Lim YY, Maruff P, Barthélemy NR, Goate A, Hassenstab J, Sato C, Fagan AM, Benzinger TL, Xiong C, Cruchaga C, Levin J, Farlow MR, Graff-Radford NR, Laske C, Masters CL, Salloway S, Schofield PR, Morris JC, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network. Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease. JAMA Neurol. 2022 Mar 1;79(3):261-270. PubMed.

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  1. This study is very interesting in showing that the BDNF Val66Met polymorphism is associated with increasingly abnormal tau levels and cognitive decline, as well as with lower hippocampal volume, in the transition from presymptomatic to symptomatic dominantly inherited AD (DIAD). While the variability in the data and sample size are limiting, as is the study of subjects with DIAD, a subset of AD, the data are consistent with the general view that BDNF is important in the prevention of AD and that interfering with BDNF will promote AD.

    The authors conclude that neurotrophin support is important to potentially prevent the effects of the Val/Met polymorphism, but I think this may not be the best therapeutic approach because supporting all neurotrophins, or even just increasing BDNF, may have negative consequences in AD. The reason being that some of the aspects of BDNF synthesis and action will not necessarily correct what the Val/Met polymorphism impairs.

    One additional negative consequence of increased BDNF synthesis is the production of proBDNF, which can cause cell death. In the setting of a neurodegenerative state, glia are quite different than they are in control conditions, and can interact with neurotrophins and their receptors to negative effect.

    View all comments by Helen Scharfman

  2. This Lim/DIAN report describes their cross-sectional cohort study of mutation carriers who also carry the BDNF Val66Met allele. This allele has been associated with decreased episodic memory, reduced hippocampal volume, and higher CSF p-tau217/tau217, p-tau181/tau181, and total tau. The findings are interpreted to suggest that changes in BDNF function resulting from the Val66Met polymorphisms influence amyloid effects on tau and enhance the ability of amyloid to promote neural degeneration. Given these apparent effects, it is of interest to consider the potential mechanisms triggered by this allele and the ways in which these mechanisms might point to therapeutic strategies.

    The mature form of the BDNF protein is derived from the pro-form of BDNF, and the Val66Met site lies within the prodomain, which is cleaved from the mature domain and may have independent functions. Mature BDNF binds to the p75 neurotrophin receptor (p75NTR) and TrkB co-receptor to promote neuronal survival, dendritic spine density and maturation, and synaptic plasticity (Brown et al., 2020). In contrast, in many systems, pro-BDNF binds to p75NTR and the sortilin co-receptor to promote degenerative patterns of signaling, including alteration of RhoA/Rac/cofilin mechanisms, which promote loss of dendritic spines as well as excess tau phosphorylation (Aguilar et al., 2017). 

    In preclinical models, the Val66Met polymorphism has been associated with reduced secretion of mature BDNF (Egan et al., 2003) and compromised synaptic plasticity (Ninan et al., 2010). In addition to this loss-of-function model, a gain-of-function model has been suggested by the demonstration that the Val66Met prodomain interacts with the SorCS2 receptor to inhibit Rac activity and promote growth cone retraction (Anastasia et al., 2013). Moreover, in in vitro and mouse models, the BDNF Met prodomain has been found to act through SorCS2 in association with p75NTR to perturb Rac function and disrupt actin regulation and thereby promote disassembly of mature mushroom spines on hippocampal neuron dendrites resulting in loss of synapses (Giza et al., 2018). 

    Future BDNF Val66Met human studies that include assessment of synapses and spines will be of great interest, but the present findings regarding changes in tau phosphorylation, hippocampal volume, and cognition begin to create a picture that is at least consistent with the prior preclinical studies and proposed mechanisms of loss and gain of function triggered by this prodomain alteration. Therapeutic strategies targeting promotion of TrkB activation to accommodate BDNF deficiency in the context of the Val66Met allele (Warnault et al., 2016), or to reduce p75NTR-mediated signaling promoting excess tau phosphorylation and dendritic spine degeneration (Yang et al., 2020; Yang et al., 2020), might serve to counteract the degenerative effects of the Val66Met allele.

    References:

    Brown DT, Vickers JC, Stuart KE, Cechova K, Ward DD. The BDNF Val66Met Polymorphism Modulates Resilience of Neurological Functioning to Brain Ageing and Dementia: A Narrative Review. Brain Sci. 2020 Mar 25;10(4) PubMed.

