Ask a firefighter if you can put out a blaze by only tackling the smoke, and not the flames themselves, and you can imagine their response.
Yet this is the same situation neurologists have been facing for decades when treating Alzheimer’s disease: merely being able to temporarily treat the ‘smoke’ of the disease – the symptoms.
I have been a neurologist for more than 40 years, and specialise in treating people with Alzheimer’s and other neurodegenerative diseases.
When I lecture around the world about the ‘smoke, not fire’ challenge, people ask me about the slow pace of research to find an effective treatment.
Why, they ask, if drug companies have been pouring billions of dollars into Alzheimer’s research, have scientists not yet found something to cure, or even prevent, this pernicious disease?
The short answer I believe is because researchers have been focused on the wrong issue when it comes to Alzheimer’s.
We have been told effective treatment for the disease requires the removal of beta- amyloid plaques in the brain that are common in patients.
But while beta-amyloid plaques do contribute to Alzheimer’s, by increasing inflammation, they are not the root cause of it.
Dr David Perlmutter, a neurologist for more than 40 years, says researchers have been focusing on the wrong area when trying to treat Alzheimer’s
Dr Perlmutter argues the fundamental cause of Alzheimer’s lies in the activation of the brain’s specialised resident immune cells, called the microglia
Instead – as I discuss in my new book, Brain Defenders: Harness The Power Of Your Immune Cells To Protect Your Brain For Life – the fundamental cause of Alzheimer’s almost certainly lies elsewhere: in the activation of the brain’s specialised resident immune cells, called the microglia. They clean up dead cells, fight infections and help keep brain tissue healthy.
But studies also show that chronic (rather than acute, i.e. short term) activation of these immune cells by, for example, having type 2 diabetes or obesity – can drive increased beta-amyloid production, as well as impair its clearance.
So beta-amyloid build-up in Alzheimer’s patients is a consequence of the behaviour of the microglia – and research, then, should have been focusing on ways to target this behaviour as a way to treat the condition effectively.
Yet the ‘amyloid hypothesis’, as it is known, continues to wield incredible influence – something I find shocking considering the often serious side-effects caused by the medications created to ‘treat’ amyloid plaques, including brain bleeds and swelling.
Indeed, the dominance of the amyloid hypothesis means not one single medication available for Alzheimer’s treats the underlying disease process.
For example, drugs such as Aricept or Exelon – known as cholinesterase inhibitors and first developed in the 1990s – are commonly given to people who receive an Alzheimer’s diagnosis.
They might boost cognitive function in the short term, but only give patients and families temporary relief, at most, while Alzheimer’s continues to ravage the brain.
It’s a similar story with the newer drugs. Take lecanemab, a monoclonal antibody that clears beta-amyloid: in an 18-month trial it was shown to slow cognitive decline by 27 per cent.
Medications such as lecanemab do not stop the progression of Alzheimer’s – they only slow it down
This sounds promising, but only until we look more closely at the numbers. The patients’ ‘before’ and ‘after’ cognition was measured on an 18-point scale. The difference between the two was less than half a point – a change so small that it is unlikely to be noticeable in daily life.
In real terms, lecanemab does not in any way stop Alzheimer’s progression. It only slows down the decline, minimally at best, according to a 2023 report in the New England Journal of Medicine.
According to a 2026 evaluation of studies, by the respected Cochrane group, amyloid-targeting drugs probably make little to no difference in the decline of memory and thinking, or the ability to manage everyday activities.
Focusing on beta-amyloid, then, seems to be tragically myopic. Yet this approach is still so popular – which I would argue is largely because it is hugely profitable for drug development and sales. But I feel so strongly that the worldwide neurological establishment needs to now focus its combined efforts on microglia.
Not least because as the research accumulates, exciting evidence has emerged that the behaviour of your microglia can be positively influenced through a combination of lifestyle changes, dietary supplements and certain medications – fascinatingly, HRT is among them (see box, above right) – thus reducing your chances of developing Alzheimer’s.
To understand how we can achieve this, we need first to understand how the microglia work.
Microglia, which account for around 5-10 per cent of our total brain cells, play a pivotal role in brain function. Like all immune cells, they react to incoming threats and pathogens to protect us. But what makes microglia unique is their ability to dramatically change shape and function.
One shape is the ‘friendly’ version of microglia, known as the M2 phenotype – or, as I’ve dubbed it, the ‘good twin’. The other is the ‘evil twin’ – or the M1 phenotype.
Microglia respond aggressively and negatively to a diet high in sugar and ultra-processed foods (UPFs) – with a strong association between a high-UPF diet and significantly increased risk for cognitive decline
The good microglia, M2, can be best thought of like a friend who can fix anything, owns all the best tools, cleans like a professional and truly listens and responds appropriately when you answer their question: ‘Are you OK?’ We are fortunate to have billions of these friends in our brains right now.
M2 cells on patrol are constantly vibrating, their long arms reaching out and waving in order to detect the presence of potential threats – including harmful viruses or cellular waste – and sweep them out. They also pick up signals from nearby injured or dying neurons (nerve cells in the brain) and synapses (tiny junctions between neurons through which electrical messages pass).
