Lithium, Alzheimer's Disease and... Diabetes?
- Bowie Matteson
- 3 days ago
- 14 min read
Nature recently published an article titled "Lithium deficiency and the onset of Alzheimer’s disease". It was looking for trends in data collected from a cohort of Alzheimer's patients (AD) and those in the progressive stages of its development (AKA Mild Cognitive Impairment, or MCI). They compared the levels of certain metals in a range of patients:
Researchers measured 27 different metals in brain tissue and blood from people with:
No cognitive impairment (NCI),
Mild cognitive impairment (MCI),
Alzheimer’s disease (AD).
They focused on two brain areas:
Prefrontal cortex (PFC) — heavily affected in AD
Cerebellum — relatively spared in AD
✅ Results:
Lithium (Li) was the only metal that was significantly reduced in the PFC of both MCI and AD patients.
Lithium levels were not significantly altered in the cerebellum, suggesting regional specificity.
Serum lithium levels were not different between groups—this implies the lithium deficiency is brain-specific, not systemic.
Other metals showed changes too, but only in AD (not MCI), and lithium had the strongest statistical association.
This lead the researchers to question the exact sequence of lithium depletion. Might lithium be sequestered elsewhere? Was lithium a casualty of something further upstream? What about lithium's apparent absence impacted the brain?
To understand why lithium was low in the brain, researchers looked at its relationship with amyloid-beta (Aβ) plaques:
They found that Li was concentrated within Aβ plaques in the frontal cortex of every MCI and AD brain examined.
The amount of lithium trapped in plaques increased from MCI to AD.
When brain tissue was subfractionated, the plaque-free (soluble) part of the cortex had significantly less lithium in AD vs. control brains.
So there was a dose-dependent, plaque-specific placement of lithium in the spectrum of neuro-degeneration. The lower the amount of detectable serum lithium, the more concentrated the lithium was in the plaques. The more plaques there were, the more significant the cognitive impairment. This led the researchers to conclude: Lithium is being pulled out of circulation and trapped inside Aβ plaques, making it less available to neurons and other brain cells. And this wasn't just true of those diagnosed with MCI or AD. In both the general aging population and within AD patients specifically, lower levels of lithium in the non-plaque (soluble) cortical areas:
Correlated with worse memory (episodic and semantic),
And with lower global cognitive function scores.
The research article goes on to explore lithium-speciifc impacts on the genetic and epigenetic mechanisms of plaque formation, as well as lithium manipulation in mouse models of AD and MCI. They found that lithium depletion (via diet) led to increased plaque formation and decreased cognitive function in mice. Furthermore, iron supplementation (with lithium orotate) improved cognitive scores and decreased plaque formation for every group (normal, MCI, and AD).
Alzheimer's and Diabetes Overlap
Where in all of this does diabetes come into play? We've talked previously about the possible connections between insulin resistance, diabetes and Alzheimer's disease.
Amylin, the appetite regulator co-secreted by beta cells with insulin, has ties to amyloid plaque formation. It is a peptide that has been shown to serve as the scaffolding for amyloid-beta and Tau aggregation in the brains of those with neurodegenerative diseases (1). While not intrinsically inclined to aggregate at normal levels, in states of excess amylin aggregates into larger "clumps" which serve as a landing spot for the other materials that make-up the plaques. This state of excess amylin is what connects diabetes and alzheimer's disease. Because amylin orginates from the beta cells, there needs to be conditions within the body that spurn higher amylin output.
Enter hyperinsulinemia and beta cell stress.
The state of insulin resistance requires increased output of insulin (and thus amylin) to better regulate blood sugars. A chronic state of high insulin output, high amylin output and chronic inflammation serves as fertile ground for amyloid-B plaque formation.
Hyperinsulinemia is well documented in the presentation and progression of T2D, thus the attention being given to obesity, T2D and neurodegenerative diseases. But what about T1D?
