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Recent research suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors can mitigate memory impairment linked to Alzheimer\u2019s disease and are now being explored for their cognitive benefits. However, their mechanisms were not thoroughly studied. This research investigates the hypothesis of the neuroprotective effect of empagliflozin administration against scopolamine-heavy metal mixture (SCO\u2009+\u2009HMM)-treated Alzheimer\u2019s rat models in comparison with memantine as a reference drug and the impact of their combination. Yet, the neuroprotective effects of memantine and empagliflozin combination against cognitive impairment have not been previously explored. This study employed adult male albino rats categorized into five groups. The impact of empagliflozin, memantine, and their concomitant administration on cognitive performance was assessed in a scopolamine and heavy metal mixture-treated Alzheimer\u2019s disease model in rats. The assessment of rats\u2019 cognitive behavior, memory, and spatial learning was conducted, followed by an evaluation of hippocampal brain-derived neurotrophic factor (BDNF), beta-secretase (BACE-1), oxidative stress (OS), and inflammatory marker activity. And, a western blot analysis was conducted to detect phosphorylated 5\u2019 AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of rapamycin (p-mTOR), and heme oxygenase-1 (HO-1). Hippocampal and cerebellar histopathology were thoroughly examined, in addition to the expressions of amyloid \u03b2 (A\u03b2). The current data demonstrate the involvement of the pAMPK\/mTOR\/HO-1 signaling pathway in empagliflozin neuroprotection against SCO\u2009+\u2009HMM-induced AD. In addition, it reduces AD hallmarks (A\u03b2 and BACE1), neuro-inflammation, and oxidative stress sequelae, and enhances neurogenesis and synaptic density via BDNF. This study proposes that EMPA, especially when co-administered with other conventional anti-Alzheimer therapy, may be formulated into an innovative therapeutic strategy for the enhancement of cognitive impairments associated with neurodegenerative disorders.<\/jats:p>","DOI":"10.1007\/s10787-025-01755-5","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T16:33:50Z","timestamp":1746462830000},"page":"3479-3498","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Empagliflozin and memantine combination ameliorates cognitive impairment in scopolamine + heavy metal mixture-induced Alzheimer\u2019s disease in rats: role of AMPK\/mTOR, BDNF, BACE-1, neuroinflammation, and oxidative stress"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8995-3649","authenticated-orcid":false,"given":"Ebtsam S.","family":"Abdel-lah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda S.","family":"Sherkawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafaa H.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam A.","family":"Fawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa A.","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa A.","family":"Muhammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira F.","family":"Taha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer A.","family":"Tony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nashwa","family":"Hamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa G.","family":"Gamea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"1755_CR1","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.3390\/ph16101370","volume":"16","author":"MA Abd Elmaaboud","year":"2023","unstructured":"Abd Elmaaboud MA, Estfanous RS, Atef A et al (2023) Dapagliflozin\/hesperidin combination mitigates lipopolysaccharide-induced Alzheimer\u2019s disease in rats. 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