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Persistent neuropathological effects 14 years following amyloid-β immunisation in Alzheimer’s disease

Persistent neuropathological effects 14 years following amyloid-β immunisation in Alzheimer’s disease
Persistent neuropathological effects 14 years following amyloid-β immunisation in Alzheimer’s disease
We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer’s disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunisation (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status.
Seventeen of 22 (77%) participants had Alzheimer’s neuropathological change, whereas five of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) Alzheimer’s disease patients receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer’s patients who died 14 years after immunisation had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (=-0.664, p=0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI).
In conclusion, Alzheimer’s patients actively immunised against amyloid-β can remain virtually plaque–free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunisation protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer’s disease in Alzheimer’s therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer’s pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.
Alzheimer’s disease, Dementia, immunotherapy, neuropathology, Amyloid-beta (Aβ)
0006-8950
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Buckland, George
7e0ac1a4-f418-4769-a96f-3756b6ca3530
Harrison, Charlotte
bb8f66bc-972d-435c-ac6b-1283718f0f51
Page, Anton
76ebbfb8-4fe3-495c-afff-1f2f34977fee
Harris, Scott
19ea097b-df15-4f0f-be19-8ac42c190028
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Neal, James W.
12d0ba0f-b29d-43ca-8e61-af46a430367b
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Buckland, George
7e0ac1a4-f418-4769-a96f-3756b6ca3530
Harrison, Charlotte
bb8f66bc-972d-435c-ac6b-1283718f0f51
Page, Anton
76ebbfb8-4fe3-495c-afff-1f2f34977fee
Harris, Scott
19ea097b-df15-4f0f-be19-8ac42c190028
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Neal, James W.
12d0ba0f-b29d-43ca-8e61-af46a430367b
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Nicoll, James, Buckland, George, Harrison, Charlotte, Page, Anton, Harris, Scott, Love, Seth, Neal, James W., Holmes, Clive and Boche, Delphine (2019) Persistent neuropathological effects 14 years following amyloid-β immunisation in Alzheimer’s disease. Brain. (doi:10.1093/brain/awz142). (In Press)

Record type: Article

Abstract

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer’s disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunisation (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status.
Seventeen of 22 (77%) participants had Alzheimer’s neuropathological change, whereas five of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) Alzheimer’s disease patients receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer’s patients who died 14 years after immunisation had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (=-0.664, p=0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI).
In conclusion, Alzheimer’s patients actively immunised against amyloid-β can remain virtually plaque–free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunisation protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer’s disease in Alzheimer’s therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer’s pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

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revised iAD 15 year follow up_v2 - Accepted Manuscript
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Accepted/In Press date: 4 April 2019
Keywords: Alzheimer’s disease, Dementia, immunotherapy, neuropathology, Amyloid-beta (Aβ)

Identifiers

Local EPrints ID: 429925
URI: https://eprints.soton.ac.uk/id/eprint/429925
ISSN: 0006-8950
PURE UUID: 65d1e625-d21a-48ce-a192-58a633d0df96
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 09 Apr 2019 16:30
Last modified: 11 May 2019 00:35

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Contributors

Author: James Nicoll ORCID iD
Author: George Buckland
Author: Charlotte Harrison
Author: Anton Page
Author: Scott Harris
Author: Seth Love
Author: James W. Neal
Author: Clive Holmes ORCID iD
Author: Delphine Boche ORCID iD

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