BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Abstract

) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-b-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-b in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) "4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation noncarriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-b and cerebrospinal fluid amyloidb 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-b levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-b on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-b in autosomal dominant Alzheimer's disease.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

“…Determining the mechanisms that account for preferential differences in treatment response will enable future treatment strategies to exploit alternative pathways and molecular players in subsets of patients who do not respond to conventional medications. Moreover, since VGF has diverse roles in the hippocampus, including learning and memory [1,45,46], and is associated with impaired memory and Alzheimer’s Disease [11,12,66,67], it will also be important in future studies to explore the role of the VGF SNPs in neurodegenerative diseases as has been done for Val66Met BDNF polymorphism [68,69]. …”

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

“…10 These cross-sectional findings also suggested that Met66 influenced clinical expression in DIAD by increasing tau because DIAD mutation carriers who carried the Met66 allele showed CSF tau and phosphorylated tau (ptau 181 ) levels that were 25% greater than DIAD mutation carriers who were Val66 homozygotes. 10 …”

“…Standardized scores were then averaged to form a composite score for episodic memory (Logical Memory delayed recall, word list learning delayed recall) and for global cognition (Logical Memory delayed recall, word list learning delayed recall, Digit Symbol, MMSE). 10 …”

“…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. 6, 7 This led us to propose that in β-amyloid-positive non-demented older adults, Met66 reduces resilience to β-amyloid associated neurotoxicity, 11, 12 possibly through modifying CNS BDNF levels as a response to inflammatory processes that occur early in the course of AD.…”

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

“…However, due to complexity of p75NTR signaling, it is not clear if Aβ toxicity is mediated by p75NTR in the AD brain and how p75NTR contribute to the etiology of the disease [188]. Importantly, the BDNF Val66Met polymorphism has been demonstrated regulating synaptic excitation and neuronal integrity, being the only genetic factor that is able to moderate the effects of Aβ on memory decline and hippocampal atrophy, both in sporadic and autosomal dominant AD [189,190]. …”