Higher glycated hemoglobin amplifies the effect of apolipoprotein E epsilon 4-related cognition and olfaction impairments in type 2 diabetes

Apolipoprotein E epsilon 4 (APOE4) is recognized as a genetic risk factor for cognitive decline and neurodegeneration in both type 2 diabetes mellitus (T2DM) and Alzheimer's disease, while glycated hemoglobin (HbA1c) reflects persistent hyperglycemia and serves as a key indicator of long-term glycemic control in T2DM. Although both factors have been individually linked to neurobehavioral deficits, it remains uncertain whether HbA1c contributes to APOE4-related cognitive and olfactory impairment in individuals with T2DM.

To investigate the role of HbA1c in APOE4-associated cognitive and olfactory dysfunction in patients with T2DM.

Of 636 T2DM patients were recruited from five medical centers in Wuhan, Hubei Province, China. APOE genotyping was evaluated by polymerase chain reaction using Gerard's method. Cognitive and olfactory functions were assessed by mini-mental state examination and Connecticut chemosensory clinical research center test, respectively. Regression analysis was employed to assess the independent and interactive effects of HbA1c on APOE4-associated cognitive and olfactory function.

APOE4 was associated with increased risks of cognitive impairment [odds ratios (OR) = 1.815, P = 0.021] and olfactory dysfunction (OR = 2.588, P < 0.001). Higher HbA1c levels were also related to worse cognitive (OR = 1.189, P < 0.001) and olfactory performance (OR = 1.149, P = 0.011). HbA1c exerted a moderating effect, yet not a mediating effect, between APOE4 and its impacts on cognition and olfaction. Specifically, a higher level of HbA1c exacerbated the damaging effect of APOE4, as shown by significant interaction effects on both cognitive impairment (OR = 2.687, P < 0.001) and olfactory dysfunction (OR = 1.440, P = 0.027).

Elevated HbA1c levels are associated with increased risks of cognitive and olfactory impairments in patients with T2DM and may exacerbate the detrimental effects of APOE4. These findings underscore the need for early preventive strategies targeting individuals with both poor glycemic control and APOE4 carriage to mitigate neurodegenerative risk.