Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Prim. 7, 33 (2021).

Article  PubMed  Google Scholar 

Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Frisoni, G. B. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat. Rev. Neurosci. 23, 53–66 (2022).

Article  CAS  PubMed  Google Scholar 

Selkoe, D. J. Alzheimer’s disease is a synaptic failure. Science 298, 789–791 (2002).

Article  CAS  PubMed  Google Scholar 

Mummery, C. J. et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat. Med. 29, 1437–1447 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stefanoska, K. et al. Alzheimer’s disease: ablating single master site abolishes tau hyperphosphorylation. Sci. Adv. 8, eabl8809 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res. Ther. 13, 80 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023).

Article  PubMed  Google Scholar 

Longo, F. M. & Massa, S. M. Next-generation Alzheimer’s therapeutics: leveraging deep biology. J. Prev. Alzheimers Dis. 7, 138–139 (2020).

CAS  PubMed  Google Scholar 

Lopera, F. et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat. Med. 29, 1243–1252 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shanks, H. R. C., Onuska, K. M., Massa, S. M., Schmitz, T. W. & Longo, F. M. Targeting endogenous mechanisms of brain resilience for the treatment and prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis. 10, 699–705 (2023).

CAS  PubMed  Google Scholar 

Underwood, C. K. & Coulson, E. J. The p75 neurotrophin receptor. Int. J. Biochem. Cell Biol. 40, 1664–1668 (2008).

Article  CAS  PubMed  Google Scholar 

Mufson, E. J. et al. Nerve growth factor pathobiology during the progression of Alzheimer’s disease. Front. Neurosci. 13, 533 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Conroy, J. N. & Coulson, E. J. High-affinity TrkA and p75 neurotrophin receptor complexes: a twisted affair. J. Biol. Chem. 298, 101568 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Meeker, R. B. & Williams, K. Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J. Neuroimmune Pharmacol. 9, 615–628 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Meeker, R. B. & Williams, K. S. The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen. Res. 10, 721–725 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Patnaik, A., Zagrebelsky, M., Korte, M. & Holz, A. Signaling via the p75 neurotrophin receptor facilitates amyloid-β-induced dendritic spine pathology. Sci. Rep. 10, 13322 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ibáñez, C. F. & Simi, A. p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci. 35, 431–440 (2012).

Article  PubMed  Google Scholar 

Wong, L.-W., Tann, J. Y., Ibanez, C. F. & Sajikumar, S. The p75 neurotrophin receptor is an essential mediator of impairments in hippocampal-dependent associative plasticity and memory induced by sleep deprivation. J. Neurosci. 39, 5452–5465 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wong, L.-W. et al. Age-related changes in hippocampal-dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor. Aging Cell 20, e13305 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bruno, F. et al. The nerve growth factor receptor (NGFR/p75NTR): a major player in Alzheimer’s disease. Int. J. Mol. Sci. 24, 3200 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Coulson, E. J., May, L. M., Sykes, A. M. & Hamlin, A. S. The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer’s disease. Neuroscientist 15, 317–323 (2009).

Article  CAS  PubMed  Google Scholar 

Demuth, H. et al. Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease. Front. Mol. Neurosci. 16, 1163087 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Andrade-Talavera, Y. et al. Ablation of p75NTR signaling strengthens gamma–theta rhythm interaction and counteracts Aβ-induced degradation of neuronal dynamics in mouse hippocampus in vitro. Transl. Psychiatry 11, 212 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Knowles, J. K. et al. The p75 neurotrophin receptor promotes amyloid-β(1–42)-induced neuritic dystrophy in vitro and in vivo. J. Neurosci. 29, 10627–10637 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Murphy, M. et al. Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease. Neurobiol. Aging 36, 740–752 (2015).

Article  CAS  PubMed  Google Scholar 

Sotthibundhu, A. et al. β-Amyloid1–42 induces neuronal death through the p75 neurotrophin receptor. J. Neurosci. 28, 3941–3946 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wei, X. et al. Mapping cerebral atrophic trajectory from amnestic mild cognitive impairment to Alzheimer’s disease. Cereb. Cortex 33, 1310–1327 (2023).

Article  PubMed  Google Scholar 

Cheng, H.-C. et al. Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer’s disease. J. Negat. Results BioMed. 11, 5 (2012).

Article  PubMed  PubMed Central  Google Scholar 

Cozza, A. et al. SNPs in neurotrophin system genes and Alzheimer’s disease in an Italian population. J. Alzheimers Dis. 15, 61–70 (2008).

Article  CAS  PubMed  Google Scholar 

Di Maria, E. et al. Possible influence of a non-synonymous polymorphism located in the NGF precursor on susceptibility to late-onset Alzheimer’s disease and mild cognitive impairment. J. Alzheimers Dis. 29, 699–705 (2012).

Article  PubMed  Google Scholar 

Reitz, C. et al. Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). Transl. Psychiatry 3, e256 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bruno, M. A. et al. Amyloid β-induced nerve growth factor dysmetabolism in Alzheimer disease. J. Neuropathol. Exp. Neurol. 68, 857–869 (2009).

Article  CAS  PubMed  Google Scholar 

Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M. D. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol. Cell. Neurosci. 18, 210–220 (2001).

Article  CAS  PubMed  Google Scholar 

Malerba, F. et al. proNGF measurement in cerebrospinal fluid samples of a large cohort of living patients with Alzheimer’s disease by a new automated immunoassay. Front. Aging Neurosci. 13, 741414 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Tiveron, C. et al. proNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ. 20, 1017–1030 (2013).

Article  CAS  PubMed  PubMed Central