Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian brain. Preclinical studies suggest that BDNF influences the pathophysiology of Alzheimer's disease. In humans, higher blood BDNF levels have been associated with a lower risk of dementia. However, the relationship between serum BDNF levels and the progression to mild cognitive impairment (MCI) in cognitively normal (CN) individuals remains uncertain. OBJECTIVES: To examine whether higher serum BDNF levels in CN older adults are associated with a reduced incidence of MCI over a 4-year follow-up period and to identify potential moderators of this relationship. DESIGN: Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study. Data were collected from January 1, 2014, to May 31, 2021, and analyzed from May 1, 2023, to September 30, 2023. SETTING: Community and memory clinic setting. PARTICIPANTS: A total of 274 CN older adults aged 55-90 years were included at baseline. MEASUREMENT: Progression to MCI over the 4-year follow-up period. RESULTS: Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio [HR], 0.27; 95 % confidence interval [CI], 0.11-0.69; P = 0.006). This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14; 95 % CI, 0.05-0.40; P < 0.001). Subgroup analyses further revealed that the association was significant only in women (HR, 0.12; 95 % CI, 0.03-0.48; P = 0.002), individuals aged <75 years (HR, 0.16; 95 % CI, 0.03-0.77; P = 0.022), those with less than a college degree (HR, 0.23; 95 % CI, 0.07-0.74; P = 0.013), and amyloid PET-negative (HR, 0.29; 95 % CI, 0.11-0.72; P = 0.014) individuals. CONCLUSIONS: These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.