BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

Abstract

Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether b-amyloid (Ab) burden plays a moderating role in this relationship.Methods: One thousand twenty-three adults (baseline age 54.94 6 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 6 3.22 years). A subset (n 5 140) underwent 11 C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Ab burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Ab burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. Results:

Effect ofBDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease

“…In age-matched mutation non-carriers who showed no evidence of amyloidosis, rates of cognitive decline, hippocampal volume loss, increases in CSF tau and ptau 181 , and cortical Aβ accumulation did not change with increasing age for either Met66 carriers or Val66 homozygotes (Figure 2). This is consistent with observations by us, 6–8 and others 9 that BDNF Val66Met has no effect on cognitive decline or hippocampal volume loss in β-amyloid-negative adults. The necessity of β-amyloid positivity for cognitive decline in Met66 carriers led us to propose that equivocal findings on the effect of BDNF Val66Met on cognitive decline observed in previous studies, 20 is likely due to their not accounting for the presence of β-amyloid positivity in their samples.…”

“…10 These results also accord with observations in preclinical and prodromal sporadic AD, where β-amyloid-positive Met66 carriers also showed faster cognitive decline and hippocampal volume loss when compared to β-amyloid-positive Val66 homozygotes. 6–9 …”

“…6–9 In sporadic AD, Met66 carriers show faster cognitive decline and hippocampal volume loss in both preclinical and prodromal stages. 6–10 However, the Met66 allele does not increase Aβ accumulation, and in β-amyloid-negative individuals, does not influence cognitive decline or neurodegeneration.…”

“…Converging evidence from sporadic AD and DIAD studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset. [6][7][8][9] In sporadic AD, Met66 carriers show faster cognitive decline and hippocampal volume loss in both preclinical and prodromal stages. [6][7][8][9][10] However, the Met66 allele does not increase Aβ accumulation and, in β-amyloid-negative individuals, does not influence cognitive decline or neurodegeneration.…”

BDNF Integrity in Ageing and Stress

“…Val66Met single nucleotide polymorphism, exacerbates AD symptoms and biomarkers and other neurodegenerative brain disorders. 12 Taking these aspects into consideration, with a middle-aged cohort presenting enhanced risk-for-AD, the evidence showed that the carriage of the BDNF Met allele was associated with a sharper decline of episodic memory performance and executive function expressions and this decline was aggravated by the greater weight of the beta-amyloid biomarker (ibid). Furthermore, the reduced levels of BDNF in AD have been shown patients in comparisons with healthy control volunteers.…”