Illustration by the wonderful Kerry Squires

According to a report from the Centers for Disease Control and Prevention (CDC) published this autumn, the number of people in the US suffering from Alzheimer’s will almost triple in the space of 40 years, from 5 to almost 14 million. People are now surviving diseases such as cancer and heart disease thanks to ever-advancing developments in healthcare, and more are living into old age. With a larger elderly population, the number of people going on to develop Alzheimer’s also increases.

Is this an inevitability we have to accept? Is the slow decline into Alzheimer’s inevitable, or is there something we can do to avoid it?

How do we develop Alzheimer’s?

Whether through its prevalence in the media or knowing a friend or relative suffering from the disease, most people are familiar with the symptoms of Alzheimer’s: a deterioration of cognitive function and memory loss. Stories become repeated, names of loved ones eventually vanish. These symptoms are associated with a build up of protein inside brain cells called tau tangles, or outside them as amyloid-beta plaques. They develop as a consequence of your body protecting itself from bad things. These responses fall into three groups(1):

  • An inflammatory subtype. Inflammation is a bodily response to things like illness or injury, and is characterised by heightened levels of inflammatory signalling molecules called cytokines.
  • An atrophic subtype. This means low levels of the molecules your brain needs to form synaptic connections between neurons (e.g. nerve growth factor, testosterone, vitamin D), meaning your neural network cannot be sustained as it should.
  • A cortical subtype. This one relates to environmental toxins like heavy metals and toxic moulds.

The possession of a single gene, called APOE4, has been consistently associated with the development of Alzheimer’s. 23% of Americans have at least one allele for this gene, and a consequent 30% likelihood of developing the disease. Just over 2% have two alleles for APOE4, which means a whopping 50–90% chance of developing Alzheimer’s. For people who have two copies of a similar but less scary gene, APOE3, the likelihood is only 9%(2).

It’s scary to think there’s something like that lurking inside of you — and even scarier to know that you can find out if you carry it. Advances in genetic profiling have made it so cheap that you can do it from the comfort of your own home through companies like 23andMe. Whilst some biohacking fanatics jump at the chance to find these clues to their fate, most people would rather not know and live life in blissful ignorance.

This is assuming however that we are helpless to do anything if we are the carriers of an APOE4. For decades, the focus of medical research has been on the development of pharmaceuticals to cure a disease only once it has taken hold and been diagnosed. But this is all now changing. The rise in personal health technology which allows us to track anything from blood glucose and ketone levels to the biological age of our DNA means that healthcare will gradually shift from being curative, to preventative. The biggest names in the game are betting on it — Apple is now driving itself forward as a healthcare company(3), Google is looking to cure aging with its offshoot Calico(4) and Amazon’s Jeff Bezos has teamed up with Warren Buffet and Jamie Dimon to specifically disrupt the US healthcare market(5).

This shift however is still very much in its infancy. The big budgets are still with the pharmaceutical giants which profit from people being on medication long-term, and have no interest to invest in preventative therapies. All the same, there are glimmers out there for the people who want to find it. In this article I set out the most promising nutritional and behavioural changes I have found from reputable research to show you that if we take a preventative view of Alzheimer’s, there is a good case to believe that we shouldn’t worry as much as we do. I’ll discuss some key physiological problems and how they contribute to Alzheimer’s development, and look at research which suggests how we can keep these in check: deficits in autophagy, increased bodily inflammation, low levels of neurotrophic chemicals and exposure to environmental toxins. If scientific detail isn’t your thing, then I’ve rounded this all up into a simple cheat sheet of simple changes you can make to strengthen your dementia resilience — find it at the end of the article.

Increasing autophagy

Let’s return again to the cellular level, and think again about the Alzheimer’s brain accumulating all of that protein gunk. A key area of research into how Alzheimer’s develops looks at the role of process called autophagy. Research has found that it reduces as we age(10), and deficits in its operation precedes protein accumulation in the Alzheimer’s brain(6).

From the Greek ‘auto’ (self) and ‘phagein’ (eating), autophagy is a process which takes place in all human cells and is essential for their survival. It describes how cell components are broken down and removed from cells or recycled into useful cellular apparatus. About 100–200g of protein is re-synthesised this way, to add to the ~70g we gain through eating. Whilst there is always some level of autophagy going on in your body, it is hugely ramped up when your cells need to look inside for energy and nutrients — like during a fast.

