Clinical trial evidence related to calling Alzheimer’s “Type 3 Diabetes”

Attention conservation notice: These are just a few impressions from only 2-3 years of following the AD field — I’m certainly not an expert in any of this. Also, I am not a doctor.

The evidence behind calling Alzheimer’s “type 3 diabetes” is at least two-fold. First, insulin and insulin-like growth factor pathways are thought to decrease in levels in AD patients. Second, diet and vascular risk factors are strongly linked to AD diagnosis.

The purpose of this post is that I’m trying to learn about the idea and how valuable I think it is as a framework for AD.

First, let’s look at some history. On Pubmed, there are 48 results for “type 3 diabetes” OR “type III diabetes”. Which, out of 83658 total hits for “Alzheimer’s”, is not that many.

The first mention on PubMed is in 2000. Although I don’t have access to the full-text, I don’t think it’s about Alzheimer’s.

Instead, it seems that the first mention is in 2005, by Steen et al. [1] — and indeed, in their abstract they say that they are coining the term. Their argument is that insulin-related proteins, especially IGF-I and IGF-II, have reduced expression in postmortem human brain tissue from AD patients, suggesting a lack of sufficient insulin in the brain.

To get a sense of how it has seeped into the public consciousness, let’s look at how much people are searching for this term using Google trends:

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searches for “type 3 diabetes” on Google trends

So I don’t think it is old news.

Yesterday, Gabrielle Strobel from AlzForum reported on two pieces of data from CTAD 2015 that seem relevant to the case for Alzheimer’s as type 3 diabetes:

  1. Metformin (a drug that increases insulin sensitivity and is used to treat type 2 diabetes) was ineffective in improving cerebral perfusion in 20 patients with mild-to-moderate AD.
  2. Intranasal Determir (an insulin analog) did not have an improvement on memory or MRI volume, but regular insulin did.

There are also a couple of other relevant pieces of data:

  1. Previously, numerous studies have shown that intranasal insulin leads to memory improvements in AD patients (e.g., here, here, and here).
  2. The SNIFF trial is a study of year-long treatment of twice-daily intranasal insulin with 240 enrollees nation-wide. The results are set to be in in February 2016, so we should hear about it soon.

Notably, intranasal insulin has also been shown to improve cognition in non-AD trials:

  1. It improves cognition in people with type 2 diabetes (e.g., here).
  2. In rats, it improves cognition in normal aging (here).
  3. It improves some measures of cognition in healthy subjects age 18-34 (n = 38; here; note: this study did not correct for multiple hypothesis tests).

Since mixed vascular and Alzheimer’s dementia is probably the most common form of dementia (e.g. see here), and vascular dementia is often related to poor perfusion in part due to insulin-related metabolic problems, it makes total sense that intranasal insulin would help to improve cerebral vascular function and thus appear to be helping the memory of AD patients, when in reality it is helping the mixed vascular dementia component.

So although I definitely hope that the SNIFF trial receives positive results on cognition, I don’t think it’s fair even in that case to call it as necessarily a “win” for the case for Alzheimer’s as type 3 diabetes.

For that to be the case, I’d want to see better data that not only is cognition improving following insulin treatment, but also that measures of AD pathology such as amyloid and tau are improving. This seems to be one of the major goals of the SNIFF trial, since they are also measuring amyloid and tau in the CSF of the enrollees.

So, in an attempt to quantify my actual beliefs, and knowing absolutely nothing about the SNIFF trial itself (i.e., this is based solely on public info, mostly listed above), I predict with 60% probability that the trial will show a significant improvement in cognition. I also predict that neither CSF Abeta nor Abeta/tau ratios will change significantly based on treatment, this time with 75% probability.

Since the results are meant to be completed in February 2016, we should know the actual results by the end of 2016 latest.

Although the terminology, classification, and mechanisms around AD are extremely important for research priorities, the most important thing is to get better therapies for all types of dementia into clinical practice ASAP. And on that note, hopefully intranasal insulin will turn out to be a really valuable therapy for patients.