Despite several disappointing outcomes for several H3R antagonists/inverse agonists in clinical studies addressing their effectiveness in Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SCH), numerous H3R antagonists/inverse agonists showed great potentials in modulating memory and cognition, mood, and sleep–wake cycle, thus suggesting its potential role in neurocognitive and neurodegenerative diseases such as AD, PD, SCH, narcolepsy, and major depression in preclinical rodent models. The gene discussed is HRH3; the disease is early-onset autosomal dominant Alzheimer disease.