Endogenous retroviruses (ERVs) are inherited retroviral genomic elements that integrated into the mammalian genome through germline infections and insertions during evolution. Human ERVs (HERVs) comprise approximately 8 % of the human genome and are increasingly recognized to be involved in the etiology and pathophysiology of numerous brain disorders. In this narrative review, we summarize the existing evidence linking abnormal HERV expression to neurodevelopmental and psychosis-related disorders and discuss how these retroviral elements may contribute to the heterogeneity in clinical outcomes. We also review the findings suggesting that aberrant HERV expression contribute to late-onset cognitive disorders with neurodegenerative components, such as Alzheimer's disease (AD) and other forms of dementia. The evidence implicating abnormal HERV expression in neurodevelopmental, psychotic, and cognitive disorders is manifold and stems from diverse research fields, including human post-mortem brain studies, serological investigations, gene expression analyses, and clinical trials with HERV-specific pharmacological compounds. The recent establishment and use of animal models offer a complementary experimental platform that will help establish causal relationships and identify specific disease pathways affected by abnormal HERV expression. Yet, significant gaps persist in understanding the role of HERVs in neurodevelopmental, psychotic, and cognitive disorders, particularly concerning the specificity and stability of abnormal HERV expression in these conditions. Addressing these questions appears crucial for optimizing the potential benefits of therapeutic interventions aimed at targeting abnormal HERV expression across the broad spectrum of HERV-associated disorders of the central nervous system.
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