I initially questioned this hypothesis because of T1D's seeming absence of the hyperinsulinemia stage so often seen with T2D. It would seem T1D develops way too fast for there to be any significant amylin aggregation. While T1D and T2D aren't a direct pathological match, is it possible that T1D has the prolonged insulin/amylin dysregulation that plants the seeds for AD? Absolutely. Let's be real. T1D is not the acutely-developed disease we've come to know it as. It isn't "triggered" or brought about in a series of days. Not a virus. Not a vaccine. It's a long-arc of metabolic instability and compensation failure that open us up to advantageous infection and metabolic injury. Rather than seeing early-stage T1D as a brief episode of overwork due to a viral insult or acute immune misdirection, I'm proposing that β-cell exhaustion is the result of chronic systemic imbalance, particularly from:
Progressive iron overload
Electrolyte disturbances (e.g., calcium/magnesium imbalances)
Redox collapse (glutathione, SOD, catalase depletion)
Inflammatory burden and altered signaling (IL-1β, TNF-α, NF-κB)
Mitochondrial ROS load and ATP deficit in islet cells
These factors could create a prolonged environment of metabolic compensation, where:
β-cells secrete more insulin and amylin to maintain glycemic homeostasis
Endoplasmic reticulum (ER) and mitochondrial stress gradually rise
Autophagy and proteostasis become overwhelmed, impairing amylin clearance
This opens the door to subclinical hyperamylinemia, with localized amylin accumulation long before overt hyperglycemia or antibody positivity. This makes T1D a consequence of failed compensation, not the initiation.
Importantly, amylin deposition has been found in the pancreas and cerebral vasculature of both T1D and T2D patients, supporting the theory of a shared pathologic terrain between β-cell failure and neurodegeneration—even in autoimmune contexts.
While T2D is widely associated with amylin-derived islet amyloidosis, amylin aggregates are also seen in T1D, especially in:
Slow-onset autoimmune diabetes (e.g. LADA)
Postmortem pancreatic tissue from T1D donors
Cerebral vasculature of T1D patients with cognitive decline
Prolonged amylin secretion without adequate chaperone proteins or clearance capacity (e.g., insulin-degrading enzyme, IDE) promotes:
Local cytotoxicity
Inflammasome activation
Peripheral amyloid spillover, potentially crossing the BBB
So yes—a prolonged pre-diagnostic phase of β-cell stress would naturally increase systemic amylin exposure. Even without a long period of overt hyperinsulinemia, the ratio and context of secretion could still skew toward pathological amylin buildup. And we have no way of truly knowing when the compensatory mechanisms begin - because T1D and its symptoms are when the compensations fail. Might there be room for the possibility that our body has been slowly building up to these systemic defects, nutrient deficiencies and the resulting consequences?
These ties to altered glucose metabolism and specific nutrient interactions leaves a door open for crossover in potential therapies. Let's think about it:
Lithium deficiency promotes plaque formation + neurological dysfunction (IE: Alzheimer's etc)
Research suggests less lithium, more plaques
Alzheimer's has distinct ties to beta cell health, insulin resistance and the inflammatory conditions conducive to diabetes (amylin overproduction, iron overload etc)
Pre-diabetic beta cells = excess amylin
Excess amylin = more plaques
Via the transitive property, if less lithium = more plaques AND excess amylin = more plaques, might less lithium have some impact on excess amylin?
The answer? There's a strong case for it.
Lithium's Potential as a Diabetes Therapy
The same way that the cellular pathways impacted in Alzheimer's development mirror those in diabetes, lithium metabolism has distinct ties to blood sugar regulation and beta cell health. How It May Help:
🧠 Reduces Aβ plaque aggregation via GSK-3β inhibition
🧪 Enhances autophagy and cellular clearance mechanisms (including in β-cells and neurons)
💡 Improves insulin signaling through PI3K/Akt and mTOR modulation
🔬 Supports β-cell survival and function (GSK-3β is also involved in β-cell apoptosis and dedifferentiation)
🧠 Lithium is known to increase GABA levels in the brain
Lithium has been shown to exhibit insulin-like actions, improving glucose regulation in patients on lithium therapy. This could indirectly support β-cell function by enhancing peripheral glucose uptake and reducing β-cell stress (2). This is largely attributed to lithium's impact on the glycogen synthase kinase-3 beta pathway (GSK-3β) .
