Stephen P.Salloway, Butler Hospital/Brown University, 345 Blackstone Boulevard Providence, RI 02906ssalloway@butler.org
Ronald Black, M.D., Reisa Sperling, M.D., Nick Fox, M.D., Sid Gilman, M.D., Dale Schenk, Ph.D., Michael Grundman, M.D., M.P.H.
Submitted February 22, 2010
We appreciate the comments by Drs. Laskowitz and Kolls on the observed association between APOE4 and vasogenic edema in our phase 2 trial of bapineuzumab for the treatment of mild-moderate AD. [1] The mechanisms that produced vasogenic edema in this study are unclear.
Spontaneous vasogenic edema has been reported in patients with cerebral amyloid angiopathy (CAA). [6] AD patients who are carriers of APOE4 tend to have higher levels of vascular amyloid burden (CAA) than non-carriers [7], possibly placing them at risk for developing alterations in vascular permeability. The APOE E4/E4 genotype has been associated with inflammation and vasogenic edema in patients with CAA. [8]
Treatment with anti-amyloid immunotherapeutic agents may transiently alter vascular amyloid burden, further modifying vascular permeability. [9] As Drs. Laskowitz and Kolls suggest, it is possible that altered inflammatory responses mediated by APOE4, with or without abnormal vascular amyloid, contribute to the fluid shifts seen in patients with vasogenic edema in this trial.
Vasogenic edema also occurred in non-carriers of APOE4, particularly at higher doses of bapineuzumab. We agree with Laskowitz and Kolls that further work is needed to better elucidate the mechanisms underlying vasogenic edema.
7. Chalmers K, Wilcock GK, Love S. APOE4 influences the pathological phenotype of Alzheimer’s disease by favouring cerebrovascular over parenchymal accumulation of A_ protein. Neuropathol Appl Neurobiol 2003;29:231–238.
8. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology 2007;68:1411-1416.
9. Boche D, Zotova E, Weller RO, et al. Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain 2008;131:3299-3310.
Disclosures: See original article for full disclosure list.
We appreciate the comments by Drs. Laskowitz and Kolls on the observed association between APOE4 and vasogenic edema in our phase 2 trial of bapineuzumab for the treatment of mild-moderate AD. [1] The mechanisms that produced vasogenic edema in this study are unclear.
Spontaneous vasogenic edema has been reported in patients with cerebral amyloid angiopathy (CAA). [6] AD patients who are carriers of APOE4 tend to have higher levels of vascular amyloid burden (CAA) than non-carriers [7], possibly placing them at risk for developing alterations in vascular permeability. The APOE E4/E4 genotype has been associated with inflammation and vasogenic edema in patients with CAA. [8]
Treatment with anti-amyloid immunotherapeutic agents may transiently alter vascular amyloid burden, further modifying vascular permeability. [9] As Drs. Laskowitz and Kolls suggest, it is possible that altered inflammatory responses mediated by APOE4, with or without abnormal vascular amyloid, contribute to the fluid shifts seen in patients with vasogenic edema in this trial.
Vasogenic edema also occurred in non-carriers of APOE4, particularly at higher doses of bapineuzumab. We agree with Laskowitz and Kolls that further work is needed to better elucidate the mechanisms underlying vasogenic edema.
References
6. Oh U, Gupta R, Krakauer JW, Khandji AG, Chin SS, Elkind MS. Reversible leukoencephalopathy associated with cerebral amyloid angiopathy. Neurology 2004;62:494-497.
7. Chalmers K, Wilcock GK, Love S. APOE4 influences the pathological phenotype of Alzheimer’s disease by favouring cerebrovascular over parenchymal accumulation of A_ protein. Neuropathol Appl Neurobiol 2003;29:231–238.
8. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology 2007;68:1411-1416.
9. Boche D, Zotova E, Weller RO, et al. Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain 2008;131:3299-3310.
Disclosures: See original article for full disclosure list.