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The primary source of debate is the discrepancy between robust biological effects\u2014namely, effective \u03b2\u2010amyloid clearance\u2014and modest clinical improvements, which, although statistically significant, often fail to reach the minimal clinically important difference (MCID) compared to placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This paper highlights a confounding factor in the interpretation of the results of clinical trials: limited sensitivity of neuropsychological outcome measures. These tools, developed in the 1980s and only marginally updated, are not suited to detect subtle but meaningful cognitive changes in early disease stages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The ADAS\u2010Cog, the most commonly used cognitive endpoint, suffers from a substantial ceiling effect, impairing its ability to capture cognitive decline over short durations in prodromal populations. Likewise, functional scales such as the CDR\u2010SB are inherently insensitive in mild cognitive impairment (MCI), as functional independence is, by definition, preserved. Moreover, the use of composite multidomain scales with high baseline scores may mask domain\u2010specific improvements, further limiting a drug's capacity to reach MCID thresholds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Methodological limitations risk undervaluing the therapeutic impact of treatment, particularly in trials targeting early or preclinical phases where changes are subtle and domain\u2010specific. Urgent reconsideration of outcome measures is necessary to ensure accurate assessment of clinical efficacy and to avoid prematurely discarding potentially beneficial therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70590","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T06:18:06Z","timestamp":1775110686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Low Sensitivity of Neuropsychological Scales Hinder Detection of Potential Benefit of Treatments in Alzheimer's Disease: A Position Paper"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3802-2320","authenticated-orcid":false,"given":"Simona","family":"Luzzi","sequence":"first","affiliation":[{"name":"Unit of Cognitive and Behavioral Neurology, Neurologic Unit, Department of Experimental and Clinical Medicine, Polytechnic University of Marche Azienda Ospedaliero Universitaria Delle Marche  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie S.","family":"Snowden","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Faculty of Biology and Mental Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n156"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102161"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.17219\/acem\/172673"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000266476"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000525639"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0000000000200127"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.141.11.1356"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.158.9.1021"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.318.7184.633"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.54.12.226"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013128"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2015.62"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010016\u20100170\u20105"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/ane.12153"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010170991"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2012.05.2187"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11682\u2010012\u20109166\u20103"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/WAD.0b013e3181f883b7"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u20102008\u201015312"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/10888683241258406"},{"key":"e_1_2_15_27_1","volume-title":"Neuropsychological Assessment","author":"Lezak M. 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