Cerebrospinal fluid glial cell line-derived neurotrophic factor levels interact with <i>APOE</i> ε4 genotype to influence cognitive decline in older adults without dementia

Background Although both apolipoprotein E ( APOE ) ε4 and glial cell line-derived neurotrophic factor (GDNF) are implicated in the pathogenesis of Alzheimer's disease (AD), it remains unclear whether they interact to affect cognitive decline among older adults without dementia. Objective This study aimed to examine the interactive effects of APOE ε4 and GDNF on longitudinal cognitive decline. Methods A total of 543 individuals (mean age 73 [±7] years; 43% female) with cognitively unimpaired (CU) or mild cognitive impairment (MCI) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear mixed-effects models were used to examine the contributions of cerebrospinal fluid (CSF) GDNF levels and APOE ε4 status to longitudinal changes in cognitive measures, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the 13-item Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog-13), and the Rey Auditory Verbal Learning Test (RAVLT) total score. Results We found that the 3-way interaction ( APOE ε4 × GDNF × time) was significant for MMSE, CDR-SB, and ADAS-Cog-13, and of marginal significance for RAVLT total score, after adjusting for age, sex, and education. Specifically, individuals who were APOE ε4 carriers with low CSF GDNF levels showed the fastest rate of cognitive decline among the four groups (Low/ APOE4 -, High/ APOE4 -, Low/ APOE4 +, and High/ APOE4 +). Conclusions APOE ε4 appears to interact with CSF GDNF levels to affect longitudinal cognitive decline among older adults without dementia.