Diabetes in youth and adults, both type 1 (T1D) and type 2 (T2D), is a significant risk factor for cognitive dysfunction, especially within the executive function sub-domains of attention, processing speed, and cognitive flexibility^1-6. Adults with diabetes-related complications, such as nephropathy, retinopathy, and cardiovascular disease, as well as those with poor glycemic control, are more likely to present with cognitive deficits^7-9. However, as prior studies have almost exclusively focused on single diabetes complications and their relationship to cognitive outcomes, it remains unknown whether multiple complications and underlying clinical factors co-occur with lower cognitive functioning in discernable patterns.

The influence of diabetes complications, alone or in combination, on cognitive functioning in young individuals with youth-onset diabetes is understudied. Youth and young adults with youth-onset diabetes, T1D or T2D, may be at particularly high risk of poor cognitive outcomes since, in these individuals, diabetes complications occur at a younger age when the brain and cognitive skills are rapidly developing. Whereas severe hypoglycemia^10-12 and diabetic ketoacidosis^13-15 have been consistently shown to independently impact cognitive functioning in youth with diabetes, no studies to date have investigated the association between microvascular complications such as retinopathy, nephropathy, and neuropathy, or macrovascular complications such as major cardiovascular disease, and cognition in youth-onset T1D or T2D. This dearth of data is perhaps owing to the lack of large youth-onset diabetes cohorts where diabetes complications are systematically assessed. Further, it remains unclear whether the co-occurrence of diabetes complications and their influence on poor cognitive outcomes differs by youth-onset diabetes type, T1D versus T2D.

Investigating the co-occurrence, or clustering, of multiple complications and clinical factors with cognitive outcomes among both T1D and T2D could provide insight into potential shared mechanisms of diabetes complications and cognitive function and may also highlight possible avenues for intervention and treatment of early cognitive dysfunction. Thus, the primary purpose of the present analysis was to examine clustering of diabetes complications, their underlying diabetes clinical factors, and performance on cognitive tests among youth and young adults with youth-onset T1D or T2D who participated in the SEARCH for Diabetes in Youth Study.

Among the participants included in the analytic sample, those with T1D (n = 646) had an average diabetes duration of 11 (3.3) years, were on average 22 (4.2) years old at the second follow-up visit, and predominantly identified as being NHW (63%). Participants with youth-onset T2D (n = 165) had an average diabetes duration of 10 (3.6) years, were on average 25 (4.4) years old at the second follow-up visit, and half identified as NHB (50%) (Table 1).

In each of the T1D and T2D groups, a three-cluster solution was identified. In youth and young adults with T1D, individuals in cluster (C) 3 (n = 196) presented with composite fluid cognition scores that were, on average, 11 points below the population mean (Table 2a; 89.1 [15.3] vs. 100 [15]). Although their scores remained within the normative range, individuals in C3 also scored lower, on average, on tests of processing speed, working and episodic memory, and cognitive flexibility. However, individuals with T1D across all clusters scored, on average, at least 9 points below the population mean on tests of inhibition and attention (81.1 in C3; 82.2 in C2; 90.8 in C1). Youth and young adults with T1D in C3 were more likely to report having had at least one episode of hypoglycemia in the previous 12 months (24.0% vs. 1.5% in C1 and 1.7% in C2). These individuals also had the highest prevalence of peripheral neuropathy (15.8% vs. 0% in C1 and 1.1% in C2).

Individuals with T1D in C2 (n = 177) exhibited average composite fluid cognition scores similar to those in C3 but were more likely to present with an overall worse diabetes complications and clinical profile. For example, compared to C1 and C3, the C2 group had a higher proportion of individuals who reported having at least one episode of DKA in the previous 12 months (20.9% vs. 9.9% in C1 and 16.3% in C3), and higher prevalence of microalbuminuria (15.8% vs. 0.4% in C1 and 0% in C3) (p<0.001 for each, respectively). Additionally, individuals in C2 had higher HbA1c AUC and LDL-C, VLDL-C, and TGs (p<0.001 for each, respectively). C2 also had greater depressive symptomology as indicated by higher average CESD scores (11.2 vs. 8.2 in C1 and 9.9 in C3; p<0.001).

Individuals with T1D in C1 (n = 273), who presented with above average composite fluid cognition and subdomain scores (excepting inhibitory control and attention), presented with the most favorable clinical profile. This included the lowest prevalence of each complication and of episodes of DKA, and lowest average values for depression, lipids, and measured blood pressures.

