New research suggests that Alzheimer’s disease may involve more than the accumulation of amyloid plaques and tau proteins. The brain’s ability to produce, share and adapt its energy supply could be another important piece of the puzzle.
When we think about Alzheimer’s disease, we tend to think about memory loss, amyloid plaques and tau tangles. These abnormal proteins have dominated Alzheimer’s research for decades.
But what if another important part of the story is the brain’s ability to generate and use energy?
A fascinating review published in the Journal of Neurochemistry in 2025 explores exactly this question. The researchers propose that Alzheimer’s may be better understood, in part, as a disorder of metabolic inflexibility — where brain cells progressively lose their ability to adapt to changing energy demands.
This is an important concept because it helps explain why metabolic health, inflammation, mitochondrial function and vascular health are all so relevant to cognitive ageing.
And perhaps most importantly, these changes may begin many years before someone notices problems with their memory.
Your brain is an energy-hungry organ
Although the brain accounts for only around 2% of our body weight, it uses approximately 20% of our body’s energy.
Every thought, memory, movement and conversation depends on a constant supply of energy.
Glucose is the brain’s primary fuel, but the brain is far more adaptable than we might imagine. Different brain cells can also use other energy sources, including lactate and ketones, depending on their needs and availability.
Healthy brain function relies on an extraordinary level of cooperation between neurons, supporting cells known as glia, and the blood vessels supplying nutrients and oxygen.
These cells don’t simply work independently. They share resources, communicate and adjust their metabolism to support one another.
This ability to adapt is known as metabolic flexibility.
Think of it as a hybrid car that can switch between different energy sources depending on the conditions. When one source becomes less available, the system can adapt to maintain performance.
But what happens when that flexibility begins to disappear?
Alzheimer’s may begin with metabolic disruption, not simply energy failure
One of the most interesting ideas explored in this review is that Alzheimer’s disease may involve two broad phases of metabolic dysfunction.
Phase 1: The brain becomes metabolically overactive
In the early stages of Alzheimer’s pathology, sometimes 15–20 years before cognitive symptoms appear, certain brain cells may actually become more metabolically active.
This sounds positive, but the increased activity isn’t necessarily supporting healthy brain function.
Microglia, the brain’s resident immune cells, become activated in response to changes associated with Alzheimer’s pathology.
Initially, this response may be protective. However, when activation becomes prolonged, these cells can shift their metabolism towards supporting inflammatory processes.
Energy and metabolic resources are increasingly directed towards the immune response rather than the normal maintenance and support of neurons.
The brain is still metabolically active, but its energy is not necessarily being used efficiently.
Phase 2: The brain begins to experience energy failure
Over time, these compensatory mechanisms may become less effective.
Communication between different brain cells deteriorates, mitochondrial function becomes disrupted and the ability to deliver and use energy declines.
This later phase is characterised by hypometabolism — reduced metabolic activity in affected brain regions.
Reduced glucose metabolism is already a well-recognised feature of Alzheimer’s disease and can be detected using specialised brain imaging such as FDG-PET.
As energy production and neuronal support decline, problems with memory, communication between brain networks and other cognitive functions become increasingly apparent.
The researchers suggest that the transition from early metabolic overactivity to later energy failure may be an important part of Alzheimer’s progression.
This is a proposed model drawn from several lines of research, rather than a sequence established in every person with Alzheimer’s disease.
The surprising role of inflammation
We often discuss inflammation in relation to cardiovascular disease, autoimmune conditions and metabolic health.
But inflammation also plays a complex role in the brain.
Microglia are essential for maintaining a healthy brain. They help clear cellular debris, respond to injury and support normal immune surveillance.
However, when these cells remain persistently activated, their metabolism changes.
The review describes how disease-associated microglia increasingly rely on glycolysis, a process that breaks down glucose to provide energy for cellular activity.
This shift can support inflammatory responses, but may also interfere with the metabolic cooperation needed to maintain healthy neurons.
Over time, inflammation, oxidative stress, mitochondrial dysfunction and abnormal protein accumulation may reinforce one another.
This creates a potentially damaging cycle in which Alzheimer’s pathology and metabolic dysfunction contribute to each other’s progression.
Importantly, this doesn’t mean that all inflammation is harmful or that reducing inflammation alone will prevent dementia.
It does, however, highlight why understanding the wider inflammatory and metabolic environment may be valuable when considering long-term brain health.
What about insulin resistance and blood sugar?
The relationship between metabolic health and dementia has attracted increasing attention.
We know that type 2 diabetes and several cardiometabolic conditions are associated with an increased risk of cognitive decline and dementia.
But the relationship is more complex than simply having too much glucose in the bloodstream.
Most glucose uptake in the brain does not depend directly on insulin. Nevertheless, insulin signalling, blood vessel function, glucose transport and mitochondrial activity all influence how effectively brain cells obtain and use energy.
The researchers explain how systemic insulin resistance may contribute to changes in brain fuel availability, inflammatory signalling and cellular metabolism.
