BDNF Val66Met moderates increases in CSF t-tau and p-tau181 in early sporadic Alzheimer’s disease: A prospective cohort study

Background: Allelic variation in the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer’s disease (i.e., Aβ+ older adults), and pre-symptomatic autosomal dominant AD (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau 181 ). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau 181 in Aβ+ older adults in early-stage sporadic AD. Methods: : Aβ+ Met66 carriers ( n =94) and Val66 homozygotes ( n =192) enrolled in the Alzheimer’s Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over 10 years, covarying for CSF Aβ 42 (except when examining changes in CSF Aβ 42 ), APOE ε4 status, sex, age, baseline diagnosis and years of education. Results: : Aβ+ Met66 carriers demonstrated significantly faster memory decline ( d =0.33; 95% CI [0.08, 0.58]) and significantly greater increases in CSF t-tau ( d =0.30; 95% CI [0.05, 0.55]) and p-tau 181 ( d =0.29; 95% CI [0.04, 0.54]) compared to Val66 homozygotes, despite showing equivalent rates of change in CSF Aβ 42 . Conclusions: : These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction and cognitive decline in the early stages of sporadic AD. Additionally, these findings highlight the need for clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.