After identifying damaged neurons or synapses, M2 cells move in to clear them out, create space and redirect nutrients to facilitate new growth. M2 also gets rid of misfolded proteins (like beta-amyloid) or damaged and ageing cells that can release harmful inflammatory chemicals if left unchecked.
Beyond caretaking, housekeeping, gardening and diagnosis, M2 microglia play a central role as a mechanic, triggering the release of molecules that support neuron growth and orchestrate the repair of synapses and brain tissue.
As all-purpose helpers and healers, they truly are our brain’s defenders. But M2 microglia can also shape-shift into its evil twin, M1, which can behave in a far more destructive fashion.
Once activated, these microglia cells retract their spidery arms, allowing them to move quickly toward their target.
When on the offensive, M1 microglia cells strip away not only compromised synapses but also perfectly functional ones critical for learning and memory.
In doing so, they flood the surrounding environment with inflammatory chemicals, creating a toxic milieu that places otherwise healthy neurons at risk of injury or death.
This shift from M2 to M1 transforms microglia into agents of damage, accelerating cognitive decline and neurodegeneration.
Why does our body harbour such damaging cells, you might wonder? Well, M1 microglia exist to protect the brain against assaults such as infection, trauma and toxicity. A short burst of them can limit damage and help with repairs, like a controlled wildfire.
The problem is, once these M1 microglia are formed, they can get stuck in this state. Under certain biological conditions – more of which later – it’s difficult to revert them to the kinder, gentler M2 type.
And once a brain tips into having too many M1s, problems ensue. Ongoing inflammation, like smouldering embers that never go out, slowly sizzles the brain, consuming neurons and synapses. This is what makes M1 cells dangerous for our brain health.
For example, having the right number of healthy synapses in our brain means normal communication between neurons. But while M2 clears just the dead wood, M1 goes after healthy synapses, too.
Research indicates the early stages of Alzheimer’s are marked by a measurable reduction in synaptic density, which correlates with cognitive decline. The loss of synapses is a central feature of the disease, and it’s caused by unregulated M1 attacks.
As I mentioned, there are several biological and physical situations that turn M2 cells into M1 cells – and keep them stuck there.
Most prominent is the impact of metabolic conditions such as obesity and type 2 diabetes.
This is because they lead to a state of chronic inflammation that releases harmful inflammatory cytokines throughout the body, with the eventual cause being that microglia are kept in the destructive M1 state.
You could see it like this: an obese or diabetic body is constantly whispering to the brain’s immune cells that something is wrong. Over time, this relentless low-grade ‘alarm signal’ activates our microglial cells.
The links between cognitive decline and insulin resistance (where the cells are no longer as responsive to insulin, so glucose levels build up in the blood) are so significant that some researchers have dubbed Alzheimer’s ‘type 3 diabetes’.
Indeed, in a 2023 study in the Journal of Cerebral Blood Flow & Metabolism, researchers gave brain scans to 60 people (average age 69) and found that higher levels of insulin resistance was associated with elevated levels of translocator protein – which is a telltale internal marker of the shift of microglial cells to the dangerous M1 state.
It should come as no surprise, then, that microglia, so highly influenced by our metabolic health, would respond aggressively and negatively to a diet high in sugar and ultra-processed foods (UPFs) – with a strong association between a high-UPF diet and significantly increased risk for cognitive decline.
Research published in JAMA Neurology in 2022 followed more than 10,000 individuals for an average of eight years.
Those who consumed higher UPFs experienced a staggering 28 per cent increased rate of global cognitive decline (meaning all areas of decline, including memory, language abilities and attention), compared to those who ate the least.
Another study, published in 2021 using data from the landmark Framingham Heart Study, followed participants for nearly two decades and found that the risk of Alzheimer’s was more than two-and-a-half times higher among those consuming the most sugary beverages, compared with those consuming none, reported The Journal of Prevention of Alzheimer’s Disease.
Artificial sweeteners are no better for you than sugar – proven to lead to insulin resistance and metabolic syndrome (a group of conditions that include high blood pressure and obesity), posing a direct threat to the microglial cells and helping to turn M2 friends into M1 foes.
So great a threat do they pose, that I recommend everyone gives up sweetened drinks entirely, immediately (they simply pose too great a risk to your gut microbiome and thus, your microglia), because a deficient gut microbiome has been proven to provoke inflammatory symptoms in your brain.
As for booze, there is research which says no amount is safe for your brain. Studies have consistently linked chronic alcohol use to microglial activation and neuroinflammation.
In a 2024 Science Advances study, researchers examined human microglial cells’ responses to alcohol. They found exposure triggered clear signs of microglial activation – including an increase in one of M1’s chemical markers and noticeable physical changes into the M1 amoeboid shape.
And a 2018 study found that microglia exposed to binge-level alcohol for 24 hours showed a 15 per cent decrease in their ability to clear out beta-amyloid.
Antibiotics, too, have been linked to M1 activation.
Think of antibiotics as a kind of microbial carpet bomb. Yes, they take out the ‘bad guys’ of an infection, but they also decimate the beneficial bacteria that help keep your gut ecosystem in balance.
