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Proton pump inhibitors like omeprazole and histamine\u20102 receptor antagonists such as ranitidine are widely prescribed for gastrointestinal disorders, but their long\u2010term impact on brain function. Forty\u2010eight male Wistar rats were assigned to six groups receiving either control diet, B\n                    <jats:sub>12<\/jats:sub>\n                    alone, omeprazole, ranitidine, or co\u2010treatment with B\n                    <jats:sub>12<\/jats:sub>\n                    for 90 days. Behavioral and cognitive assessments revealed early deficits in the drug\u2010only\u2010treated groups (omeprazole and ranitidine). Notably, B\n                    <jats:sub>12<\/jats:sub>\n                    ameliorated omeprazole\u2010induced impairments but failed to reverse ranitidine\u2010associated deficits, suggesting divergent neurotoxic pathways. Biochemical profiling included serum B\n                    <jats:sub>12<\/jats:sub>\n                    , homocysteine, cortisol, glucose, insulin, liver enzymes, and neurotransmitter. To complement these in vivo findings, an in silico approach was employed to explore molecular interactions of omeprazole and ranitidine with proteins critical for vitamin B\n                    <jats:sub>12<\/jats:sub>\n                    transport (CBLIF and TCN2) and cholinergic neurotransmission (CHRNA7). Together, these in vivo and in silico results suggest that omeprazole\u2010induced cognitive decline may involve B\n                    <jats:sub>12<\/jats:sub>\n                    depletion and other mechanisms, whereas ranitidine likely acts via alternative pathways. This study provides novel mechanistic insights into differential cognitive risks associated with chronic acid\u2010suppressing therapy, with implications for long\u2010term management in populations vulnerable to neurodegeneration.\n                  <\/jats:p>","DOI":"10.1002\/mnfr.70382","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T04:16:35Z","timestamp":1770696995000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Signal\u2010Level Determinants of Cognitive Decline With PPIs versus H\n                    <sub>2<\/sub>\n                    RAs: Transportome (CBLIF\/TCN2) and CHRNA7 Nodes"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4335-7443","authenticated-orcid":false,"given":"Hajir A. 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