Fasting has been an integral part of health and healing practices throughout the recorded history of mankind. This ancient tradition may be partially rooted in a cellular process we are now beginning to understand in modern scientific terms. One of the most evolutionary conserved cellular responses to organismal fasting is…autophagy, a process in which the cell self-digests its own components.

Levine & Kroemer, 2008(7)

Fasting, that is not taking in any calories, is a potent inducer of autophagy in almost all species(8). The length of time we need to fast to achieve this is still up for debate, but research in mice suggests that neuronal autophagy can be drastically increased with as little as 24 hours of non-eating(9).

Autophagy gets switched on when cells need to remodel themselves. This might be during developmental period in order to grow, or because they need to rid themselves of damage. The process helps our cells to deal with oxidative stress, infection or protein accumulation. Faulty autophagy is therefore likely to prevent these issues being fixed, and all are implicated in the development of Alzheimer’s.

With this in mind, I like to think of a heightened state of autophagy as a ‘repair mode’. Day to day, when we are eating glucose-rich foods, our cells are in ‘grow mode’, synthesising new proteins and creating energy from our food and a lot of metabolic junk as a by-product. When we stop eating, we burn through all of our remaining glucose and stored glycogen and start breaking down fats for fuel instead. This also triggers our cells get the hoovers out and clear out all of the accumulated cellular detritus — if we’re eating all the time, they don’t ever get the break they need to do this.

Ensuring your body enters this fasted repair state has led to the hypothesis shared by some scientists that it’s not actually about what you eat, but when you eat — a huge topic which I will cover in a later post. This ‘time-restricted eating’ recommends that you eat daily within a 12 hour window in order to give your body adequate time to recover from its feeding period — and even better if you can get it down to an eight or four hour window if you’re particularly keen. To put this into perspective, the current average eating window is 15 hours or more(60).

The beneficial impact of fasting isn’t just isolated to Alzheimer’s — it’s good for a whole host of neurodegenerative diseases. Rodents subjected to intermittent fasting diets show fewer clinical symptoms in models of Parkinson’s(11,12) and Huntington’s(13) and and fare better after neurological injury such as epileptic seizures, stroke and brain and spinal trauma(14,15,16).

Reducing inflammation

Fasting is also good for reducing inflammation, another key route that we know leads to the development of Alzheimer’s. Inflammation is usually a useful response to fight illness and injury, but can become heightened over the long term and lead to disease and suffering.

This includes Alzheimer’s, where it seems more important than protein build up. Some people have been seen to develop the characteristic amyloid-beta plaques in their brains, but not demonstrate any clinical symptoms of cognitive decline — because they also have low levels of inflammation(2). In other words, whilst all Alzheimer’s patients have excessive protein build up in the brain, not all people with excessive protein build up in the brain have Alzheimer’s.

Alzheimer’s patients who suffer regular infections, such as coughs and colds, have a fourfold greater decline in memory tests compared to patients with lower rates of infection(17). This suggests that inflammation, as well as causing its onset, also serves to hasten the development of Alzheimer’s.

There is also a fascinating line of research which has found that social isolation is strongly correlated with increased inflammatory responses to social stress such as rejection or threatening behaviour. This operates in a particularly vicious circle. Inflammatory cytokines encourage the individual to indulge in ‘sickness behaviours’ such as sleepiness, social withdrawal, fatigue and anhedonia — the inability to enjoy things(18). In this heightened state of inflammation you become more sensitive to threatening behaviour(19,20,21), and will withdraw from general society(21,22) whilst gravitating towards those who you’re close to or can offer support.

This behaviour has led some to think that when you become socially isolated, your body will try to get you to seek out support from your nearest and dearest by upregulating your levels of inflammation(25,26). To put that another way — your body will make itself purposely ill if you’re not spending enough time with other people, to con you into spending time with your friends. Next time you’re working late at your desk with a cold that won’t go away, it might actually be a sign from your own body that you need to get out more and socialise.

