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We previously discovered that the age\u2010dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We observed the elevated UBE2N during the amyloid beta (A\u03b2) generation in the brains of 5\u00d7FAD, APP\/PS1 mice, and patients with AD, in comparison to healthy individuals. <jats:italic>UBE2N<\/jats:italic> overexpression exacerbated amyloid deposition in 5\u00d7FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR\/Cas9 reduced A\u03b2 generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated A\u03b2 pathology and subsequent transcript defects in 5\u00d7FAD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>We have discovered that age\u2010dependent expression of <jats:italic>UBE2N<\/jats:italic> is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Ubiquitin Conjugating Enzyme E2 N (UBE2N) level\u00a0was elevated during amyloid beta (A\u03b2) deposition in AD mouse and patients' brains.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>UBE2N exacerbated A\u03b2 generation in the AD mouse and senescent monkey.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Drug inhibition of UBE2N ameliorated A\u03b2 pathology and cognitive 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