In this study, we observed that Tert haploinsufficiency affected the expression of genes integral to AD pathogenesis and that neurons from amyloid-based AD models exhibited early epigenetic repression of neuronal TERT expression. We established that physiological increases in TERT levels resulted in a marked reduction of Aβ levels in neurons in the brains of two AD mouse models and in cultured human iPSC-derived neurons harboring genomic APP duplication. Mechanistically, TERT induces the β-catenin/TCF7 complex to upregulate key neuronal genes governing synaptic signaling and learning pathways and protecting neuron health in both mouse and human neurons. Notably, neuronal TERT expression improved dendritic spine formation and cognitive function in aging AD mouse models. Together, this work highlights somatic TERT activation as a potential disease modification strategy for AD. Cross-species transcriptomic profiles revealed that TERT activation in neurons upregulated genes promoting learning, action potential and synaptic signaling pathways as well as neuronal protection in the setting of toxic Aβ accumulation in human and mouse AD models. Our work aligns with observations that TERT protein can exert potent neuroprotective effects against oxidative damage/pathological tau in human postmortem AD brains and Aβ peptide-induced apoptosis of cultured embryonic neurons. It also provides additional mechanistic insights that TERT can reinforce the survival and functioning of neurons through the enhancement of HSP70-mediated neuroprotection, NRF2/HO1-regulated anti-oxidant defense and BDNF-induced cell survival system. Current evidence supports the involvement of repressive histone modifications in the TERT gene and associated downregulation of genes governing neuronal transcriptional homeostasis, memory formation and brain function. Inhibition of histone methyltransferases, which represses transcription in terminally differentiated cells, can induce dendritic spine formation in the hippocampus and restore learning and memory function in aged animals. Conversely, loss of histone demethylase KDM1A/LSD1 can result in widespread neuronal cell death and severe neurodegeneration. These collective insights prompt speculation that TERT serves as a key target of disease-associated epigenetic dysregulation of gene networks critical to neuronal health in the aging AD brain. Our finding of the TERT/β-catenin intersection in AD pathobiology gains significance in light of previous work showing that disruption of Wnt/β-catenin signaling has been implicated in the selective vulnerability of neurological disorders, including AD, autism and schizophrenia. Along these lines, it is intriguing that several single-nucleotide polymorphisms have been identified in the TERT locus from patients with autism spectrum disorder as well as patients with schizophrenia2; thus, our findings encourage the study of TERT biology in these diseases. With respect to AD, our findings of the physical association of TERT and the β-catenin/TCF transcription complex and TERT enhancement of β-catenin/TCF transcriptional activity in AD neurons point to important roles for TERT and Wnt signaling in the progression of AD. At the same time, while Wnt surfaced as the top TERT-modulated gene network, we acknowledge that additional neuronal pathways, such as N-methyl-d-aspartate receptor-dependent signaling cascades and calcium signaling pathway, are also influenced by TERT activation. Furthermore, our functional findings of the beneficial impact of TERT expression also rationalizes why mature neurons would sustain TERT expression in the postmitotic state. Finally, our data do not exclude the possibility that TERT plays additional roles, including cooperation with transcriptional regulatory factors and/or functions in other subcellular compartments, such as mitochondria. Emerging evidence has suggested that TERT is a potent protector from brain aging and age-associated pathologies. Telomerase plays a critical role in aging and age-related diseases and its activation has been proposed as a potential therapeutic for human aging and age-related degenerative diseases. While the role of TERT in these processes has focused primarily on its classical functions in telomere synthesis and end protection in proliferative cells, there is a growing appreciation that TERT also functions in postmitotic tissues via modulation of gene expression. Our findings provide a deeper understanding of how TERT and its transcriptional regulatory networks contribute to neuronal health in the setting of amyloid pathology and cognitive deficits in both mouse and human models of AD at the molecular level. Our genetic and mechanistic study justifies the testing of various somatic TERT therapies, such as exosome-mediated TERT mRNA, small-molecule activators of TERT gene expression and/or small molecules decreasing H3K9 methyl marks at the TERT locus as potential therapeutic options for patients with AD The paper, “Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer’s Disease Model” can be retrieved here. The DOI for this paper is 10.1038/s43587-021-00146-z.