Increased incidence of neurodegenerative diseases in Finnish individuals with type 1 diabetes

Introduction

The life expectancy of individuals with type 1 diabetes has improved in recent years. In the Pittsburgh Epidemiology of Diabetes Complications study, the life expectancy at birth was 15 years longer among individuals with diagnosed type 1 diabetes during 1965–1980 compared with those diagnosed during 1950–1964.1 In a recent Finnish register study, the survival probability was further improved in those diagnosed with type 1 diabetes in 2000–2017, compared with 1964–1999.2

The main reason for the life expectancy improvement is the improved prevention and treatment of the chronic complications of diabetes.1 3 4 The improved life expectancy exposes, however, individuals with type 1 diabetes to aging-related diseases, and conditions, such as cognitive impairment, which may have an impact on well-being and safe self-management.5 Type 1 diabetes is linked to milder degrees of cognitive decline.5–8 The identified risk factors include poor glycemic control, elevated blood pressure,6 8 depression,9 sleeping disorders,10 and longer duration of type 1 diabetes.6 11 Chronic hyperglycemia and diabetic ketoacidosis during childhood are especially harmful to the developing brain,5 7 8 and these may be linked to reduced brain growth.12 The cognitive changes are usually mild, appearing typically as a decline of psychomotor and mental efficiency and flexibility, as well as problems with verbal episodic memory and language.5 7 8

In brain MRI studies, type 1 diabetes has been linked to signs of focal brain atrophy and cerebral small-vessel disease.13 14

Whether these early signs of cognitive impairment translate into increased risk for different neurodegenerative diseases (ND) is not clear. We know that in type 2 diabetes, the overall risk of dementia is increased 1.5–2-fold,15 16 but less is known about type 1 diabetes. There is also some evidence that type 2 diabetes is associated with increased risk of Parkinson’s disease,17 but studies in type 1 diabetes show conflicting results.18–20

The aim of this study was to examine whether the incidences of different NDs are increased in individuals with type 1 diabetes compared with the background population without diabetes. To achieve this goal, we calculated standardized incidence ratios (SIRs) between these two groups. We also evaluated the impact of diabetic kidney disease, severe retinopathy, history of cardiovascular events, and age at onset of type 1 diabetes on the incidences of NDs.

Results

Of the 4261 participants with type 1 diabetes, 2226 (52.2%) were men and the median age at onset of diabetes was 13.9 (IQR 9.2, 22.1) years. The 11 653 controls without diabetes were matched for this sex and age distribution.

At the FinnDiane baseline visit, median age was 37.4 (28.7, 46.6) years, duration of type 1 diabetes was 21.4 years (12.0, 30.9), and mean HbA1c was 8.4±1.5% (69±16.3 mmol/mol). Diabetic kidney disease was present in 1605 (37.7%) of participants, and 1438 (34.4%) had a history of severe retinopathy and 493 (9.5%) had a history of cardiovascular events. During a median follow-up of 37.5 (28.5, 45.5) years from the time of diabetes diagnosis, 845 (19.8%) individuals with type 1 diabetes died, while the number of deaths was 1062 (9.1%) in the control cohort, p<0.001 (online supplemental table 2).

Risk of NDs in people with type 1 diabetes

The SIRs for the different NDs are presented in table 1 and divided by the age of the participants at the onset of ND in figure 2. Cumulative incidences for different NDs are provided in online supplemental figure 1 and median age at NDs in online supplemental table 2.

Figure 2Figure 2Figure 2

Standardized incidence ratios (SIRs) of neurodegenerative diseases between individuals with type 1 diabetes and controls without diabetes in 10-year age groups.

Table 1

Number of events, standardized incidence ratios (SIR), and subdistribution HRs (SHR) for different neurodegenerative diseases

Competing risk of death

Also, the SHRs for the different NDs were higher in individuals with type 1 diabetes compared with individuals without diabetes, except for Parkinson’s disease and other dementias (table 1).

Impact of vascular complications

The impact of diabetic vascular complications on SIRs of NDs is presented in table 2 comparing SIRs by presence and absence of diabetic complication at the FinnDiane baseline visit. The number of events in each group is provided in online supplemental table 3. The median follow-up time was 16.8 (14.0, 18.8) years. For vascular dementia, SIRs were increased both in the presence and absence of complications compared with control population, and similarly for Alzheimer’s disease except for those without severe retinopathy. For other dementias, SIRs were increased only in the presence of any of diabetic complications, while SIR for Parkinson’s disease was increased only in those with diabetic kidney disease.

Table 2

Standardized incidence ratios (SIRs) for the different neurodegenerative diseases by the presence and absence of the different diabetic vascular complications

Diabetic kidney disease was significantly associated with higher SIR of Alzheimer’s disease, while cardiovascular disease was linked to higher SIR of both Alzheimer’s disease and other dementias. Severe retinopathy was not associated with increased SIRs of any ND (table 2).