Among youth and young adults with T2D, individuals in C3 (n = 38) presented with the lowest composite fluid cognition scores (Table 2b; p<0.001), which were, on average, 31 points (2 standard deviations) below the population mean (69.2 [11.0] vs. 100 [15]), suggestive of significant cognitive deficits. The C3 group also performed poorly, on average, across all cognitive subdomains, with scores below the population mean by at least one full standard deviation, excepting episodic memory. Individuals in C2 (n = 61) had an average composite fluid cognition score of one standard deviation below the normative mean (84.5 [11.2]), suggestive of mild cognitive deficits, whereas the C1 group (n = 66) scored, on average, within the normative range (96.8 [11.8]).

Individuals with T2D in C3 had the highest prevalence of peripheral neuropathy (34.2% vs. 10.6% in C1 and 13.1% in C2). The C3 group also had poor cardiovascular clinical indicators. Specifically, they presented with the highest average cDBP, cSBP, and peripheral/brachial SBP (p<0.05 for each, respectively). Further, compared to C1 and C2, depressive symptomology was greater, on average, in C3, as indicated by higher average CESD scores (16.0 vs. 9.8 in C1 and 12.4 in C2; p<0.01).

Like the T1D cluster results, above, individuals with T2D who clustered in C2 were more likely to present with an overall worse clinical profile. Individuals clustered in C2 had the poorest glycemic control with higher prevalence of self-reported episodes of DKA in the prior 12 months, and elevated lipids (LDL-C, VLDL-C, TGs), compared to the other clusters. Again, as seen in the T1D results, individuals with T2D who clustered in C1 with the highest average cognition scores also had the most favorable clinical profile.

We found both shared and unique complications and clinical factors that co-occur with sub-optimal cognitive outcomes among a large and diverse cohort of young adults with youth-onset T1D or T2D. Specifically, peripheral neuropathy was found at the highest prevalence within both the T1D and T2D cluster groups who had the lowest overall cognitive test performance, on average, compared to all other cluster groups. These results are consistent with the current but limited literature in middle age and older adults with peripheral neuropathy and T1D or T2D^27-32. In a recent cross-sectional analysis of the Glycemia Reduction Approaches in Diabetes Study (GRADE) data, Barzilay et al. (2021) found significant deficits in episodic memory (immediate recall) and processing speed among adults with peripheral neuropathy and T2D, compared to adults with T2D but without peripheral neuropathy²⁷. Among a smaller study of adults with peripheral neuropathy and T1D, Ding et al. (2019) also found global cognitive deficits and lower performance on tests of language fluency, attention, and memory, compared to a healthy control group without diabetes³¹. Together, our results and the extant data support peripheral neuropathy as a potentially significant correlate to cognitive deficits in subgroups of people with diabetes regardless of diabetes type and life stage. Unfortunately, all studies to date, including SEARCH, involve cross-sectional analyses of cognition and diabetes-related peripheral neuropathy. Thus, the sequence of events cannot be determined given the current data, and longitudinal, repeated evaluation of cognition and peripheral neuropathy development are needed to draw further insight.

Despite our limited understanding about whether peripheral neuropathy or cognitive dysfunction precedes the other, the clinical implications of their co-occurrence are potentially significant. While the literature remains sparse, studies have shown worse clinical outcomes in peripheral neuropathy, including more frequent and severe foot ulceration^29,33, among people with lower cognitive functioning and diabetes. These studies are in-line with other work demonstrating a strong relationship between cognitive abilities and self-care and treatment adherence in people with diabetes^34-36. Individuals with cognitive deficits and concurrent peripheral neuropathy may therefore be at greater risk of lower extremity complications such as foot infections, ulcers, and limb amputation secondary to limited self-care practices, compared to individuals with higher cognitive abilities. Thus, considering cognitive testing during initial evaluation and clinical follow-up for peripheral neuropathy may help to facilitate improved resource management for the highest risk patients, regardless of diabetes type.

In our analysis, diabetes type-specific clinical factors were also found to co-occur with lower cognition. Unique to the young adults with T1D, those with worse fluid cognitive performance overall and across all cognitive subdomain tests also had the highest prevalence of self-reporting at least one hypoglycemic episode in the prior 12 months. Our results again align with the extant literature, where hypoglycemia, specifically repeated severe hypoglycemic episodes, is a known correlate of poor cognition among people with T1D across all life stages^37-41. However, due to the self-report instrument used in SEARCH, we were not able to distinguish between severe (e.g., coma, seizures) and non-severe episodes of hypoglycemia experienced in the 12 months prior to cognitive testing or investigate co-occurrence of glycemic variability among the participants included in this analysis. Further, while hypoglycemia has also been linked to higher risk of cognitive decline or dementia in older adults with T2D^42,43, due to low prevalence (<5%) of self-reported hypoglycemic episodes, we were not able to assess hypoglycemia and poor cognition co-occurrence among young adults with T2D in the current analysis.

