In summary
* Last week we reviewed the April 2026 Cochrane report, which evaluated a class of drugs (amyloid-beta-targeting monoclonal antibodies) for the treatment of Alzheimer’s disease (AD).
* The report concluded that these drugs likely have no clinically meaningful positive effects for AD, while increasing the risk of bleeding and swelling in the brain. The report went further, by suggesting that future research needs to move away from the amyloid-beta protein hypothesis and focus on other pathways.
* This week’s note reviews an alternative hypothesis for AD – is it type 3 diabetes?
* The hypothesis was first proposed in a 2005 paper by a team led by Suzanne de la Monte and Jack Wands. The researchers noted that the neurodegeneration that occurs in AD is consistently associated with a number of characteristics. These characteristics include amyloid-beta deposits, but focusing on one characteristic may not have explained the whole condition.
* The 2005 paper reported on examinations of postmortem brain tissue from 28 cases with AD and 26 control cases without AD. The brain tissue of people with AD had low levels of insulin, IGF-1, and IGF-2 (the brain’s own growth/survival hormones) and their receptors compared to the brains of the control group.
* de la Monte and Wands published another paper in 2008, which is the most cited article in this research area. This examined the evidence for the type 3 diabetes hypothesis in four areas: i) what we know about obesity, insulin resistance and type 2 diabetes; ii) human studies (their own 2005 pathology work); iii) animal studies; and iv) the impact of diabetes drugs on neurodegeneration.
* This note examines the plausibility of the type 3 diabetes hypothesis and suggests why it didn’t become as dominant as the amyloid-beta theory.
* The note closes by mentioning the Bredesen protocol. Bredesen’s decades long research also implicates glucose levels and insulin resistance alongside other factors that broaden the hypothesis further.
Introduction
Last week we reviewed the April 2026 Cochrane report, which evaluated a class of drugs (amyloid-beta-targeting monoclonal antibodies) for the treatment of Alzheimer’s disease (AD) (Ref 1). The report concluded that drugs that target amyloid-beta proteins in the brain likely have no clinically meaningful positive effects for AD, while increasing the risk of bleeding and swelling in the brain. The report went further, by suggesting that future research needs to move away from the amyloid-beta protein hypothesis and focus on other pathways.
The note about the Cochrane report generated much interest. (Thank you to those who shared the work of Dr Dale Bredesen in reply. I’ll close this note with that). The response to last week’s note prompted me to follow up this week with an alternative theory for AD. The one that has always ‘stuck with me’ is that Alzheimer’s disease might be type 3 diabetes. One of the papers in my EndNotes library, which I have often shared, is a paper by Suzanne de la Monte and Jack Wands called “Alzheimer’s disease is type 3 diabetes – evidence reviewed” (Ref 2).
The research question “Is AD type 3 diabetes?” would be big even for a PhD. We can’t unpack a topic of this size in a Monday note. But we can cover some basics: what is this hypothesis? When was it first posited? Who are the key researchers and what are the key papers in this field? What is the evidence for the hypothesis? Is it plausible? Why isn’t it the dominant theory?
Zoe
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