You’re even conscious of how horrible inflammation makes you feel. Increasing inflammation levels experimentally* in humans makes them feel depressed and disconnected socially(19,25), an effect that is more pronounced in women than men(26). And it makes you stupid. In healthy people, even low levels of inflammation are associated with cognitive decline and a smaller hippocampus — the area of your brain key in memory formation and recall(27,28).

So, if you’re lonely you’re more likely to succumb to inflammatory-related diseases, of which we know Alzheimer’s to be one. Once your inflammation is up, you also react more strongly to social stressors like isolation and rejection, worsening the effects. Intervening in this cycle has already shown great effect in one community project in Frome, UK, which connected the socially isolated to a community support network and saw hospital admissions drastically fall(29).

A more controversial way of reducing inflammation has come to the fore more recently. Let’s go back to the study I mentioned where the people who had lots of colds developed Alzheimer’s at a much greater rate(17). Looking at the physiological profiles of these people, it was found that the rate of their decline correlated with high levels of an inflammatory cytokine called tumour necrosis factor-alpha (TNF-α). One way to reduce its activity is through intermittent fasting diets(14) — another is through taking psychedelics. TNF-α activity is reduced when a neuronal receptor called serotonin-2A is activated — which happens to be the key site of action for both LSD and psilocybin (magic mushrooms), suggesting that they can act as potent anti-inflammatories.

In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines. That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.

Juan Sanchez-Ramos, neuroscientist at the University of South Florida(31)

Whilst this does raise the possibility that psychedelics could be useful in delaying the onset and progression of Alzheimer’s, they remain illegal and out of the reach on the basis that the law deems them to have no therapeutic value**. Whilst the research against that stacks up, there’s an alternative option being explored. A chemical called DOI has been shown to have an even stronger inhibitory effect on TNF-α levels(30), and is currently being tested to see its effects on an array of inflammatory conditions(31).

So, if you’re keeping your inflammation low through fasting and maybe taking psychedelics once in a while whilst surrounded with close friends, your odds for avoiding Alzheimer’s are looking good. And to boot, you’ll be able to handle social sleights and rejection better.

Maintaining synaptic connectivity

The secondary type of Alzheimer’s is associated with low levels of chemical signalling molecules that play roles in promoting healthy synaptic connections in the brain. These include, out of a long list, agents such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), testosterone, insulin and vitamin D.

Let’s start with BDNF***. Its expression increases when our bodies undergo mild stresses, such as exercise, fasting or even slightly challenging cognitive tasks(32). These mild stresses are examples of hormesis — when something is bad for you at high doses but actually incredibly beneficial at low doses(33). Sauna use also increases the expression of BDNF(34) — good for 30mins, deathly for 3 hours.

BDNF has been shown to stimulate the production of neurons, particularly in the hippocampus — the memory formation and recall place(35). This is known to happen during intermittent fasting, where BDNF helps to restore damaged neural circuits by patching them up with brand new brain cells(35). Our old friend autophagy is also involved in this process — when you increase or decrease the level of autophagy experimentally, it has a direct corresponding effect on synapse size(36). More BDNF, more autophagy, better brain networks — got it?

Probably during evolution, BDNF evolved to play an important role in increasing neuroplasticity in the brain and forming new synapses crucial to learning and memory as well as mood and motivation.

Mark Mattson, National Institute of Aging(61)

If we’re going to start exercise more, then we’re also helping to boost our levels of testosterone(37) — another important signalling molecule for enhancing synaptic connectivity. Another way of boosting this hormone with less effort and gym fees is with Cordyceps(38). This is a mushroom that preys on ants by bursting out of their heads to release spores(39), and is taken by bodybuilders for its ability to improve exercise performance and muscle development. In its native country, it is sometimes referred to as ‘Himalayan Viagra’(40) — I’ll leave you to wonder why that might be.

Another popular mushroom supplement, Lion’s Mane, increases the levels of Nerve Growth Factor (NGF, 41,42,43), and helps to reduce cell death when stressed(44). In one Japanese study, 50–80 year men and women with symptoms of cognitive decline took 750mg of the mushroom a day for 16 weeks, with cognitive function improving significantly over the period(45). Mushroom megaenthusiast and personal hero Paul Stamets likes to often quote research where Lion’s Mane has remyelinated damaged neurons — although I’m not too hot on the quality of these studies(46,47).

