Abstract: Lifestyle and demographics of the world’s population are causing serious health problems impacting the brain, increasing the incidence of Alzheimer’s disease (AD) and other types of dementia. Although we have gained important insights into the pathogenic mechanisms of AD, only palliative care is available to patients. AD is characterized by the abnormal deposition of protein aggregates in the brain formed by amyloid β and hyper-phosphorylated, Tau in addition to neuroinflammation. The current failure to treat neurodegenerative diseases underlies the fact that the brain is highly plastic and clinical symptoms are manifested when extensive brain damage has progressed. Thus, new concepts need to be tested to develop preventive strategies that extend healthspan. For half of a century, biomedicine has focused on disease as a means to understand health, developing approaches to target pathogenic features. But health is not simply the absence of disease. It is an active process that enables the organism to cope with intrinsic and extrinsic changes (López-Otín and Kroemer, 2021). Thus, a sensible strategy should focus on extending brain healthspan to prevent disease, by improving synaptic function and connectivity, the initial pathological targets, before neurodegeneration and irreversible brain damage have occurred. The decay in the buffering capacity of the proteostasis network has been pointed out as a primary hallmark of aging (Kaushik and Cuervo, 2015), a phenomenon that may contribute to AD pathogenesis. Strategies to improve proteostasis have been tested in multiple models of neurodegenerative diseases, observing outstanding protective effects. The current challenge is to move forward those interventions into suitable strategies that can be tested in the clinic. Because proteostasis is essential to the normal functions of many organs, it is predicted that the chronic administration of small molecules to target proteostasis may have adverse effects in the long term. Gene therapy is emerging as an alternative because specific brain regions can be targeted locally without affecting the function of other organs. We recently tested a gene therapy strategy to improve proteostasis by artificially enhancing the repair programs to improve proteostasis in the context of AD. Our results indicated outstanding effects in improving cognition and reducing amyloid-β plaques in models of AD (Duran-Aniotz et al., 2023).