Alzheimer’s disease (AD) is a neurodegenerative disease that causes severe neurocognitive deficits, including AD-related dementia (ADRD). The β-amyloid (Aβ) theory has been used to define the mechanism and considered as a causative factor of AD for more than three decades, but challenges for this hypothesis exist because all therapeutic strategies based on it to cure AD are failed. Although numerous upstream mechanisms that may cause AD are proposed, none of which is identified. Meanwhile, it is established that AD is associated with neuronal calcium dyshomeostasis (i.e., excessive Ca2+ influx/intracellular-free Ca2+, [Ca2+]in), which induces dysfunction, injury, or even death of pyramidal neurons in the brain regions that regulate neurocognition. These findings suggest a realistic likelihood to decrease excessive [Ca2+]in-induced neurotoxicity, a downstream mechanism that induces neurocognition in the AD brain, by diminishing overactivation and/or overexpression of glutamatergic NMDA receptors (NMDARs) and voltage-gated Ca2+ channels (VGCCs, including those formed by accumulated Aβ at late-stage AD) in hyperactive pyramidal neurons. Unfortunately, the medicines approved for treating AD, for example, memantine (which blocks NMDAR) and Aβ antibody (which removes a small portion of accumulated Aβ but does not prevent Aβ production), lack the ability to eradicate such neurotoxicity induced by excessive [Ca2+]in. Thus, a novel pharmacological intervention that can jointly antagonize NMDAR/VGCC overactivation/expression would be more effective for treating AD. This review discusses the dysfunction of pyramidal neurons with Ca2+ dyshomeostasis in a critical brain region that regulates neurocognition (i.e., the medial prefrontal cortex, mPFC), the effects of Aβ on live pyramidal neurons in the brain, the pros and cons of some medicines currently using to treat AD, and a potential novel hypothesis and working model. The latter one may switch the focus of the current AD study from searching the original upstream mechanism of AD, to reducing excessive [Ca2+]-induced neurotoxicity, a downstream mechanism that underlies neurocognition. Further, it may also help to develop a new therapeutic approach for treating AD, as well as certain other neurodegenerative diseases that are also complicated by excessive [Ca2+]in.