Is it time to repurpose geroprotective diabetes medications for prevention of dementia?

Diabetes mellitus is a well-recognized risk factor for dementia. In prospective studies, diabetes confers a greater than 80% increase in risk for all-cause dementia and Alzheimer’s disease, and greater than 180% increase in risk for vascular dementia.1 One in seven adults in the United States are estimated to have diabetes, and more than 90% of them have type 2 diabetes (T2D).2 With an aging population and increasing obesity, the incidence and prevalence of T2D is expected to continue to increase worldwide.3

Insulin resistance, which is a metabolic hallmark of T2D, has been postulated as a pathophysiologic connection between diabetes and dementia. Hyperinsulinemia, a biomarker of peripheral insulin resistance, is a risk factor for Alzheimer’s disease even in the absence of diabetes.4 At the same time, ex-vivo studies have shown evidence of brain insulin resistance in people with Alzheimer’s disease who did not have diabetes.5 While insulin signaling in the brain has an important role in neuronal and glial metabolism, synaptic neurotransmission, neuroinflammation and neurovascular coupling, it is presently unclear whether the observed associations between T2D and dementia are caused by insulin resistance in the brain or metabolic consequences of peripheral insulin resistance (as reviewed in Reference 6). T2D is also characterized by endothelial dysfunction and microvascular insufficiency, which can lead to vascular dementia even in the absence of macrovascular insults, through mechanisms involving ischemia, blood–brain barrier leakage, and disruptions in white matter integrity.7

Given the strong epidemiologic and pathophysiologic connections between diabetes and dementia, it is not surprising that glucose-lowering drugs have been of interest for the prevention of dementia. In the current issue of the Journal of the American Geriatrics Society, Tang and co-authors8 aimed to resolve inconsistencies in the existing observational data by performing a systematic review and a meta-analysis to examine the associations between the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in people with T2D and the risk for incident all-cause dementia, Alzheimer’s disease and vascular dementia. Ten observational prospective studies that met the inclusion criteria for meta-analysis encompassed more than 800,000 people with T2D (44% men), with a mean baseline age of 68 years and a median duration of follow-up of 4.5 years. Included studies were predominantly deemed to be of high methodological quality, but with substantial heterogeneity. Seven studies involved DPP-4 inhibitor users who, compared to non-users, had significantly lower relative risk for all-cause dementia by 17% and vascular dementia by 41%, but without significant difference in the risk for Alzheimer’s disease. Compared to non-users, users of GLP-1RAs (five studies) and SGLT2 inhibitors (three studies) had a significantly lower risk for all-cause dementia by 28% and 38%, respectively; meta-analysis by dementia subtype was not performed due to a limited number of studies.

Full Paper:


It’s odd that they didn’t also include acarbose or metformin in the diagram. I haven’t looked at the paper but i hope they’ve shared their perspective on DPP-4 inhibitors as well.


Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction


Anyone know what the optimal dosage is per day for Metformin?

I think the best info we have to go on is the design of the TAME Metformin study - and its 1500mg slow release 1X day.

Details here (PDF of a presentation on TAME Study):

1 Like

A little diatribe about why I don’t like doctors.

When I was working as an electronics design engineer, I had to be constantly studying the latest developments. If you were not current you soon would be left behind and possibly without a job.

My observation that applies to most primary care doctors, as opposed to doctors doing research, is: Most primary physicians are not keeping current with the latest in medicine. Maybe they don’t have the time or energy after seeing patients all day.

This results in the patient not being prescribed the most effective treatments and medications.
A typical example is rapamycin. I suppose by now most doctors have heard of it but are unlikely to give you a prescription.

My primary doctors have on the whole been very smart but were seldom up to date on anything medical. I have always taken a proactive approach to my health care and have frequently taken the latest studies with me to my doctor in order to get the best medications.

A typical example is metformin. My doctors never suggested that I take metformin as a prophylactic or any other medication for prevention rather than as a treatment.
The medications that I am taking are all my suggestions given by me to my doctors as a preventative measure rather than a treatment. Other than rapamycin, my doctors have been willing to prescribe the medications that I suggested. What they are not willing to do for the most part is to prescribe nonstandard tests such as Apo-B, Apo-A1. They say I don’t need it. Once again the mindset is for treatment rather than prevention.

Now that I am in my 80’s my doctors don’t give a sh*t. Won’t even prescribe a PSA test because “you will die of old age before you die of prostate cancer”.

No doctor that I have ever been to has practiced preventive medicine other than to tell patients to lose weight, stop smoking, etc.


I don’t understand doctors. If a customer was paying me (directly or indirectly) for something trivial I would gladly oblige even if I don’t agree with it.

1 Like

They can be sued. Like if they write you a prescription for rapamycin and you start eating it like candy, getting sepsis and dying or losing a bunch of your limbs, they had to have had a justification for prescribing it. But I don’t know the laws very well.


I meant doing a PSA test. Prescribing medications is legally iffy, doing a hundred health tests is not.


You need to buy the additional blood tests at a private clinic and pay out of your own pocket if they won’t prescribe it. Unfortunately the options for what you can order without a doctors referral aren’t great in some countries.

1 Like