Young adults with T2D in our analysis were found to have lower fluid cognitive function that co-occurred with worse clinical cardiovascular disease factors such as elevated brachial/peripheral systolic blood pressure and higher central blood pressures. These results, while not previously reported in the youth-onset diabetes literature, are consistent with a large meta-analysis of middle age and older adults (diabetes status unknown) where elevated blood pressure and diagnosed hypertension were associated with cognitive disorders like cognitive impairment or dementia⁴⁴. Some studies in older adults with T2D also report significant associations between high blood pressure and cognitive dysfunction^45,46, although the data are mixed depending on the age at which high blood pressure developed⁴⁷. Additional studies in adults with T2D have found a significant relationship between lower cognition and elevated central blood pressure measures⁴⁸, which are considered robust prognostic indicators of cardiovascular disease. Despite limited information on brain structure and function in people with youth-onset T2D, the effect of hypertension on cognitive function is likely mediated through its impact on the cerebrovascular system including cerebrovascular endothelial dysfunction, inhibited cerebral blood flow (CBF), and microinfarcts in the brain, all of which have been found in adult-onset T2D with hypertension and T2D and in one youth study^49,50,51,52. Indeed, cerebrovascular dysfunction in T2D is shown to be involved in sub-optimal cognitive and psychiatric health such as worse executive functioning and depression⁵³. Given these data in adult-onset T2D, further research is needed to explore the links between blood pressure, cerebrovascular health, mental wellbeing, and cognitive functioning in young people with youth-onset T2D.

Our cluster analysis also yielded unexpected results such that, among the young adults with T2D, one cluster group (C2) appeared to have attenuated cognitive decrements, relative to the group with the poorest cognitive performance (C3), despite also appearing to have the poorest diabetes control. This unique, and possibly cognitively resilient, group of individuals with T2D demonstrated cognitive performance that was nearly a full standard deviation above the C3 group (poorest cognition). A potentially important distinction between the C2 group compared to the other clusters are the better cardiovascular and obesity outcomes. Specifically, the C2 group had the lowest blood pressure profile (peripheral and central blood pressures) and lowest waist-height ratio AUC, on average, compared to both C1 and C3. This contrasts with the C3 group of young adults with T2D who had the highest blood pressure across all peripheral and central measures, which coincided with the poorest cognitive functioning. Together, these observed differences between the C2 and C3 groups suggest that, in young people with youth-onset T2D, there may be a predominantly vascular contribution to acquiring significant cognitive deficits. This warrants further study.

So too did we see a potentially resilient group among the young adults with T1D. Despite having an average fluid cognitive score suggestive of only mild deficits, young adults with T1D in the C2 group presented with the worst overall clinical profile. This included the highest prevalence of microalbuminuria (16%) and self-report of at least one episode of DKA in the prior 12 months (21%), as well as worse cardiovascular outcomes (e.g., higher BP, cholesterols, etc.) relative to the other cluster groups. These findings suggest that factors beyond what were included in the current analysis may contribute to potential cognitive resilience among young adults with T1D (e.g., social support) and additional investigation is needed to draw further conclusions.

Amongst the significant body of literature focusing on cognition and diabetes complications, we believe that this is the first study to investigate the co-occurrence of multiple diabetes-related complications, their underlying clinical contributors, and cognitive outcomes in youth-onset diabetes. Furthermore, no study has investigated the different patterns of diabetes complications and clinical risk factors between youth-onset T1D and T2D and their co-occurrence with lower cognitive function, as done here. However, the novelty of our results may only be interpreted within the context of this study’s limitations. Namely, the SEARCH cohort study did not collect baseline cognitive data. Thus, we are not able to interpret our results within the context of changing cognitive function due to development of diabetes complications or worsening of underlying clinical factors. Further, as noted before³, the SEARCH Cohort Study did not collect information about functional outcomes, such as academic performance, that would help to corroborate the level of cognitive impairment reflected by the NIHTB-C scores. Finally, the current analysis did not consider participant medication use, such as blood-pressure lowering, lipid-lowering, or insulin-sensitizing medications. Therefore, our results may only be interpreted independent of the potential positive or negative effects of such medications on cognitive functioning in youth-onset diabetes.

In conclusion, our results provide new evidence of shared and unique overlap of diabetes complications and associated clinical factors to cognitive function in youth-onset T1D and T2D. While replication of these results by other large cohorts is encouraged, our findings should motivate a broader discussion in the field for assessing cognition and tailoring management strategies to address cognitive difficulties and improve outcomes in youth people with diabetes.