Excess brain lactate may modify tau — and that has practical implications for metabolic brain care.

Jan 23

Excess brain lactate may modify tau — and that has practical implications for metabolic brain care.

Most people think of lactate as a “workout byproduct”, you know that sore muscle feeling after you do a leg day at the gym. In reality, lactate is a normal and essential metabolite in the brain—used as fuel and involved in signaling.

What’s shifting in the Alzheimer’s research landscape is the idea that chronically elevated lactate in the brain may be more than a marker of metabolic stress. It may actively participate in pathology.

A December 2024 paper by Zhang and colleagues, Lactylation of tau in human Alzheimer’s disease brains (Alzheimer’s & Dementia), highlights a mechanism that helps connect metabolic dysfunction → tau toxicity.

The key idea in plain language: lactate can “tag” tau.

You may be asking, remind me what tau is? Tau is a structural protein that helps stabilize neuronal “tracks” (microtubules). In Alzheimer’s disease (AD), tau can become abnormal—misfold, fragment, and aggregate—contributing to neurodegeneration.

Zhang et al. describe a chemical modification called lactylation, where lactate-derived groups attach to proteins. In AD brain samples, they report elevated tau lactylation, with a particularly prominent site (K331).

In experimental models, they found that lactate can induce tau lactylation and that this was associated with downstream changes that are concerning in Alzheimer’s biology:

increased tau phosphorylation
increased tau cleavage (fragmentation)
reduced ubiquitination (a key “tag” cells use to send proteins for disposal and cleanup)

They also identify the acetyltransferase p300 as a catalyst for tau lactylation and show that reducing lactate production can reduce tau lactylation in models.

Why this matters for patients? It strengthens the concept that Alzheimer’s risk and progression are deeply connected to brain energy metabolism—not only the amyloid and tau as isolated “protein problems,” that we have been treating for so long, but the metabolic environment that pushes those proteins toward toxicity.

Where ketogenic metabolic therapy fits

Ketogenic metabolic therapy (KMT) is not a claim of “curing Alzheimer’s.” But it is a clinically relevant strategy for shifting fuel utilization away from heavy reliance on glucose-driven glycolysis toward fatty acid oxidation and ketone utilization—and that shift can reduce glycolytic flux, which is upstream of lactate production. In functional medicine we are always thinking about what is happening upstream.

Several lines of evidence support this “lower glycolysis / lower lactate” direction in ketogenic states:

In human exercise physiology, nutritional ketosis and/or ketone strategies have been shown to reduce glycolysis and lower blood lactate under certain conditions.
In preclinical brain metabolism work, a ketogenic diet environment has been associated with lower baseline lactate and reduced lactate production rate in astrocytes.
Mechanistically, ketone bodies may reduce glycolytic flow through feedback effects related to cellular energy state and redox balance (among other pathways).

This matters because the Zhang paper suggests lactate is not only “present when things go wrong,” but may be part of the biochemical chain that makes tau more harmful.

Here are three practical steps to reduce lactate production using ketogenic metabolic therapy:

1) Establish consistent nutritional ketosis (reduce glycolytic load at the source)

The most direct lever for lactate production is the amount of glucose traffic moving through glycolysis.

How to implement? Her is the general framework:

Set a low carbohydrate target (commonly individualized; many therapeutic approaches start in the ~20–50 g/day net carb range).
Maintain adequate protein (not “high protein” by default, but sufficient to preserve lean mass). This can vary by age, gender and physical activity.
Use higher-quality fats to meet energy needs (e.g., olive oil, avocado, nuts/seeds as tolerated, wild caught fatty fish, pasture-raised options), individualized to lipid profile and GI tolerance.
Track response using glucose + ketones, not just diet “compliance.” Many patients benefit from periodic checks of fasting glucose and morning ketones to ensure the metabolic shift is happening. Keto-Mojo is great for this!

Why it helps: nutritional ketosis reduces reliance on rapid glycolysis, which can translate into lower lactate generation in many contexts.

2) Use meal timing to “quiet” glycolysis (especially in the evening)

Even with a ketogenic food pattern, timing matters—because late eating and frequent snacking can keep glucose/insulin signaling higher and metabolic flexibility lower.

Practical implementation:

Consider a 12–14 hour overnight fasting window most days (individualized; not appropriate for everyone).
Aim for earlier dinners, by 4pm if possible and avoid late-night grazing.
For some patients, two meals/day (without snacking) improves stability—when clinically appropriate and well tolerated.

Why it helps: fewer post-meal glucose surges generally means less glycolytic throughput, which may reduce lactate pressure over the 24-hour cycle.

3) Improve mitochondrial “throughput” so pyruvate is burned—not fermented to lactate

Lactate rises when glycolysis outpaces mitochondrial oxidation (or when oxygen delivery/utilization is impaired). KMT is stronger when paired with interventions that build oxidative capacity.

Practical implementation:

Add Zone 2 aerobic training (e.g., brisk incline walking, cycling) most days of the week, starting small and building gradually. Examples include:

Cycling 30 minutes at 12–16 mph
Walking 30 minutes at 3.2-4.2mph, can add incline at 4-12%
Running 20-45 minutes at 5.0-6.5mph
Hiking 45-90 minutes 2.0-3.5mph depending on terrain and elevation
Rowing 20-45 minutes 18-22 strokes/minute
Swimming 2:00-3:00 minutes per 100m for 20-40 minutes

Include resistance training 2–3x/week to improve insulin sensitivity and metabolic flexibility.
Prioritize sleep quality and breathing/oxygenation (screen for sleep apnea when indicated). Poor sleep and hypoxia can worsen metabolic stress and push the system toward higher lactate.

Why it helps? Improved oxidative metabolism supports using fuels efficiently and it reduces the tendency to divert carbon into lactate. The literature on brain metabolism supports that ketone availability can shift cellular energetics and reduce glycolytic flow.

The Zhang paper does not say “lactate causes Alzheimer’s,” nor does it prove that lowering lactate will prevent dementia. But it does something clinically valuable: it tightens the link between metabolic dysfunction and tau pathology through a specific biochemical modification—tau lactylation.

For patients, this can be empowering: brain health is not only about genetics or aging—it is also about the metabolic environment we can influence through nutrition, timing, movement, sleep, and targeted metabolic therapy.

Medical note: KMT should be individualized and supervised when used therapeutically—especially for patients on glucose-lowering medications, with kidney disease, pregnancy, eating disorder history, or other complex conditions.

Source

Zhang et al. “Lactylation of tau in human Alzheimer’s disease brains,” Alzheimer’s & Dementia (Epub Dec 30, 2024). Findings summarized from the abstract: elevated tau lactylation (notably K331), lactate-induced tau lactylation increasing phosphorylation/cleavage and reducing ubiquitination; p300 catalysis; lowering lactate production reduced tau lactylation.

Shana Balaguera