This is why looking at metabolic health can be relevant even in people who have never been diagnosed with diabetes.
At CogMission, we are particularly interested in understanding patterns of glucose regulation, insulin resistance and broader cardiometabolic health as part of an individualised brain-health assessment.
The aim isn’t simply to identify whether someone has diabetes, but to understand their wider metabolic risk profile and identify opportunities for improvement.
Could alternative fuels help the brain?
One of the most fascinating aspects of brain metabolism is its ability to use alternative energy sources.
Although glucose is the primary fuel, the brain can also use ketones, which are produced mainly by the liver during periods of reduced carbohydrate availability.
Ketones can cross the blood–brain barrier and provide an additional energy source for brain cells.
This has generated considerable interest in ketogenic approaches, ketone supplementation and other interventions designed to support brain energy metabolism.
The review highlights these as promising areas of investigation, particularly where glucose metabolism is impaired.
However, the research is still evolving. We cannot conclude that a ketogenic diet prevents Alzheimer’s disease or that ketone supplementation is appropriate for everyone.
The broader principle is particularly interesting: supporting the brain’s ability to access and use energy efficiently may offer an additional avenue for protecting cognitive function.
Why sleep and vascular health matter too
Brain metabolism doesn’t operate independently of the rest of the body.
The brain relies on healthy blood vessels to deliver oxygen and nutrients, and on coordinated cellular activity to maintain its energy supply.
When vascular function is impaired, the brain may struggle to match energy delivery with demand.
The review also explores how metabolic inflexibility may contribute to disrupted neuronal activity, altered brain network connectivity and sleep disturbances.
These relationships can become self-reinforcing, with metabolic disruption affecting brain function and changes in brain activity potentially contributing to further metabolic stress.
This reinforces the importance of looking at brain health as a whole-body issue rather than focusing on memory alone.
What does this mean for dementia prevention?
Perhaps the most encouraging aspect of this research is the possibility that metabolic dysfunction could become an important therapeutic target.
The authors discuss emerging treatments aimed at improving glucose metabolism, mitochondrial function, lipid handling and other aspects of brain energy regulation.
Clinical trials are already investigating several metabolic approaches, although we still need more evidence to establish which interventions are effective, for whom and at what stage of disease.
This paper is a scientific review, not a clinical trial demonstrating that restoring metabolic flexibility reverses Alzheimer’s disease.
Nevertheless, it adds to a growing body of research suggesting that the metabolic environment of the brain deserves far greater attention.
At CogMission, this fits closely with our approach to personalised dementia prevention.
Rather than considering cognitive health in isolation, we look at the wider factors that may influence how the brain functions and ages.
Depending on someone’s individual history and risk factors, this may include:
- Glucose and insulin regulation, to identify metabolic disturbances that may affect long-term brain health.
- Cardiovascular and vascular health, including blood pressure, lipid patterns and circulation.
- Inflammatory health, exploring potential contributors to persistent inflammation.
- Nutrition and physical activity, supporting metabolic health, cardiovascular function and healthy ageing.
- Sleep and circadian rhythms, recognising their importance for cognitive and metabolic function.
- Cognitive assessment, helping identify changes in memory and other areas of brain function.
Not everyone needs extensive investigations, and no single blood test can measure all aspects of brain metabolic flexibility.
The value lies in understanding the individual and identifying modifiable factors that may be contributing to their overall risk.
Looking beyond amyloid and tau
Amyloid and tau remain important features of Alzheimer’s disease, and research targeting these proteins continues to advance.
But Alzheimer’s is an extraordinarily complex condition.
This review reminds us that brain cells depend on much more than the absence of abnormal proteins. They need a reliable energy supply, healthy mitochondria, functioning blood vessels, appropriate immune responses and effective communication with neighbouring cells.
When these systems begin to lose their ability to adapt, the consequences may extend far beyond energy production.
The brain doesn’t simply need fuel. It needs the flexibility to use that fuel effectively.
For me, this is one of the most important messages emerging from the research.
If metabolic changes are developing many years before memory symptoms become apparent, we have good reason to pay attention to metabolic health much earlier in life.
We cannot yet say that correcting these changes will prevent or reverse Alzheimer’s disease. But supporting established, modifiable risk factors remains a valuable part of protecting long-term cognitive health.
And that is precisely why dementia prevention should begin long before memory problems appear.
Taking a proactive approach to brain health
At CogMission, we believe that understanding your individual risk factors is an important first step towards protecting your cognitive health.
Our personalised approach considers metabolic, vascular, inflammatory, nutritional and lifestyle factors alongside cognitive function, helping identify opportunities to support long-term brain resilience.
Whether you’re concerned about your memory, have a family history of dementia or simply want to take a more proactive approach to healthy brain ageing, we’re here to help.
Find out more at www.cogmission.co.uk.
Research reference
Constantino, N. J., Ashley, C. C. & Macauley, S. L. (2025). The Energetic Collapse of the Alzheimer’s Brain: Metabolic Inflexibility Across Cells and Networks. Journal of Neurochemistry, 169, e70294.