GSK-3β is the real star in all of this. It is a key player in beta cell stress, autoimmunity and islet cell identity.
GSK-3β is a serine/threonine kinase that sits at the crossroads of multiple cellular signaling pathways, including:
Wnt/β-catenin signaling
Insulin and IGF-1 signaling
Inflammation (NF-κB activation)
Apoptosis and cell cycle regulation
Autophagy and mitochondrial function
In the context of T1D and beta cell stress:
Overactivation of GSK-3β promotes:
Beta cell apoptosis
Dedifferentiation of mature beta cells
Impaired insulin transcription
Increased inflammatory cytokine sensitivity
Thus, GSK-3β functions like a brake on regeneration and a promoter of dysfunction in stressed islets. Those with T1D have an islet cell dynamic locked into place. All brakes, no fluidity or resilience. Lithium is a non-competitive inhibitor of GSK-3β.
This inhibition leads to:
Stabilization of β-catenin, a co-activator that promotes gene transcription involved in:
Beta cell replication
Cell survival
Islet integrity
Suppression of NF-κB and proinflammatory cascades, which protects:
Beta cells from cytokine-induced damage
The islet environment from immune activation
Promotion of anti-apoptotic signals and improved ER stress tolerance, increasing beta cell resilience in the autoimmune terrain.
And this aligns beautifully with the current research looking into transdifferentiation as a means of addressing beta cell scarcity and alpha/beta cell balance. We talked about the newest research on harmine and its ability to induce transdifferentiation (alpha -> beta cell conversion) in another video.
GSK-3β inhibition (as through lithium) enhances the Wnt/β-catenin pathway, which has been shown to:
Promote islet cell plasticity
Support beta cell maturation
Encourage conversion of alpha cells to insulin-producing phenotypes
Lithium may foster an islet environment where alpha cells “step in” to rebuild the beta cell population. This alpha cell conversion helps in multiple ways: Not only do they stop overproducing glucagon and overstimulating glycogen release, they can also develop beta-like characteristics, essentially rebranding themselves as insulin producers.
Inhibiting GSK-3β with lithium may act like opening a gate: allowing dormant beta cells to recover, alpha cells to convert, and the autoimmune terrain to soften—setting the stage for islet rebalancing.
As if this wasn't exciting enough, lithium also impacts another facet of diabetes development.
🧠 Lithium, GABA, and Beta Cell Function
If you're like me, your knowledge of lithium comes from its use in mental health. I had only ever heard of lithium in the context of behavior and mood disorders. As it turns out, this is because of lithium's impact on the body's GABA production. GABA being a neurotransmitter responsible for influencing the nervous system's sympathetic/parasympathetic tone. Namely, GABA helps us relax.
GABA supports parasympathetic tone via:
Enhancing vagal input,
Modulating baroreflexes,
Promoting a “rest-and-digest” state which favors insulin secretion and digestive enzyme output.
And in the context of T1D, GABA isn’t just a neurotransmitter—it’s secreted by pancreatic beta cells, where it acts in a paracrine/autocrine manner:
Inhibits alpha cells, reducing glucagon secretion.
Stimulates beta cell replication, particularly during metabolic stress.
Supports immune tolerance—important in T1D.
This could be especially relevant in Type 1 and Type 2 diabetes, where sympathetic dominance and beta cell stress converge. Lithium may, therefore, promote metabolic harmony by reducing excitotoxicity, restoring vagal dominance, and supporting beta cell regeneration.
We talked about GABA's role in T1D here. GABA is greatly underproduced in those with T1D. The GAD autoantibody used in early T1D detection? That's glutamic acid decarboxylase. It's the enzymes responsible for converting the excitatory (and potentially toxic) glutamate into GABA. Ever wonder why all the people with T1D you know are chronic worriers, hyperactive and/or find it difficult to relax? That's a GABA deprived system.