Impact of kidney disease severity

The worsening of diabetic kidney disease severity increased the SIRs of any dementia. SIR was increased in individuals with diabetes already in those with normal AER SIR of 1.99 (1.44–2.68), and 2.28 (1.24–3.88) in moderate albuminuria, 2.92 (1.66–4.78) in severe albuminuria, and 4.93 (2.40–9.04) in those with kidney replacement therapy. The between-group comparison was significant for those with kidney replacement therapy versus normal AER (SIR ratio 4.93, p=0.002).

Impact of age at onset of type 1 diabetes

Age at onset of type 1 diabetes did not have a major impact on most of the NDs (online supplemental table 4). The incidence of Alzheimer’s disease was, however, significantly higher in those diagnosed under 15 years of age, compared with those diagnosed at 15 years or older, SIR 3.89 (2.21–6.35) vs 1.73 (1.16–2.48), p=0.001 for between-group comparison.

Discussion

In this study of 4261 individuals with type 1 diabetes, the incidences of dementias were increased compared with the background population without diabetes. Our study setting enables us to assess the standardized incidences of NDs already since diabetes onset onward, and this has not been reported previously to our knowledge. As a novel finding, our results indicate that the incidence of NDs was increased even in individuals without vascular complications, but the presence of vascular complications further modified this risk. Diabetic kidney disease increased the incidence of Alzheimer’s disease, and the presence of cardiovascular diseases increased the incidence of both Alzheimer’s disease and other dementias. Severe diabetic retinopathy was not associated with increased incidence of any NDs. Younger onset of type 1 diabetes (<15 years) increased the incidence of Alzheimer’s disease, but not other NDs.

In this study, we found the highest SIR for vascular dementia, which was 3.4. This is in line with findings from other studies showing an excess risk of especially vascular dementia in relation to type 1 diabetes.16 22 This finding is expected, since type 1 diabetes is linked to cerebrovascular disease, both to cerebral small-vessel disease,14 and to overt stroke.4 Cerebrovascular disease is also known to predispose to dementia in the general population and type 2 diabetes.23

We found increased SIR also for Alzheimer’s disease at 2.3, other dementias at 1.7, and for any dementia at 2.3 compared with controls without diabetes. These ratios are slightly higher than the risk ratios in a large British register-based study that included hospitalized individuals with type 1 diabetes and assessed the prevalence of dementia in comparison to individuals hospitalized for other causes.16 They found the overall risk ratio of Alzheimer’s disease to be slightly, but significantly increased, risk ratio at 1.1, and the risk ratio of any dementia at 1.7. The SIR in our study cannot be directly compared with risk ratios in this cross-sectional setting, but differences in reference population (general population vs hospitalized individuals) probably explain some of the observed differences. In the British study, there was, interestingly, a clear tendency toward higher relative risk ratios for any dementia in younger age groups, being, for example, fourfold in 40–60 year-olds.16

In a Danish national registry-based study, the HR for dementia was assessed for approximately 10 years of follow-up.22 Especially the younger individuals with type 1 diabetes were found to have a higher risk of developing dementia. Type 1 diabetes increased the risk of any dementia 2.8-fold in those diagnosed with dementia under 65 years of age, and 1.3-fold in those diagnosed after 65 years, compared with matched controls without diabetes.22 In the present study, we observed the highest relative risk of dementia in the 60–69 year-olds, 4.0-fold for any dementia (figure 2).

There are several possible etiological features that link diabetes with dementia. Diabetes is thought to cause dysfunction of the blood–brain barrier, structural and morphological chances in hippocampus and other parts of the brain, chronic inflammation, and/or oxidative stress.23 24 In the Diabetes Control and Complications Trial (DCCT) cohort, the apolipoprotein E and ACE genes were not associated with cognitive decline in middle-aged individuals with type 1 diabetes.25 As well, the recent genetic study with Mendelian randomization approach showed no significant association between genetically determined type 1 diabetes and Alzheimer’s disease, suggesting a lesser genetic susceptibility than in the general population, in support of our hypothesis that the metabolic risk factors, such as long-term hyperglycemia, might be more important in type 1 diabetes.20

Interestingly, Ouwens et al found elevated levels of phosphorylated tau, ß-amyloid 42, and soluble lipoprotein receptor-related protein 1 in cerebrospinal fluid of individuals with type 1 diabetes compared with controls; and in type 1 diabetes, increased tau levels were associated with the decreased integrity of the white matter of right fronto-occipital tract.26 The meaning of this finding is unclear, considering that in Alzheimer’s disease tau levels in cerebrospinal fluid are elevated, but ß-amyloid 42 levels reduced.27 In addition, frequent severe hypoglycemia and hyperglycemia are also associated with sixfold risk of dementias.28

As a novel finding, our study showed a higher incidence of Alzheimer’s disease in individuals with diabetic kidney disease and cardiovascular disease. The latter was also linked to other dementias. We also explored the impact of diabetic kidney disease severity on different NDs and found that incidence of any dementia was increased already in those without albuminuria, and further increased by kidney disease severity, but reached statistical difference in between-group comparison only between those with kidney replacement therapy compared with those with normal urinary albumin excretion.

