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BDNF Val66Met modifies outcomes in dominantly inherited Alzheimer’s disease

By Shreeya Nanda, medwireNews Reporter

The Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) may be “an important moderator” of clinical and tau outcomes in people with dominantly inherited Alzheimer’s disease (DIAD), say researchers.

They report in JAMA Neurology that the BDNF Met66 allele was “associated with moderate cognitive impairment and levels of site-specific tau phosphorylation” in both the presymptomatic and symptomatic stages of DIAD, as well as in patients with preclinical sporadic AD.

“This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial”, write Yen Ying Lim, from Monash University in Clayton, Victoria, Australia, and co-workers.

The study included data on 374 participants of the Dominantly Inherited Alzheimer Network who provided a cerebrospinal fluid sample and completed clinical and cognitive evaluations. Of these, 144 did not carry a DIAD mutation (ie, PSEN1, PSEN2 or APP mutations), 156 were presymptomatic mutation carriers and 74 were symptomatic mutation carriers.

Among presymptomatic DIAD mutation carriers, those with one or two copies of the BDNF Met66 allele (n=56) had significantly worse episodic memory and reduced hippocampal volume relative to BDNF Val66 homozygotes (n=100), with effect sizes of 0.62 and 0.40, respectively. But the groups were comparable with respect to global cognition.

The results were the other way around for symptomatic DIAD mutation carriers, such that the Met66 carriers (n=28) had significantly poorer global cognition than Val66 homozygotes (n=46), with an effect size of 1.17, but equivalent episodic memory and hippocampal volume.

Lim and colleagues also looked at the relationship between BDNF status and site-specific tau phosphorylation, which they explain is “associated with different clinical aspects of the AD spectrum.”

The team found that in presymptomatic mutation carriers, the Met66 carrier group had significantly higher levels of phosphorylated (p)-tau217/tau217, p-tau181/tau181 and total tau than the homozygous Val66 group (effect sizes=0.64, 0.65 and 0.43, respectively), but equivalent levels of p-tau205/tau205.

The results were similar among symptomatic mutation carriers for p-tau217/tau217 and total tau (effect sizes=0.53 and 0.78, respectively), but in this subgroup Met66 carriers had significantly higher levels of p-tau205/tau205 than Val66 homozygotes (effect size=0.97) and similar levels of p-tau181/tau181.

When the researchers assessed data from 125 cognitively normal older adults who were positive for amyloid-β (Aβ; preclinical sporadic AD cases) and enrolled in the Alzheimer’s Disease Neuroimaging Initiative, once again Met66 carriage was associated with poorer episodic memory and higher p-tau181 and total tau than Val66 homozygosity.

They therefore write: “These data reinforce earlier clinical and biomarker findings that BDNF Val66Met moderated the downstream association of Aβ with AD clinical disease progression.

“The absence of any impairment in memory or general cognition in presymptomatic DIAD mutation carriers who are Val66 homozygotes suggests these individuals have some resilience to AD, potentially through higher BDNF levels acting to minimize hyperphosphorylation of tau or its downstream consequences on neuronal and synaptic loss.”

Lim et al believe, however, that “presymptomatic DIAD mutation carriers need to be followed up over longer periods of time to determine whether rates of progression from presymptomatic to symptomatic are higher in Met66 carriers relative to Val66 homozygotes.”

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Neurol 2022; doi:10.1001/jamaneurol.2021.5181