The more I learned about lithium and its poetential impact on the diabetic state, the more all of these details started to fall in line.
Lithium removes the brakes on islet cell fluidity and resilience - This allows for alpha cells to reconfigure themselves to support (instead of oppose) the overtaxed and undernourished beta cells.
Lithium increases GABAergic tone - More GABA, and a more relaxed state, creates a bodily environment conducive to healthy beta cell signaling and more complete digestion.
Lithium has antioxidant capabilities - Upregulates superoxide dismutase (SOD) and glutathione peroxidase (GPx), downregulates NOX enzymes (reducing ROS production), increase Nrf2 expression (a master regulator of antioxidant response).
That's a lot of good from a single metal!
Lithium → ↑ GABA → ↑ Parasympathetic tone & Beta cell protection
Lithium → ↑ Nrf2 / SOD / GSH → ↓ Oxidative damage → Protection of iron-handling tissues like liver & brain
System | Lithium Effects |
Beta Cells | GABA stimulation, insulin-mimetic, reduced demand, possible replication support |
Parasympathetic | GABAergic tone increases vagal activity, supports insulin secretion & gut motility |
Cortisol/HPA | Indirectly lowers stress response via neuronal resilience and antioxidant support |
Iron Regulation | May alter iron efflux/storage, reduce systemic iron bioavailability, and buffer ROS |
Liver Health | Protects mitochondria, enhances antioxidant enzymes, may support iron recycling |
Brain Metabolism | Enhances glucose uptake, reduces tau hyperphosphorylation, inhibits amyloid seeding |
🧪 Additional Lithium Benefits Supporting T1D Healing Process
Lithium Effect | Impact on Islet Healing |
↑ GABA levels | Suppresses alpha cell glucagon, supports beta cell regeneration |
↑ BDNF, ↑ neurotrophic factors | Preserves islet innervation and autonomic signaling |
↓ NF-κB, ↓ IL-1β signaling | Lowers autoimmune “volume” in the islet microenvironment |
↑ β-catenin stabilization | Drives beta cell gene transcription and structural remodeling |
↑ PDX1 / MAFA expression | Maintains beta cell identity and insulin-producing phenotype |
↓ Tau hyperphosphorylation (brain & pancreas) | May preserve intracellular trafficking of insulin and GABA |
🔄 Integration into Metabolic Health
Now that we know what we know about lithium, how do we integrate it into our lives? Is it like any other supplement?
Low-dose lithium orotate (1–5 mg/day elemental lithium) may offer the neuroprotective and beta-cell stabilizing benefits without disrupting trace mineral homeostasis.
Combined with magnesium, zinc, NAC, and dietary GABA precursors, lithium could be part of a broader islet-healing strategy.
Timing may matter: Using lithium during periods of high regenerative signaling (e.g. after fasting, after GLP-1 agonist use, or during beta cell stress-reduction protocols) may help "lock in" improvements.
🕰️ 1. Timing & Dosing Strategy
Starting Dose:
Begin with 5 mg lithium orotate daily for 5–7 days.
Observe mood, digestion, sleep, and energy. Some people are sensitive to trace lithium and may notice subtle changes early.
Uptitration:
If no adverse effects are noted, increase to 10 mg lithium orotate daily, ideally providing ~1–2 mg elemental lithium (depending on brand).
When to Take It:
Best time: Early evening (~5–7 PM)
Supports parasympathetic tone, neurochemical balance before bed, and GSK-3β inhibition during peak melatonin activity.
May enhance GABAergic tone and sleep depth without causing sedation during the day.
Alternative timing (if fatigue occurs in the evening):
Mid-morning (~10–11 AM) with food—when cortisol has already peaked and you want a second-phase GABA/glucose balancing effect.
Avoid Taking:
With caffeine or high-stress events, as these can increase sympathetic output and mask lithium’s calming effects.