Avoiding environmental toxins

Patients with the toxic subtype of Alzheimer’s also seem to have low levels of serum zinc. Copper and zinc compete in the body to be absorbed as they go via the same machinery, meaning that often if you have too much of one, you have too little of the other. This imbalance is epidemic in the world right now, with 1bn people on earth estimated to be zinc deficient(2). Copper piping, PPIs for gastric reflux and possibly even copper contraceptive coils have all been floated as contributors.

It has been known now for a while that people with a high copper:zinc ratio in their body are more likely to have dementia. Both have important roles to play in our physiology, but copper can also generate free radicals which contribute to cellular oxidative damage. Zinc on the other hand is important in the functioning of insulin and immune responses, helping us avoid the Alzheimer’s development risks of obesity and inflammation(48).

Exposure to mercury is also well-established with cognitive decline, and many suspect that accumulation of it in the body can contribute to the development of Alzheimer’s(49). Most people are aware that fish are in some way a problem: tuna and shark particularly as bigger fish live for longer, accumulating more mercury. When choosing a fish to dine upon, it’s best to stay within the SMASH selection: salmon, mackerel, anchovies, sardines and herring.

Amalgam dental fillings are also 50% mercury. These are the silver ones you can get on the NHS, but have this year been restricted by the Department of Health in the UK to reduce the amount of mercury in the environment. The research on whether the vapour (yes, vapour) from the fillings is enough to damage your health is still debated(50). Many people claim removing them has caused huge health improvements, but it’s unsure at the moment whether this is anything more than just placebo(51). It’s still probably a good idea to opt for the luxe white ones (particularly if you love tuna sashimi) — in controlled studies with young people, having amalgam fillings is associated with symptoms such as forgetfulness.

Selenium, a trace mineral and potent anti-oxidant found especially in Brazil nuts, has a high affinity for mercury and protects the body against mercury toxicity(49). Low levels of selenium are found in the brains of Alzheimer’s patients(49), and one study found that the APOE4 allele was associated with lower levels of selenium(53). Selenium supplementation has so far not been able to shown a significant effect in curing existing Alzheimer’s(54) but has been shown to improve some symptoms of cognitive impairment(55,56). I haven’t yet come across any studies which look at how effective it is for preventing future developments of Alzheimer’s, but from the above it looks pretty promising.

Given current pollution levels, it’s almost impossible to avoid heavy metal exposure. However, it seems that our bodies have a pretty efficient way of removing it from our systems — through sweating. A Canadian study measured levels of a variety of metals in blood, sweat and urine pre- and post- exercise and after sauna use, and found that sweat contained high concentrations of toxins compared to blood, suggesting it as a key way for our body to excrete them(57). The way we shower afterwards also appears to be important — unless you use a non-emollient soap such as Castile soap, the toxins can be reabsorbed back into your body(2). Frequent sauna use has been linked to lower rates of Alzheimer’s and dementia in Finnish men(58), but we’re talking more than four sessions a week. Time to bring back public baths for the good of us all.

And if you’re cleaning your body in the right way, then you should probably give your house a deep clean too. The seemingly harmless moulds we have around our home — black mould in the bathroom, bread mould in the kitchen perhaps — are also putting us more at risk of developing Alzheimer’s. Fungi have highly developed immune systems which we piggyback on when taking antibiotics — the fungi also have to fight the same pathogens we do so we ingest them to help out. However, when allowed to flourish in a rogue environment, they can also fight back against us when we try to wipe them out. In much the same way as bacteria are becoming immune to antibiotics, fungi are adapting to fungicides. So, whilst I am a huge fan of mushroom supplementation for its health benefits, not all fungi were created equal. Some are dicks, and trying to kill us.

We’re going to be just fine

So, as you can see from my round up, there’s actually a fair amount that we can be doing to avoid the dementia crisis painted in the CDC report. So why aren’t these things being talked about more? Why aren’t these being recommended to us by the healthcare industry?

