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Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26\u201328 weeks age; 0.6 Gy \u00d7 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (A\u03b2) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-\u03b1, IL-6, and IL-1\u03b2), while increasing anti-inflammatory cytokines (TGF-\u03b1, TGF-\u03b2, and IL-10), and was associated with marked reductions in A\u03b2 and tau levels. Furthermore, the expression levels of A\u03b240 and A\u03b242 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.<\/jats:p>","DOI":"10.3390\/ijms27125458","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:31Z","timestamp":1781675791000},"page":"5458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0241-3138","authenticated-orcid":false,"given":"Seungwon","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3838-8739","authenticated-orcid":false,"given":"Ye Jin","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-1215","authenticated-orcid":false,"given":"Gyehyeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4593-4847","authenticated-orcid":false,"given":"Eunsu","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7453-6181","authenticated-orcid":false,"given":"Subin","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5128-1963","authenticated-orcid":false,"given":"Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6544-3732","authenticated-orcid":false,"given":"Hoon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weonkuu","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10522-020-09908-5","article-title":"Low-dose ionizing radiation as a hormetin: Experimental observations and therapeutic perspective for age-related disorders","volume":"22","author":"Vaiserman","year":"2021","journal-title":"Biogerontology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"242","DOI":"10.2967\/jnmt.115.166074","article-title":"Radiation Hormesis: Historical and Current Perspectives","volume":"43","author":"Baldwin","year":"2015","journal-title":"J. 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