’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.