Small and Duff’s Dual Pathway Hypothesis

Stylised Diagram of the Hippocampus - Frank Gaillard
Diagram showing Hippocampus, an area affected by Alzheimer’s Disease (credits Appendix A)

Small and Duff’s Dual Pathway hypothesis is widely cited (e.g see here). The interested reader is referred to the paper above. However I have outlined the salient features below as I have found them

(1) The Amyloid Cascade Hypothesis does not appear to explain all cases of Alzheimer’s Disease particularly when this is late in onset.

(2) Tau  gene mutations are described as leading to Frontotemporal Dementia rather than Alzheimer’s Type Dementia

(3) A dual pathway is hypothesised which describes processes upstream to the Amyloid deposition and tau phosphorylation and which influence both

(4) Small and Duff identify APOE4, GSK and the Retromer sorting pathway as three examples of upstream drivers

(5) When Amyloid deposition is absent or minimal but the other elements are present this has implications for Amyloid reducing strategies

Appendix A – Credits

Picture by FG Designs. Creative Commons License.

Index: There are indices for the TAWOP site here and here

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TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link.

Responses: If you have any comments, you can leave them below or alternatively e-mail

Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

Conflicts of Interest: *For potential conflicts of interest please see the About section.


  1. […] The Wellcome Trust have created this video on their YouTube channel illustrating the processes involved in transporting lipids around the body. The reason I have included this video here is that Apolipoprotein is a key molecule in lipid transport and Apolipoprotein E (and more specifically the E4 allele) is a risk factor for Alzheimer’s Disease. Furthermore APOE4 is described as a regulator of Alzheimer’s pathology upstream of both Tau and Amyloid in Small and Duff’s Dual Pathway Hypothesis. […]


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