🧬 2. Expected Impacts (Weeks 1–6)
Time Frame | Expected Effects |
Week 1–2 | Improved calmness, mental clarity, GABAergic tone, and parasympathetic dominance |
Week 2–4 | Better sleep onset, potential reduction in blood glucose variability (if relevant) |
Week 4–6 | Improved stress resilience, subtle enhancement in neuroplasticity and cognition |
Beyond 6 wks | Possible support for islet repair, beta cell regeneration signaling, iron redistribution |
🔁 Subtle shifts may be more noticeable in glucose pattern stability, mood regulation, or sleep architecture before any physical symptom changes.
🧘♀️ 3. Supportive Pairings to Consider
To maximize lithium’s benefit and reduce toxicity risk, integrate these synergistic nutrients:
Compound | Purpose |
Magnesium glycinate/threonate (100–200 mg) | Buffers excitability, reduces tremor risk, co-inhibits GSK-3β |
Zinc (5–15 mg) | Supports GABA receptors and insulin packaging; balances trace minerals |
B6 (P5P, 10–20 mg) | Cofactor for GABA synthesis and neurotransmitter metabolism |
NAC or Glycine (600–1000 mg) | Enhances glutathione; supports liver, brain, and redox control |
Omega-3s (EPA/DHA) | Improves neuronal membrane fluidity and mood synergy with lithium |
🔬 4. Monitoring and Caution
While low-dose lithium orotate (≤10 mg) rarely causes toxicity, it’s still smart to monitor:
Watch for signs of sensitivity:
Muscle weakness
Tremor
Digestive disturbance
Head pressure or fogginess
Increased thirst or urination
If these occur, reduce dose or pause supplementation and ensure adequate hydration and electrolyte support (especially sodium, magnesium, and potassium).
Labs to Consider (after 6–8 weeks):
Serum lithium (optional): Rarely necessary with orotate, but can help confirm low/functional dose.
BUN/Creatinine, eGFR: To ensure no renal compromise.
TSH: Lithium can alter thyroid function in some sensitive individuals.
🔄 5. Cycling & Duration
Microdosing cycles may work well:
3 months on / 1 month off, or 5 days on / 2 days off, especially if using it for cognitive protection or islet support.
For chronic support (e.g. neurodegenerative risk): low-dose daily with breaks every 3–6 months.
**🧠 Bonus Consideration: Lithium + GLP-1 or GABA Stimulus
Combining lithium with natural GABA boosters (like taurine, glycine, magnesium, or fermented foods) may support beta cell protection and alpha-to-beta conversion.
Combining lithium with mild intermittent fasting or short-term ketogenic strategies may enhance Wnt signaling and autophagy, synergizing with lithium’s GSK-3β inhibition.
🤓 In Closing
For decades, lithium has been narrowly defined as a psychiatric stabilizer—a potent, often side-lined compound used in high doses for bipolar disorder. But emerging science is shifting that narrative. Lithium, at low physiological levels, may serve as a micronutrient-level modulator of resilience, working at the crossroads of neuroprotection, metabolic balance, and immune recalibration.
Recent research published in Nature (2025) reveals that endogenous lithium is significantly depleted in the brains of individuals with mild cognitive impairment and Alzheimer’s disease. The loss is not systemic—it’s localized, progressive, and most importantly, correlated with cognitive decline. Even more intriguing: lithium doesn’t just disappear; it gets trapped inside amyloid plaques, potentially starving neurons of a key regulatory signal that normally supports memory, synaptic plasticity, and antioxidant defenses.
But what does this mean for type 1 diabetes?
The answer lies in a shared biology of stress, degeneration, and regeneration. Lithium inhibits GSK-3β, a kinase involved not only in Alzheimer’s pathology, but in beta cell dysfunction, inflammatory signaling, and islet de-differentiation. Inhibiting this enzyme helps preserve beta cell identity, enhances alpha-to-beta cell transdifferentiation, and may activate the very regenerative programs needed to restore balance in the pancreatic islets of those with T1D.
