Identifying Links between Alzheimer's Disease and Type 2 Diabetes through Proteomics

[NNadir]

Although I work peripherally in proteomics, the paper I'll discuss now briefly is from a journal I don't always open without a cause to do so.

Thus I stumbled across this paper while looking for something else: Identifying Links between Alzheimer’s Disease and Type 2 Diabetes through Proteomics, Tong N. Chen, Adam L. Orr, Anna G. Orr, and Nathaniel M. Vacanti Journal of Proteome Research 2025 24 (8), 3733-3740.

Some excerpts:

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are each rapidly increasing in prevalence and in their burden to patients, caregivers, and the world economy. Globally, AD costs nearly $2 trillion per year and diabetes nearly $1 trillion per year. AD and related dementias are a top cause of death in patients over 60 years old. (1) Approximately 20% of adults over 60 years of age worldwide now have diabetes and approximately 90% of those have T2D characterized by insulin resistance (IR), i.e. the lack of a healthy molecular response to insulin. (2)

AD is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β (Aβ ) aggregates in the brain and formation of intracellular neurofibrillary tangles. (3) Aβ plaques are derived from altered processing of the amyloid precursor protein (APP), a transmembrane protein enriched in the central nervous system (CNS), while neurofibrillary tangles are formed by misfolding of the microtubule-associated protein tau (MAPT). (4) Notably, 80% of AD patients have impaired glucose tolerance or T2D. (5) Cohorts in the Rotterdam Study with pre-existing T2D had a risk ratio of 1.9 for developing AD relative to those without T2D. (6) Additional studies have reported increased risks ranging from 1.2 to 2.4-fold. (7−12) However, the exact mechanisms linking these diseases remain elusive, in part because of the underlying complexity of interorgan communication and age-related metabolic and cognitive decline. (13,14)

Historically, IR has been studied primarily in insulin-sensitive peripheral tissues like muscle, liver, and adipose. (15) In addition to its peripheral effects, insulin crosses the blood–brain barrier (BBB) and influences neural cells, many of which express insulin receptors. (16−19) Neural cells also express insulin-responsive proteins, such as the insulin-sensitive glucose transporter (GLUT4) and glycogen synthase kinase 3β (GSK3β ). (18) Interest in insulin signaling in the brain has been growing, with increasing awareness of the clinical and pathological similarities between AD and T2D. In particular, co-occurring chronic inflammation, increased advanced glycation end products (AGEs), and alterations in the BBB are strongly linked to both diseases. (20) Additionally, the greatest genetic risk-factor for AD is the ε4 variant of APOE, the major lipoprotein in the brain responsible for cholesterol and lipid transfer between neural cells. (21) This APOE variant can affect the interactions between APOE and the insulin receptor, (22,23)...

...Common T2D dyslipidemias, including increased circulating free fatty acids and very-low density lipoproteins, can impact neuroinflammation and dysregulation of brain cholesterol, both strongly linked to Aβ plaque and neurofibrillary tangle pathologies. (26) Moreover, brain glucose hypometabolism is an early hallmark of AD and can appear in prodromal PET scans over a decade before clinical diagnosis. (27) Presymptomatic disease-related changes, including soluble Aβ oligomer accumulation, Aβ plaque formation and glial activation, may promote compensatory glucose hypermetabolism, followed by potential failure of this process and onset of chronic glucose hypometabolism...

...In a pioneering study using 2D gel electrophoresis/MALDI-TOF of the proteome in mouse pancreatic islets, proteins related to neural protein folding and function were identified. (49) The discovery of these proteins in islets is an early indication that insulin production in the pancreas and neural protein folding or function could be coregulated/dysregulated by similar mechanisms. In a study of the proteome of cerebrospinal fluid (CSF) from cognitively normal individuals, with and without IR, levels of AD biomarkers in CSF, including Aβ and MAPT, were correlated with plasma insulin levels, suggesting a link between systemic insulin and AD biomarkers. (50) Moreover, 25 of the plasma proteins differentially expressed in IR versus non-IR groups, including IGFBP2 and MAPK12, were found to be altered in AD versus control subjects in a separate study by the same group. (51)...

There has been some fraud in Alzheimer's research using gel electrophoresis, but I think it's pretty difficult to fake MALDI-TOF. However for conformational studies - certainly at the core of Alzheimer's I would think one might prefer to utilize an ion mobility type of instrument, assuming that one can do a top down analysis without denaturing the proteins - probably not an easy task - and thus losing the information.

...AD and T2D are chronic conditions with complex etiologies impacting aging populations. Though the pathologies that define these diseases are well-documented (i.e., the formation of Aβ plaques and neurofibrillary tangles in AD and peripheral IR in T2D) and T2D is a risk factor for AD, the underlying mechanisms that may be shared between the diseases are poorly understood (e.g., neural dyslipidemia and dysregulated glucose metabolism). A deeper understanding of converging pathogenic pathways could aid in the development of novel therapeutics to treat both diseases and reduce the risk of AD for individuals with T2D. The unbiased and high-throughput proteomic approaches provide valuable new opportunities to decipher the mechanistic interactions between these diseases. Increasing availability of data sets, banked tissues, and biofluid samples from diverse model systems and patient populations provides valuable resources to further validate previous findings and discover novel mechanisms. Indeed, a study not explicitly designed to examine the interplay of AD and T2D was nonetheless able to identify proteins associated with altered glucose metabolism using samples collected from multiple AD cohorts. (73) With broader availability of data sets and samples, additional proteins associated with insulin signaling and its dysregulation could emerge...

Interesting I think. I'm border line pre-diabetic myself, somewhat controlled with Ozempic. Sometimes I scare myself, as familiar things sometimes drift away, but as best I can tell, I'm still here.

[peacebuzzard]

1. I am also drifting up and down with higher sugar

But it primarily stays in the healthy range. I shouldn’t be so impressed with some of these infomercials but i have given the Ceylon cinnamon supplement a whirl. I put a scoop of it in oatmeal if I am home and not too busy to cook. When out on trips I have started carrying the Ceylon cinnamon supplements in my travel stuff. So I am happy to be in the normal range in that symptom. I have been doing this cinnamon thing for around a couple of months. Have to be careful since I have always been addicted to sweets but I am really trying to avoid that decadent indulgence. It is especially hard when out in the world and eating correctly every day while rushing through a work day can be challenging.
Great scholarly study; thank you for sharing. I sometimes find myself forgetting my thought pattern and slurring a word or two. Kind of scary since I do speaking assignments and other customer work. I really am trying to focus harder on tasks at hand.

[I_UndergroundPanther]

2. I hope

I die before alzhiemers. Got diabeties manage it with metformin and glimperide . Mostly in the normal range.

But if I notice cognitive decline or get diagnosed with it I will off myself before it gets bad. I don’t wanna live like that.