One person who is trying to change that is Dale Bredesen, Professor of Neurology at UCLA and long-time Alzheimer’s researcher. He has recently published the book The End of Alzheimer’s, in which he claims that everyone should routinely find out their Alzheimer’s risk at the age of 45 in something he calls a “cognoscopy”. He sees no reason that, with an appropriate diet and lifestyle, the disease can’t be phased out from the population within the next generation. Bold claims.

Take a deep breath and realise that cognitive decline is, at least for most of us, and especially early in its course, addressable. Despite what you may have been told, it’s not hopeless or irreversable. To the contrary, for the first time, hope and Alzheimer’s have come together.

Dale Bredesen, quoted by Dr Rhonda Patrick(2)

He draws on a lot of the research I have covered above to devise a diet that he calls the ReCODE or Ketoflex 12/3*****:

  • Ketogenic eating, with 70% of your calories coming from good quality fats
  • A flexitarian approach, where meat should only be eaten sparingly, and if so, of the highest quality (think grass-fed, free-range, wild-caught etc.)
  • Eating within a 12 hour window everyday, if not smaller. APOE4 carriers should stay within 8–10 hours
  • Never eating within 3 hours of bedtime

In his patients, he reports that those in early stages of cognitive decline are actually able to halt and even reverse this trend through following the programme(1).

Medicine is changing in the 21st century — it’s becoming less about monotherapeutics, and more about programmatics.

Dale Bredesen, in conversation with Rhonda Patrick(14)

Anti-Alzheimer’s cheat sheet

Isn’t that a nice hopeful thought to end on? So rare in our age of doom and gloom. Pulling it all together into one nice takeaway, here’s a list of what you should be doing to live a longer life — and a more enjoyable one at that.

  • Eat within a 12-hour window of time every day. This can be hard to do if you commute or work a demanding job, but you can eat according to your schedule and your appetite. Eat early evening before leaving the office, or rule out dinner on days when it doesn’t suit.
  • Don’t eat 3 hours before bed. When your melatonin rises before bed, it switches off your insulin production for the day and therefore your ability to break down sugar. You’ll be lying in bed on an effective sugar high, and that causes all sorts of chaos for your long-term insulin response. Alcohol loves to be drunk in that 3 hour window, and is another reason it’s terrible for us (sadly).
  • Try once a month to have a water-only 36-hour fast. Much like training to run long distances, whilst it can be difficult at first it soon becomes easier and even enjoyable.
  • Exercise and get real sweaty. Then maybe have a sauna. Then clean yourself with a non-emoillient soap.
  • Get decent sleep. Even just one night of sleep deprivation causes protein to accumulate in the brain (59).
  • Eat organic. One of my greatest irks is watching people buy food that’s been showered with heavy metals, chemicals, antibiotics to save approximately £1, then drop £10 on a detox juice or activated charcoal. Just don’t put the crap in there to begin with.
  • Stick to your low-mercury SMASH fish (salmon, mackerel, anchovy, sardines and herring).
  • Supplement with Lion’s mane for NGF and Cordyceps for testosterone and better, sweatier gym performance.
  • Eat Brazil nuts — potent source of selenium and a good high fat, high protein snack.
  • Eat seeds, legumes (chickpeas, lentils, beans) and nuts to keep zinc intake high if you’ve reduced your meat consumption.
  • Keep an eye out for any mould accumulation in your home, and use mould-proof paint in particularly damp areas like the bathroom.
  • But most of all…don’t worry about it too much. Over-exercising or anxiety will deliver serious levels of oxidative damage to your body and override any positive changes you make elsewhere.

Footnotes

*They do this with something called an ‘inflammatory challenge’. I find this an incredibly amusing term.

**This places them as Class A in the UK, and Schedule 1 in the USA. There is currently a lot of evidence piling up elsewhere as to their huge beneficial value for disorders like drug addiction and chronic treatment-resistant depression, which both are problems spiralling out of control in Western countries. I imagine it is not long before these are reclassed.

***My brother also studied neurophysiology at university, and we would always sing BDNF to the tune of this song.

****I frequently tell people that one of the biggest problems preventing fasting from becoming widespread is just its poor branding. Scientists don’t do great at this, and this name is no exception.

Gabrielle Reason | thekykeon.com

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A collection of very interesting things I’ve discovered about the world and beyond: from evolutional biology and history to fasting and consciousness.

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