title: Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.
abstract: Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes.
  
  
  
  Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are significantly exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity with Alzheimer's disease may mute the response to anti-Aβ immunotherapy.
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Weekman
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Sudduth
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology.
authors.forename: Carly N
authors.initials: CN
authors.lastname: Caverly
authors.affiliation: Department of Physiology.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kopper
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology.
authors.forename: Oliver W
authors.identifier: 0000-0003-0387-2878
authors.initials: OW
authors.lastname: Phillips
authors.affiliation: Magnetic Resonance Imaging and Spectroscopy Center, Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Dave K
authors.initials: DK
authors.lastname: Powell
authors.affiliation: Sanders-Brown Center on Aging, Department of Physiology, donna.wilcock@uky.edu.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Wilcock
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015140:Dementia, Vascular / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000209:etiology / Q000235:genetics / Q000628:therapy; D007167:Immunotherapy / Q000379:methods*; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger
keywords: amyloid; immunotherapy; microglia; microhemorrhage; mixed dementia; vascular cognitive impairment