    Aguilar BJ, Zhu Y, Lu Q. Rho GTPases as therapeutic targets in Alzheimer's disease. Alzheimers Res Ther. 2017 Dec 15;9(1):97. PubMed.

    Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003 Jan 24;112(2):257-69. PubMed.

    Ninan I, Bath KG, Dagar K, Perez-Castro R, Plummer MR, Lee FS, Chao MV. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci. 2010 Jun 30;30(26):8866-70. PubMed.

    Anastasia A, Deinhardt K, Chao MV, Will NE, Irmady K, Lee FS, Hempstead BL, Bracken C. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun. 2013;4:2490. PubMed.

    Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, Lopez K, Bains H, Yang J, Bracken C, Liston C, Jing D, Hempstead BL, Lee FS. The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior. Neuron. 2018 Jul 11;99(1):163-178.e6. Epub 2018 Jun 14 PubMed.

    Warnault V, Darcq E, Morisot N, Phamluong K, Wilbrecht L, Massa SM, Longo FM, Ron D. The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation. Biol Psychiatry. 2016 Mar 15;79(6):463-73. Epub 2015 Jun 12 PubMed.

    Yang T, Tran KC, Zeng AY, Massa SM, Longo FM. Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies. Sci Rep. 2020 Nov 23;10(1):20322. PubMed.

    Yang T, Liu H, Tran KC, Leng A, Massa SM, Longo FM. Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice. Acta Neuropathol Commun. 2020 Sep 5;8(1):156. PubMed.

    View all comments by Stephen Massa

  3. This very interesting paper expands on the author’s previous work (Lim et al., 2018) providing support for the importance of early therapeutic boosting of brain BDNF levels in AD mutation carriers. The next question is whether physical exercise, which is currently the best known way of increasing brain BDNF levels, can increase BDNF sufficiently to slow cognitive decline specifically in presymptomatic Met66 carriers.

    The paper also implies a possible bi-directional interaction: higher phosphorylated tau levels are associated with BDNF-Met66, which reduces BDNF levels compared to BDNF-Val66; and pathological tau reduces BDNF expression (as shown by our lab). In future, examination of kinase activation by BDNF Val66 vs. Met66 and its pro-peptide may illuminate AD mechanisms.

    References:

    Lim YY, Hassenstab J, Goate A, Fagan AM, Benzinger TL, Cruchaga C, McDade E, Chhatwal J, Levin J, Farlow MR, Graff-Radford NR, Laske C, Masters CL, Salloway S, Schofield P, Morris JC, Maruff P, Bateman RJ, Dominantly Inherited Alzheimer Network. Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease. Ann Neurol. 2018 Sep;84(3):424-435. Epub 2018 Aug 25 PubMed.

    View all comments by Margaret Fahnestock

  4. The results in this paper are indeed interesting and suggest that CSF pTau-181 levels could be included in the workflow for clinical studies addressing therapeutic effects of molecules targeting the BDNF/TrkB pathway. Furthermore, the results are well in line with previously published data on the role of the BDNF-Val66Met polymorphism in sporadic or familial AD (Lim et al., 2013; Lim et al., 2016; Boots et al., 2017) on cognitive performance in older adults (Kennedy et al., 2015) and on the increased risk of dementia and increased risk of progression into AD when Val66Met is combined with positive Aβ status (van den Bosch et al., 2021). 

    One important aspect of the Val66Met polymorphism is the combined effects with ApoE4 status on increased amyloid load (Adamczuk et al., 2013; Lim et al., 2014; Stonnington et al., 2020) and reduced cognitive function (Ward et al., 2014; Cechova et al., 2020), suggesting that ApoE4/Val66Met carriers are at higher risk for developing AD and dementia.

    Pharmacological approaches to modulate pro-BDNF or BDNF signaling via p75NTR or TrkB, respectively, are promising options for the treatment of cognitive dysfunction in AD. Modulation of the receptor activity by a small molecule offers many advantages in comparison to direct delivery of growth factors or the use of agonist. These include easier route of administration, increased signaling regionally where NGF or BDNF are released but sufficient signaling is not reached, and less side effects than a pure agonist of Trk receptors.

    A positive allosteric modulator of Trk receptors was described to increase the kinase activity of Trk receptors and to improve cognition in a TrkB-dependent manner in scopolamine-induced memory impairment, and to improve long-term memory in aged animals with a natural decline in cognition (Dahlström et al., 2021). The described molecule ACD856 is a triazinetrione derivative identified in an extensive lead optimization program using a HTS hits, a known and well-tolerated veterinary anti-parasitic medicine, as starting point (Kennedy et al., 2001). 