Add to that lithium’s effects on:
GABA signaling, which calms the nervous system and supports beta cell replication,
Parasympathetic tone, which enhances insulin secretion and gut-resting states,
And antioxidant defenses, which protect vulnerable tissues like the brain, liver, and pancreas—
—and you begin to see lithium not as a blunt psychiatric tool, but as a subtle terrain shaper—a mineral that whispers rather than shouts.
Used at low doses, and paired with the right cofactors (like magnesium, zinc, omega-3s, and thymic peptides like Thymalin), lithium may become a foundational ally in rebalancing the inflammatory, neural, and metabolic chaos that defines both Alzheimer’s and autoimmune diabetes.
We aren’t suggesting a miracle cure—but we are opening the door to a radically expanded view of healing. One where trace minerals, neurological balance, and immune re-education aren’t separate silos—but synchronized steps in restoring the body’s internal dialogue.
Because sometimes, the keys to healing aren’t locked behind patents or protocols—they’re already within us, waiting to be freed.
Reading Material:
🧠 Lithium & Alzheimer’s Disease (AD)
1. Endogenous Lithium Deficiency in AD
Source: Nature (2025)
Title: Endogenous lithium depletion and sequestration in Alzheimer’s disease
Summary: Demonstrated that lithium is sequestered in amyloid plaques and significantly depleted in the prefrontal cortex of individuals with MCI and AD. This correlated with cognitive decline.
2. Lithium Inhibits GSK-3β in Alzheimer’s Context
Jope RS, et al. (2007). GSK3: a key player in neurodegeneration and mood disorders.
PubMed
Lithium inhibits GSK-3β, reducing tau phosphorylation and Aβ aggregation.
🔁 Lithium, GSK-3β, and Beta Cell Health
3. GSK-3β Inhibition in Islets & Beta Cell Function
Liu Y, et al. (2010). GSK-3β is involved in islet β-cell proliferation through modulating Wnt/β-catenin signaling.
PubMed
Wnt/β-catenin signaling via GSK-3β inhibition improves beta cell proliferation.
4. Lithium and Alpha-to-Beta Cell Transdifferentiation
Thorel F, et al. (2010). Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.
PubMed
GSK-3β inhibition supports islet plasticity required for this transdifferentiation.
🧪 Lithium and GABA Regulation
5. Lithium Enhances GABA Signaling
Moore GJ, et al. (2000). Lithium increases cortical GABA levels in humans: a proton magnetic resonance spectroscopy study.
PubMed
Lithium increases brain GABA, stabilizing mood and parasympathetic tone.
6. GABA in Islet Function
Soltani N, et al. (2011). GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.
PubMed
GABA enhances beta cell replication and suppresses alpha cell glucagon secretion.
💉 Lithium and Beta Cell Protection
7. Lithium Promotes Beta Cell Survival
Cornu M, et al. (2005). Beta-cell proliferation is increased by GSK-3β inhibition through an mTOR-independent pathway.
PubMed
Highlights the importance of GSK-3β inhibition (via lithium) in promoting beta cell growth.
🔄 Diabetes and Alzheimer’s Connection
8. T1D and Increased Dementia Risk
Rawlings AM, et al. (2014). Diabetes in midlife and cognitive change over 20 years.
PubMed
T1D and T2D both linked to increased risk of cognitive decline and dementia.
9. Amylin Aggregation in AD
Jackson K, et al. (2013). Amylin deposition in the brain: a second amyloid in Alzheimer’s disease?
PubMed
Amylin (co-secreted with insulin) forms amyloid deposits in brains of AD patients, contributing to pathology.
🧲 Lithium and Iron Homeostasis
10. Lithium’s Influence on Iron Metabolism
Khan MM, et al. (2012). Neuroprotective effects of lithium in neurological disorders.
PubMed
Discusses lithium’s complex interactions with tau, iron retention, and neurotoxicity prevention.
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