This in turn promotes a pro- inflammatory state in the gut, which signals the immune system – including microglia way up in the brain – to respond.
Long-term or frequent antibiotic use in adulthood has been associated with measurable changes in cognitive function.
In a 2021 study in Frontiers in Pharmacology, researchers analysed data from more than 313,000 Korean adults. Those who used antibiotics for 91 days or more were significantly more likely to develop dementia – including Alzheimer’s and vascular dementia – compared to non-users.
In another striking study, Harvard researchers followed more than 14,000 women (average age 57) who reported whether they’d taken antibiotics for at least two months in midlife. Seven years later, cognitive testing revealed that the women who had used antibiotics performed worse on memory and attention assessments than those who had not.
Commonly used drugs to tackle heartburn called proton pump inhibitors (PPIs), including omeprazole and lansoprazole, have also been linked to dubious effects on your microglia. This is because PPIs destabilise the gut wall, increasing gut permeability.
Put simply, a leaky gut allows inflammatory chemicals to enter the bloodstream. From there, they get into the brain, and aggressively shift M2 cells to damaging M1s.
This may well explain the higher risk for Alzheimer’s in those using PPI drugs very regularly.
In a 2022 study, researchers followed half a million individuals for nine years, and showed dementia risk was increased by 20 per cent – and Alzheimer’s risk by 23 per cent – in PPI users, compared to non-users.
Of course, you should always consult your doctor before stopping any prescribed medication, but if you regularly take over-the-counter PPIs without pausing to think whether you really need them, perhaps now you will.
Chronic infections, too, can contribute to microglia sticking in an M1 state.
Even seemingly innocuous microbes can become formidable threats to brain health. A compelling example is P. gingivalis, a key pathogen in periodontal disease.
While often confined to the mouth, this bacterium can cross into the brain.
Notably, it has been identified in the brains of individuals with Alzheimer’s. Laboratory studies show exposure of microglia to P. gingivalis leads to a marked increase in the production of pro-inflammatory cytokines.
This inflammatory cascade not only threatens neurons but also promotes the accumulation of Alzheimer’s-related proteins. These findings indicate that chronic oral infections may play an important role in brain degeneration by threatening our brain defenders, driving microglial activation and neuroinflammation.
A more mundane link is to the cold sore virus: herpes simplex virus type 1 (HSV-1). This can lie dormant in the body for years. Occasionally, it reactivates and, in some people, may reach the brain.
Once HSV-1 enters the central nervous system, microglia recognise the viral presence and immediately begin producing inflammatory mediators.
Essentially, whenever the virus reactivates, it nudges microglia toward M1 neuron-damaging behaviour.
All this said, we cannot ignore one of the biggest threats to microglia: ageing.
As the years go by, microglia become less agile. Their once-elaborate branching structures retract; and their surveillance and repair functions decline.
As a 2017 Frontiers in Aging Neuroscience report put it: ‘Age-dependent senescence [or cell death]-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases.’
But we should still take heart that there are practical measures we can take to help negate the impact of ageing and other factors such as infections on our microglia.
A fibre-rich, low-UPF diet to improve our gut health is an obvious one – as is regular exercise.
There is also increasing evidence for the targeted use of dietary supplements and other medication to aid our microglia.
And as I’ll reveal next week, in the second part of this serialisation, some of these treatments are far more everyday than you might imagine…
Studies that persuade me HRT can protect women’s brains
Women are twice as likely to be diagnosed with Alzheimer’s as men, a mystery that has perplexed experts in the field of neurology for decades. But thanks to new insights about our microglia friends and foes, we finally have an explanation.
A fascinating 2022 study published in Science Advances found the drop in oestrogen that accompanies menopause sends a signal to the brain to up the production of a protein called C3, which is part of the brain’s immune system.
This protein signals to M1 to start digesting the brain’s synapses.
Oestrogen exerts other brain-protective effects. It reduces microglial pro-inflammatory cytokine production and shifts microglia toward their supportive M2 state. The impact of its drop, then, is clear.
These new findings help explain why oestrogen therapy is being aggressively investigated in Alzheimer’s.
Having reviewed these studies, I find myself on the side of those who support the use of hormone replacement therapy (HRT) for Alzheimer’s prevention in women. Research makes a strong argument in favour of starting HRT early, within the first five years of menopause, to reduce Alzheimer’s risk.
Women who begin oestrogen therapy in midlife demonstrate a 32 per cent risk reduction for dementia, according to a 2023 study of more than six million participants by Weill Cornell Medicine in New York. Women beginning oestrogen later in life appeared to derive no benefit in terms of dementia risk.
It’s certainly worth the time and effort to talk to your doctor about HRT if you haven’t already. (And next week I’ll reveal treatments that work for women and men.)
Adapted from Brain Defenders, by David Perlmutter (Yellow Kite, £18.99), to be published August 27. © David Perlmutter 2026. To order a copy for £17.09 (offer valid to 31/08/26; UK P&P free on orders over £25) go to mailshop.co.uk/books or call 020 3176 2937