    The use of small molecules acting as pan-Trk positive allosteric modulators is novel and has not been described before. A drug that increases signaling of the neurotrophins could be a beneficial therapy for the treatment of neurodegenerative disorders. The ongoing Phase 1 clinical trial with ACD856, or the results obtained in the Phase 2 trial with LM11A-31-BHS, will lend further support to modulators of neurotrophin receptors as being a valid mechanism for the treatment of Alzheimer’s disease.

    References:

    Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington KD, Bourgeat P, Salvado O, Darby D, Snyder PJ, Bush AI, Martins RN, Masters CL, Rowe CC, Nathan PJ, Maruff P, . BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease. Neurobiol Aging. 2013 Nov;34(11):2457-64. PubMed.

    Lim YY, Hassenstab J, Cruchaga C, Goate A, Fagan AM, Benzinger TL, Maruff P, Snyder PJ, Masters CL, Allegri R, Chhatwal J, Farlow MR, Graff-Radford NR, Laske C, Levin J, McDade E, Ringman JM, Rossor M, Salloway S, Schofield PR, Holtzman DM, Morris JC, Bateman RJ, Dominantly Inherited Alzheimer Network. BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease. Brain. 2016 Oct;139(Pt 10):2766-2777. Epub 2016 Aug 12 PubMed.

    Boots EA, Schultz SA, Clark LR, Racine AM, Darst BF, Koscik RL, Carlsson CM, Gallagher CL, Hogan KJ, Bendlin BB, Asthana S, Sager MA, Hermann BP, Christian BT, Dubal DB, Engelman CD, Johnson SC, Okonkwo OC. BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention. Neurology. 2017 May 30;88(22):2098-2106. Epub 2017 May 3 PubMed.

    Kennedy KM, Reese ED, Horn MM, Sizemore AN, Unni AK, Meerbrey ME, Kalich AG Jr, Rodrigue KM. BDNF val66met polymorphism affects aging of multiple types of memory. Brain Res. 2015 Jul 1;1612:104-17. Epub 2014 Sep 28 PubMed.

    van den Bosch KA, Verberk IM, Ebenau JL, van der Lee SJ, Jansen IE, Prins ND, Scheltens P, Teunissen CE, Van der Flier WM. BDNF-Met polymorphism and amyloid-beta in relation to cognitive decline in cognitively normal elderly: the SCIENCe project. Neurobiol Aging. 2021 Dec;108:146-154. Epub 2021 Sep 4 PubMed.

    Adamczuk K, De Weer AS, Nelissen N, Chen K, Sleegers K, Bettens K, Van Broeckhoven C, Vandenbulcke M, Thiyyagura P, Dupont P, Van Laere K, Reiman EM, Vandenberghe R. Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers. Neuroimage Clin. 2013;2:512-20. PubMed.

    Lim YY, Villemagne VL, Laws SM, Pietrzak RH, Snyder PJ, Ames D, Ellis KA, Harrington K, Rembach A, Martins RN, Rowe CC, Masters CL, Maruff P. APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer's disease. Mol Psychiatry. 2014 Oct 7; PubMed.

    Stonnington CM, Velgos SN, Chen Y, Syed S, Huentelman M, Thiyyagura P, Lee W, Richholt R, Caselli RJ, Locke DE, Lu B, Reiman EM, Su Y, Chen K. Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer's Disease and Cognitive Decline. J Alzheimers Dis. 2020;78(2):721-734. PubMed.

    Ward DD, Summers MJ, Saunders NL, Janssen P, Stuart KE, Vickers JC. APOE and BDNF Val66Met polymorphisms combine to influence episodic memory function in older adults. Behav Brain Res. 2014 Sep 1;271:309-15. Epub 2014 Jun 16 PubMed.

    Cechova K, Andel R, Angelucci F, Chmatalova Z, Markova H, Laczó J, Vyhnalek M, Matoska V, Kaplan V, Nedelska Z, Ward DD, Hort J. Impact of APOE and BDNF Val66Met Gene Polymorphisms on Cognitive Functions in Patients with Amnestic Mild Cognitive Impairment. J Alzheimers Dis. 2020;73(1):247-257. PubMed.

    Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells. 2021 Jul 23;10(8) PubMed.

    Kennedy T, Campbell J, Selzer V. Safety of ponazuril 15% oral paste in horses. Vet Ther. 2001;2(3):223-31. PubMed.

    View all comments by Pontus Forsell

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