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000278999 1001_ $$aChen, Charles D$$b0
000278999 245__ $$aImmunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease.
000278999 260__ $$aHeidelberg$$bSpringer$$c2025
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000278999 520__ $$aClinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)-and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle 'downstream' effects.
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000278999 650_7 $$2Other$$aAlzheimer disease
000278999 650_7 $$2Other$$aAnti-amyloid-β monoclonal antibodies
000278999 650_7 $$2Other$$aCSF
000278999 650_7 $$2Other$$aClinical trial
000278999 650_7 $$2Other$$aDigital pathology
000278999 650_7 $$2Other$$aPiB PET
000278999 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal, Humanized
000278999 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000278999 650_7 $$04DF060P933$$2NLM Chemicals$$agantenerumab
000278999 650_7 $$05D6PWO0333$$2NLM Chemicals$$asolanezumab
000278999 650_2 $$2MeSH$$aHumans
000278999 650_2 $$2MeSH$$aAntibodies, Monoclonal, Humanized: therapeutic use
000278999 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000278999 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000278999 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000278999 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000278999 650_2 $$2MeSH$$aMale
000278999 650_2 $$2MeSH$$aFemale
000278999 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000278999 650_2 $$2MeSH$$aAged
000278999 650_2 $$2MeSH$$aBrain: pathology
000278999 650_2 $$2MeSH$$aBrain: drug effects
000278999 650_2 $$2MeSH$$aBrain: metabolism
000278999 650_2 $$2MeSH$$aMiddle Aged
000278999 650_2 $$2MeSH$$aImmunohistochemistry
000278999 650_2 $$2MeSH$$aAged, 80 and over
000278999 7001_ $$aFranklin, Erin E$$b1
000278999 7001_ $$aLi, Yan$$b2
000278999 7001_ $$aJoseph-Mathurin, Nelly$$b3
000278999 7001_ $$aBurns, Aime L$$b4
000278999 7001_ $$aHobbs, Diana A$$b5
000278999 7001_ $$aMcCullough, Austin A$$b6
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000278999 7001_ $$aXiong, Chengjie$$b8
000278999 7001_ $$aWang, Guoqiao$$b9
000278999 7001_ $$aMasellis, Mario$$b10
000278999 7001_ $$aHsiung, Ging-Yuek Robin$$b11
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000278999 7001_ $$aRoberson, Erik D$$b14
000278999 7001_ $$aHonig, Lawrence S$$b15
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000278999 7001_ $$aRingman, John M$$b17
000278999 7001_ $$aGalvin, James E$$b18
000278999 7001_ $$aBrooks, William$$b19
000278999 7001_ $$aSuzuki, Kazushi$$b20
000278999 7001_ $$aBlack, Sandra$$b21
000278999 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b22$$udzne
000278999 7001_ $$aAggarwal, Neelum T$$b23
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000278999 7001_ $$aFrosch, Matthew P$$b25
000278999 7001_ $$aKofler, Julia K$$b26
000278999 7001_ $$aWhite, Charles$$b27
000278999 7001_ $$aKeene, C Dirk$$b28
000278999 7001_ $$aChen, Jie$$b29
000278999 7001_ $$aDaniels, Alisha$$b30
000278999 7001_ $$aGordon, Brian A$$b31
000278999 7001_ $$aIbanez, Laura$$b32
000278999 7001_ $$aKarch, Celeste M$$b33
000278999 7001_ $$aLlibre-Guerra, Jorge$$b34
000278999 7001_ $$aMcDade, Eric$$b35
000278999 7001_ $$aMorris, John C$$b36
000278999 7001_ $$aSupnet-Bell, Charlene$$b37
000278999 7001_ $$aAllegri, Ricardo F$$b38
000278999 7001_ $$0P:(DE-HGF)0$$aLee, Jae-Hong$$b39
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000278999 7001_ $$aLopera, Francisco$$b41
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000278999 7001_ $$aBateman, Randall J$$b46
000278999 7001_ $$aPerrin, Richard J$$b47
000278999 7001_ $$aTeam, DIAN-TU Study$$b48$$eCollaboration Author
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