Abstract
AbstractBackgroundAllelic 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 dominantly inherited Alzheimer’s disease (DIAD). In DIAD, Met66 was also associated with greater increases in CSF levels of total‐tau and phosphorylated tau (p‐tau181). This study sought to determine the extent to which BDNF Val66Met is also associated with changes in episodic memory and CSF total‐tau and p‐tau181 in Aβ+ older adults in early‐stage sporadic AD.MethodAβ+ Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who did not meet criteria for AD dementia were included. Only participants with at least one follow‐up neuropsychological and CSF assessment were included. Episodic memory was measured by the ADNI Memory Composite and CSF samples were collected via lumbar puncture to determine levels of total‐tau, p‐tau181 and Aβ42. A series of linear mixed models were conducted to investigate changes in each outcome variable over 10 years, covarying for CSF Aβ42 (except when examining changes in CSF Aβ42), APOE ε4 status, sex, age, baseline diagnosis and years of education.ResultWhen followed over 10 years, Aβ+ Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF total‐tau (d = 0.30) and p‐tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent rates of change in CSF Aβ42 (Table 1; Figure 1).ConclusionIn non‐demented Aβ+ older adults, Met66 carriers showed greater memory decline and greater increases in both CSF total‐tau and CSF p‐tau181 over 10 years compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. This suggests that Met66 carriage, which is associated with lower BDNF availability and lower neurotrophic support, may confer greater vulnerability to Aβ‐related increases in tau compared to Val66 homozygosity in the early stages of sporadic AD.
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