12 July 2023
Chen et al. conducted a prospective study to investigate the association between type 2 diabetes mellitus (T2DM) status and cognitive function among middle-aged and older adults . Although T2DM was not significantly associated with overall cognitive function, a significant association between glycemic status and overall cognitive function in patients with untreated T2DM. The authors concluded that screening and early treatment for T2DM were important for keeping better cognitive function in later life. I have some comments about the study.
We have to specify the mechanism in the lack of association between T2DM and cognitive function after medication. Improvement of glycemic condition by treatment but no change in cognitive status would lead to the lack of association, although some other factors may also modify the cognitive status. I understand that medications for T2DM would improve atherosclerotic changes, but brain damage with poor glycemic status might be complicated. Vascular and non-vascular cognitive impairment cannot clearly be determined in patients with T2DM, and risk assessment for cognition should be conducted comprehensively by considering other metabolic disorders and contents of medications.
Cho et al. examined the cumulative effect of long-term glycemic exposure in patients with T2DM on the development of dementia . There was an inverse relationship between the average value of HbA1 and the time to dementia onset. I understand that long years are needed to change from cognitive impairment to dementia, and reversibility in advanced stage of cognitive impairment cannot be observed. On this point, early screening of glycemic condition may be useful to prevent cognitive impairment.
With special reference to the severity of glycemic status, Moran et al. examined the effect of HbA1c status on subsequent dementia incidence in patients with T2DM . The adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) of patients with T2DM in G1 (HbA1c<6%), G2 (6-6.9%), G3 (7-7.9%), G4 (8-8.9%), G5 (9-9.9%), and G6 (10%-) for dementia were 0.92 (0.88-0.97), 0.79 (0.77-0.81), 0.93 (0.89-0.97), 1.07 (0.98-1.16), 1.31 (1.15-1.51), and 1.74 (1.62-1.86), respectively. The data presented a non-linear relationship, and G2 was the lowest risk for development of dementia. Dose-response relationship may be effective for the risk assessment, and patients with ≥9% of HbA1c presented an increased risk of dementia, which was also recognized in Kaplan-Meier analysis by Cho et al . I think that duration of T2DM medication may also be associated with subsequent risk of dementia, and severity of dementia should also be specified.
Celis-Morales et al. investigated the effect of glycemic control on subsequent dementia in patients with T2DM with special reference to dementia subtypes . By the follow-up of median 6.8 years, the aHRs (95% CIs) of patients with T2DM for vascular dementia, nonvascular dementia, and Alzheimer disease were 1.34 (1.28-1.41), 1.10 (1.07-1.13), and 0.94 (0.90-0.99), respectively. In addition, there was a dose-response relationship between HbA1c and subsequent vascular and nonvascular dementia. These data present that the risk of Alzheimer's disease decreased in patients with T2DM, which cannot be easily explained. There is a difficulty to predict the change from cognitive impairment to specific dementia subtype, and the assessment of cognitive function in patients with T2DM should be conducted with caution.
Finally, Li et al. observed a linear dose-response relationship between diabetes duration and dementia incidence . In addition, the aHR (95% CI) of patients with diabetes duration ≥ 10 years and poor glycemic control with HbA1c ≥ 8% for all-cause dementia was 2.07 (1.45-2.94). This means that both diabetes duration and glycemic control are important for the risk of dementia incidence. I speculate that dose-response analysis may be effective to understand the relationship between T2DM status and subsequent risk of cognitive function.
Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan
 Chen X, Li W, Huang Y, Yang J, Tao Y, Huang L, Shen J, Ma Y, Liu Z, Xu X, Xu X, Zong G, Yuan C (2023) Association of type 2 diabetes mellitus with cognitive function in adults: A prospective cohort study. J Alzheimers Dis 93, 1509-1520.
 Cho S, Ok Kim C, Cha BS, Kim E, Mo Nam C, Kim MG, Soo Park M (2023) The effects of long-term cumulative HbA1c exposure on the development and onset time of dementia in the patients with type 2 diabetes mellitus: hospital based retrospective study (2005-2021). Diabetes Res Clin Pract, doi: 10.1016/j.diabres.2023.110721.
 Moran C, Lacy ME, Whitmer RA, Tsai AL, Quesenberry CP, Karter AJ, Adams AS, Gilsanz P (2023) Glycemic control over multiple decades and dementia risk in people with type 2 diabetes. JAMA Neurol, 80:597-604.
 Celis-Morales CA, Franzén S, Eeg-Olofsson K, Nauclér E, Svensson AM, Gudbjornsdottir S, Eliasson B, Sattar N (2022) Type 2 diabetes, glycemic control, and their association with dementia and its major subtypes: Findings from the Swedish National Diabetes Register. Diabetes Care 45, 634-641.
 Li FR, Yang HL, Zhou R, Zheng JZ, Chen GC, Wu XX, Zou MC, Wang JY, Fu Q, Wu XB (2021) Influence of diabetes duration and glycemic control on dementia: A cohort study. J Gerontol A Biol Sci Med Sci 76, 2062-2070.