We have synthesised evidence on diabetes, prediabetes and MetS and other cardiovascular risk factors with regards to risk of progressing from MCI to dementia. We used a thorough and inclusive search strategy with no limitations on language or date of publication. Our results are likely to represent the most up to date and comprehensive overview of this topic.

Summary of results

Diabetes, prediabetes and MetS were all associated with increased risks of progression of MCI to dementia. The pooled odds ratio for progression in people with diabetes was 1.53 (95% CI 1.20–1.97) while the pooled odds ratio in people with MetS was 2.95 (95% CI 1.23–7.05). In people with T2D, a longer duration of diabetes and the presence of retinopathy were associated with an increased risk of progression from MCI to dementia, while statins and oral hypoglycaemic agents appeared to reduce the risk. For people with MetS, the presence of multiple cardiovascular risk factors was a significant risk factor for progression from MCI to dementia. The highest rates of incident dementia were associated with raised triglycerides, abdominal obesity and hypertension, with lower rates associated with low HDL cholesterol and raised blood glucose levels. Overall, most of the studies included in this review tended towards a higher risk of progression to dementia in people with diabetes or MetS. Two studies reported results that tended towards a lower risk of progression of MCI to dementia in people with diabetes, and one of those was rated high quality [52, 57]. The higher quality study looked at rates of Alzheimer’s disease in a Chinese population [52]. Based on the results from other studies in a similar population, this study may have only detected half of all cause dementia (particularly missing cases of VaD), and therefore the risk of progression to dementia may have appeared significantly lower than other studies.

Comparison to previous literature

There was conflicting evidence in this review on the role of APOEe4 in the progression of MCI to dementia with one study reporting no evidence of links between APOEe4 and progression to dementia [53]. This study involved a community Chinese population and it was also the only study that showed a higher risk of progression to VaD than Alzheimer’s disease. Therefore, the pathways for progression of MCI to dementia might be different in different ethnic groups and the type of dementia developed may vary.

There was no clear evidence for the impact of individual cardiovascular risk factors on the rate of progression of MCI to dementia. This is similar to findings in the general population where individual risk factors such as hypertension or hypercholesterolaemia have not been shown to increase the rate of progression of MCI to dementia [4]. However, when three or more risk factors clustered together as MetS, the risks increased substantially. This may represent a cumulative effect or be due to other pathology associated with MetS that might include chronic inflammation, insulin-resistance and the endocrine influence of adipose tissue [23].

The pooled OR for progression of MCI to dementia in people with MetS tended towards being higher than people with diabetes. This might be due to more active treatment of risk factors such as hypertension and raised cholesterol in patients with diabetes. Renin–angiotensin system drugs are very commonly used in diabetes for treating hypertension and micro-albuminuria, and these medicines have been shown to be protective against cognitive impairment [30].

With regards to dyslipidaemias, previous studies have focused on hypercholesterolaemia with no evidence that raised cholesterol in later life affects dementia risk [4, 60]. However, statins have previously been shown to substantially lower the risk of dementia [61]—this effect was endorsed by another study included in this review [53] and patients with T2D are likely to be on statins because of their raised cardiovascular risk and lower target cholesterol levels. The particular dyslipidaemia associated with MetS may also point to a more significant role for raised triglycerides in the aetiology of dementia in this group.

Oral hypoglycaemic drugs (but not insulin) were also found to have beneficial effects in this review, so the combination of multiple treatments for multiple risk factors in people with T2D may explain why the risks in this group are comparatively lower than prediabetes or MetS. Pursuing a similar pro-active treatment of risk factors in prediabetes or MetS could help with a 10–25% reduction in risk factors that could prevent more than a million cases of dementia worldwide [29].

Implications for practice

The results of this review have identified a number of potential risk factors that could be targeted to reduce or slow down the progression of MCI to dementia in people with the MetS or diabetes. Optimising the treatment of cardiovascular risk factors in people with MetS may be a potentially important therapeutic opportunity. Promoting the use of statins and oral hypoglycaemic agents in patients with T2D and MCI may also be important, and needs to be weighed against the recent trend towards relaxing HbA1c targets in older people with T2D. Tight control of blood glucose levels with an HbA1c ≤ 48 mmol/mol (7%) could potentially have a meaningful impact by delaying progress to dementia that could happen within 2 years of a diagnosis of MCI.

Limitations of research

There may have been risk factors that were analysed in studies but not reported so we may have under-reported null results not described in the published articles. Most of the risk factors for progression were described in studies on patients with MetS and there was a lack of studies looking at risk factors for progression in patients with T2D. From the study reports it was also difficult to distinguish between treated and untreated risk factors. Diagnosing dementia and the types of dementia can be challenging and may have affected the accuracy of the findings. The process of measuring the conversion of MCI to dementia has limitations as the only difference between MCI and mild dementia may be the interpretation of the impact of the condition on activities of daily living and may be at risk of bias [62]. Additionally, diabetes itself could impact on a person’s function over time and contribute to frailty which makes attribution of MCI progression to risk factors even more difficult. Only 4 out of 12 studies provided details of the type of dementia diagnosed.

Suggestions for future research

There are a number of questions regarding the development of cognitive disorders in diabetes, prediabetes and MetS raised by this review. More research is needed on the role of APOEe4 in different ethnicities and whether this impacts the type of dementia that develops from MCI. Most of the studies included in this review did not distinguish between aMCI and non-aMCI, and given the significant variation in rates of progression to Alzheimer’s disease across the studies, it would be useful to know if this was reflected in the preceding MCI stage. The role of raised triglycerides in developing dementia is potentially under-researched and may be important in people with MetS. We did not find any studies that looked at the impact of identifying or treating depression in patients with MCI and diabetes, prediabetes or MetS.

Developing and evaluating multi-modal interventions to harness lifestyle and therapeutic strategies to target modifiable risk factors and reduce the progression of MCI to dementia in these high risk groups may have the potential for significant patient benefit. However, a key question for such interventions would be the optimal timing for delivery—whether treatment can be effective after the development or MCI, or whether interventions are needed in mid-life. It would also be helpful for studies to report more details about outcome measures regarding conversion of MCI to dementia. Quantifiable changes in cognition and more details about subsequent dementia diagnoses would help distinguish between progression of cognitive impairment and worsening frailty which would support better understanding of the nature of progression and provide more robust outcomes less reliant on subjective interpretation.