Cognitive performance and neuroimaging markers across the glycemic spectrum in multiethnic Asian older adults

BACKGROUND: Brain health across the glycemic spectrum in older adults remains poorly understood, particularly in prediabetes, a biologically heterogeneous condition. We aimed to explore cognitive performance and neuroimaging markers across the glycemic spectrum and to examine whether these associations vary according to cerebral microvascular dysfunction and diabetes onset. METHODS: We included 930 participants (mean age 65.7 years; 52% female) from a population-based study in Singapore with a 6-year follow-up. Participants underwent repeated medical assessments and a single neuropsychological testing and brain magnetic resonance imaging at follow-up. Cerebrovascular disease, brain atrophy, and biological aging were assessed. RESULTS: Higher HbA1c was associated with poorer brain health, with significant effects observed only at the diabetic stage. HbA1c and (pre)diabetes interacted with white matter hyperintensities, affecting cognition and brain atrophy. Over a mean (standard deviation) follow-up of 5.6 (2.1) years, among 310 participants with prediabetes, 103 (33.2%) reverted to normoglycemia, 151 (48.7%) remained as prediabetes, and 56 (18.1%) progressed to diabetes. Compared with participants who reverted to normoglycemia, those who progressed to diabetes showed greater cognitive impairment and more pronounced structural brain abnormalities. CONCLUSIONS: Hyperglycemia is strongly associated with poor brain health, particularly reaching the diabetic stage. Despite the absence of a direct effect of prediabetes on brain health, its impact is amplified by cerebral microvascular dysfunction and progression to diabetes. Longitudinal studies are warranted to confirm these findings.