We did not, however, find any association with severe retinopathy and increased incidence of any NDs, which is in line with a study by Rodill et al, where they assessed dementia risk in a type 1 diabetes register cohort with and without severe retinopathy.29

This finding is surprising, since the retinal vasculature is thought to mirror the vasculature of the brain, and diminishing of retinal diameter has been associated with cognitive decline.30 We have also reported that diabetic retinopathy severity is associated with cerebral small-vessel disease in individuals with type 1 diabetes.31 In the present study, the incidence of NDs was clearly increased also in individuals without severe retinopathy, also including individuals with milder forms of retinopathy. We did not assess milder forms of retinopathy, so we cannot rule out an impact of milder forms of retinopathy on the ND risk in those without severe diabetic retinopathy. For Parkinson’s disease, a large Danish register-based study showed no link between Parkinson’s disease and retinopathy,32 which is in line with our findings.

Parkinson’s disease has been linked to diabetes in several studies.17 The reason for comorbidity between Parkinson’s disease and diabetes is still unclear, but speculations include oxidative stress, mitochondrial dysfunction, inflammation, and common genetic pathways.17 There are conflicting results on the association between type 1 diabetes and Parkinson’s disease based on recent genetic and experimental studies, with indications that the genetic predisposition might play a lesser role in type 1 diabetes compared with the general population.18–20 In the present study, the standardized incidence of Parkinson’s disease was 1.6-fold in individuals with type 1 diabetes, but the SHR was not increased between the study group and controls. In addition, the presence of diabetic vascular complications did not influence the standardized incidence of Parkinson’s disease. Our partly conflicting results can be a result of the relatively low number of events, influencing statistical power.

For age at diabetes onset, we found little or no impact on the risk of NDs. Alzheimer’s disease was, however, clearly increased in those with diabetes onset before 15 years, indicating that a long disease duration inevitably has some negative impact on brain health. As a positive message, it is reassuring that our observations show that this is not apparent for all NDs.

The strengths of our study include the nationwide thoroughly characterized cohort of people with type 1 diabetes with population-based matched controls without diabetes, enabling us to assess the SIRs. For both groups, we had complete register-based data on NDs over a long follow-up time. Despite this, the relatively low number of NDs limited somewhat the statistical power in subgroup analyses. The excess mortality in people with type 1 diabetes might influence our results since NDs increase with aging. We explored the impact of death as a competing factor but found it not to influence our main results. This could be since those with excess mortality might be partly the same individuals who have a higher relative risk of NDs at a younger age.

We excluded 700 individuals with type 1 diabetes without matched controls. The excluded individuals did not have controls available due to later enrollment in the study. The excluded individuals showed better metabolic risk factor control, reflecting the treatment improvements over the years. The median follow-up for the excluded individuals was shorter, and thus there were a limited number of NDs in this group. Assessing temporal trends in incidence of NDs and the impact of improved control of metabolic risk factors on both survival and ND incidence would be of interest, and will be possible, when we have longer follow-up available.

Another limitation is that the NDs were assessed only based on register data, and thus potential misclassification is possible. This is, however, the same between those with type 1 diabetes and the controls without diabetes. In addition, Solomon et al showed that the validity of diagnosis of dementias and Alzheimer’s disease is good in Finnish registers.33 It is not either always easy to separate different dementia types based on ICD codes only, and dementia types, for example, vascular dementia and Alzheimer’s disease, often co-occur. This should, however, not influence the results for any dementia, where all different dementia diagnoses were pooled.

A strength of our study is that the diabetic vascular complications were verified at the clinical study visit, and they are, thus, not based on register data. It would have been of interest also to assess the association between diabetic neuropathy and risk of NDs, but unfortunately, we did not have sufficient data on neuropathy. Further investigation is still needed to explore the risk factors for NDs and to assess their similarities and potential dissimilarities to that of classic diabetic vascular complications.

Taken together, our results and previous findings make it apparent that type 1 diabetes is linked to increased risk of dementia, similarly to that observed in type 2 diabetes.15 22 We show that the incidences are increased even without the presence of vascular complications, but the presence of diabetic kidney disease and cardiovascular disease further increases the incidences of dementias. The positive finding is that the absolute risk of NDs is modest. Further investigations are needed to identify the risk factors and causes for NDs in type 1 diabetes, to identify possible prevention targets and subpopulations of interests. Studies are also needed to assess whether screening for NDs is beneficial in specific subpopulations in type 1 diabetes to be able to improve the brain health in individuals with diabetes.

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