Proton pump inhibitors (PPIs) have become virtually the sole class of histamine-2 receptor antagonists due to their greater effectiveness and general availability. However, concern has been increasing about long-term use and some possible neurological adverse effects, including a link with dementia. Several studies indicate that long-term use of PPIs can raise the risk for both Alzheimer's disease (AD) and non-Alzheimer's dementia, though there is opposing evidence. Neurological side effects of PPIs are cognitive impairment, neuropathies, depression, anxiety, and hallucinations. The mechanisms are unknown but could be due to PPIs crossing the BBB and interfering with neuronal function or causing systemic deficiencies, e.g., vitamin B12 deficiency. Vitamin B12 is essential for cognitive function, and its deficiency has been linked to dementia. PPIs also cause B12 deficiency by inhibiting gastric acid secretion, which is required for B12 absorption. B12 deficiency causes hyperhomocysteinemia, which facilitates tau hyperphosphorylation and amyloid-β (Aβ) deposition, major pathological hallmarks of AD. PPIs have also been found to disrupt amyloid precursor protein processing, mitochondrial function, and neuroinflammation, further enhancing neurodegenerative processes. Experimental evidence indicates that PPIs affect brain homeostasis through inhibition of vacuolar ATPases, modulation of microglial Aβ phagocytosis, and induction of synaptic dysfunction. While the specific molecular mechanisms are unknown, findings suggest that long-term PPI exposure could contribute to neurodegeneration, especially in elderly patients. With increasing dementia prevalence, additional clinical research is needed to ascertain whether PPIs are a causative agent or a contributing factor to cognitive impairment.