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Understanding cause and effect in Alzheimer's pathophysiology: implications for clinical trials

Understanding cause and effect in Alzheimer's pathophysiology: implications for clinical trials
Understanding cause and effect in Alzheimer's pathophysiology: implications for clinical trials
Alzheimer’s disease (AD) pathology is multi-faceted, including extracellular accumulation of amyloid-β (Aβ), accumulation of tau within neurons, glial activation and loss of neurons and synapses. From a neuropathological perspective, usually at a single time-point and often at the end-stage of the disease, it is challenging to understand the cause and effect relationships between these components. There are at least four ways of trying to unravel these relationships. Firstly, genetic studies demonstrate mutations that influence Aβ production, but not tau, can initiate AD; whereas genetic variants influencing AD risk are related to innate immunity and lipid metabolism. Secondly, studies at early time points show that pathology begins decades before the onset of dementia and indicate different anatomical locations for initiation of Aβ and tau accumulation. Thirdly, cause and effect can be studied in experimental models, but most animal models do not fully replicate AD pathology. However, induced pluripotent stem cells (iPSCs) to study live human neurons has introduced a new perspective. Fourthly, clinical trials may alter AD pathology giving insights into cause and effect relationships. Therefore, a sequence of (i) neocortical Aβ accumulation followed by (ii) a microglial inflammatory reaction to Aβ, causing neuritic dystrophy which promotes (iii) spread of tau from the limbic system to the neocortex with (iv) progressive tau accumulation and spread resulting in (v) neurodegeneration, explains the evidence. It is proposed that different therapeutic targets are required for different stages of the disease process: Aβ for primary prevention, microglia for secondary prevention, and tau for established disease.
Alzheimer’s disease, pathophysiology, treatment, Abeta, Tau, microglia, immunotherapy
0305-1846
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed

Boche, Delphine and Nicoll, James (2020) Understanding cause and effect in Alzheimer's pathophysiology: implications for clinical trials. Neuropathology and Applied Neurobiology. (In Press)

Record type: Review

Abstract

Alzheimer’s disease (AD) pathology is multi-faceted, including extracellular accumulation of amyloid-β (Aβ), accumulation of tau within neurons, glial activation and loss of neurons and synapses. From a neuropathological perspective, usually at a single time-point and often at the end-stage of the disease, it is challenging to understand the cause and effect relationships between these components. There are at least four ways of trying to unravel these relationships. Firstly, genetic studies demonstrate mutations that influence Aβ production, but not tau, can initiate AD; whereas genetic variants influencing AD risk are related to innate immunity and lipid metabolism. Secondly, studies at early time points show that pathology begins decades before the onset of dementia and indicate different anatomical locations for initiation of Aβ and tau accumulation. Thirdly, cause and effect can be studied in experimental models, but most animal models do not fully replicate AD pathology. However, induced pluripotent stem cells (iPSCs) to study live human neurons has introduced a new perspective. Fourthly, clinical trials may alter AD pathology giving insights into cause and effect relationships. Therefore, a sequence of (i) neocortical Aβ accumulation followed by (ii) a microglial inflammatory reaction to Aβ, causing neuritic dystrophy which promotes (iii) spread of tau from the limbic system to the neocortex with (iv) progressive tau accumulation and spread resulting in (v) neurodegeneration, explains the evidence. It is proposed that different therapeutic targets are required for different stages of the disease process: Aβ for primary prevention, microglia for secondary prevention, and tau for established disease.

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NAN-2020-0117.R1 - Accepted Manuscript
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More information

Accepted/In Press date: 1 July 2020
Keywords: Alzheimer’s disease, pathophysiology, treatment, Abeta, Tau, microglia, immunotherapy

Identifiers

Local EPrints ID: 442243
URI: http://eprints.soton.ac.uk/id/eprint/442243
ISSN: 0305-1846
PURE UUID: 00861a2c-52f0-4f25-87c9-3d4a8decbf0a
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

Catalogue record

Date deposited: 09 Jul 2020 16:39
Last modified: 01 Jul 2021 04:01

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