The baseline survey of the longitudinal study observed that the prevalence of the first diagnosis of prediabetes and diabetes among Chinese adults aged 45 years or older was 21.3% and 11.1%, respectively. This finding was consistent with previous studies [4, 25], suggesting that prediabetes or diabetes has been a significant public health problem among Chinese adults. In this 8-year longitudinal study, we first found that patients with the onset of diabetes can predict the cognitive decline at 8-year follow-up; nevertheless, baseline prediabetes status was not significantly associated with subsequent cognitive function decline. Similarly, previous studies have suggested that diabetes status was associated with a higher risk of cognitive decline among adults or older adults [8, 26], prediabetes was not related to poorer cognitive performance among general older adults or patients after stroke [27, 28]. Moreover, the univariable analyses also found that males, age, widowed or never married, ever smoking, poor self-comment about health, having hypertension, having dyslipidemia, and depressive symptoms scores at baseline were negatively associated with subsequent cognitive function, and these findings might be helpful to identify a profile of adults who at a higher risk of cognitive decline and provide potential confounders that may have effects on the association between diabetes status and cognitive function. Furthermore, subgroup analyses based on demographic characteristics showed that without adjusting for other variables, in females, prediabetes or diabetes was a risk factor for subsequent cognitive decline. Similarly, Chatterjee et al. reported that for vascular dementia (not for nonvascular dementia), the additional risk of diabetes is greater in women .
By extensively adjusting for age, gender, marital status, education level, ever smoking, ever drinking, self-comment about health, hypertension, dyslipidemia, and depressive symptoms at baseline, this longitudinal study observed the onset of diabetes status at baseline predicted subsequent cognitive decline. Several possible biological explanations have been proposed, including the indirect effects of diabetes on cognition through subclinical or clinical vascular disease for diabetes can cause the damage of cerebral microvascular and macrovascular contributing to cognitive decline [30, 31]. Another explanation might be related to the abnormal insulin modification in diabetes patients. In the central nervous system, insulin plays critical regulatory roles. At the same time, hyperglycemia can lead to accumulation of advanced glycation and products (i.e., the primary contributor to insulin resistance in diabetic cells), and brain insulin resistance is a key factor in the pathogenesis of Alzheimer’s disease for interacting with key proteins affected in the neurodegenerative conditions (e.g., amyloid-beta precursor protein) [32, 33]. Further adjusting for cognitive function at baseline, the significant association disappeared, indicating that the baseline cognitive function was the most vital factor associated with subsequent cognitive function. Nevertheless, further including clinical and biochemical factors (e.g., BUN, creatinine, TG, HDL-c, LDL-c, CRP, hemoglobin, and Cystatin C) as the control variables, we observed that the onset of diabetes status at baseline was associated with a 0.47-fold increase in the risk of cognitive function decline, suggesting that there might be various clinical and biochemical factors associated with cognitive function among individuals with different diabetic status.
Our further stratification analyses found that only higher triglyceride concentration was a risk factor for cognitive function among prediabetes patients. Similarly, Power et al. reported that elevated serum TGs were associated with a greater 20-year decline in cognitive function by using a cohort study of persons recruited at ages 45 to 65 years from U.S. communities ; He et al. found a significant association between high plasma TG levels and mild cognitive impairment among participants aged > 65 years . A possible explanation was that higher levels of TG might increase global cerebral amyloid-beta deposition affecting cognitive function transition, and another explanation may be that higher TG level was a risk factor for cerebrovascular disease, which may cause cognitive decline through hypoperfusion . Furthermore, the stratification analyses also revealed that among diabetes patients, CRP level was negatively associated with subsequent cognitive function. These findings were consistent with previous longitudinal studies, which suggests that CRP levels were positively related to future cognitive impairment and decline in elderly individuals with cardiovascular disease  and euthymic patients with bipolar disorder . These findings might be related to that CRP is a vital biomarker for systemic inflammation, and elevation of peripheral inflammation may activate central nervous system including brain microglia, the serotonin transporter expression, oxidative stress, and decreased neuroplasticity, all potentially contributing to structural and functional brain changes, which all with accumulation can cause cognitive performance related disease . Besides, evidence also suggested that there might be shared inflammatory pathways concerning insulin resistance and cognitive impairment . To sum up, this study suggested that the management of TG through lifestyle modification (e.g., suitable physical activity and healthy diet) or specific therapy could bring benefits to cognitive performance among prediabetes patients; another potential clinical implication is that the adjunctive anti-inflammatory treatments may improve cognitive function among diabetes patients.
The strengths of the current study included adopting the large-scale, 8-year longitudinal study design, using the onset diagnosis of prediabetes and diabetes as exposure, and the use of questionnaires and clinical and biochemical measurements to collect information.