We start with some general principles for all who have survived their feckless youth and for whom, at age 50, the gradual decline of their cognitive curves has become palpable.   I call them the three Hs. You need the three Hs, to prevent dementia, to enjoy healthy ageing, to age at all, or simply to be a successful human being,  They are what your family physician and your mother have already told you but you probably forgot.  They are keys to a healthy life.  Here they are:

HEALTH

Good health is the first H.  The incidence of dementia is going down because old people are healthier, better fed and well-educated.  The most important single medical advance with respect to preventing dementia is the stunning success of cardiovascular medicine.  Optimal cardiovascular health is the most important dementia preventive.  So, do what your family doc tells you.  At least some of the time.

Speaking of diet, everyone agrees that the Mediterranean Diet is good for you.  There is no convincing evidence in favor of any other dietary manipulation.  What’s good: fresh fruit and vegetables, nuts, garlic, olive oil and green tea.  Fish, too, although I like fried oysters and hush puppies.

HEXERCISE 

The second H is hexercise.  To  most people, that conveys doing something that makes you sweat, but the second H should really be hactivity.  Aerobic exercise is great but it conveys no more benefit than taking the dog for a good walk.  And no more benefit than leading an active life.  Strive to exercise every domain: spiritual, intellectual, creative, musical, sexual, and most important, social.  Loneliness is toxic, solitude is neither good nor bad, but social activity is the most stimulating of all human activities.

HAPPINESS

Not happy in the ha ha sense, necessarily, although I hope you get a good laugh now and then.

Happiness is many things; the first is a negative.  It is freedom from anxiety and depression.  Worry and sadness are not good for brain.  They tax the brain and run it down.  They are risk factors for dementia and  almost as dangerous as cardiovascular disease.  They are also signs that brain is over-taxed and running down.  Anxiety and depression that begin or worsen in late middle-age are early signs that a dementing disease may be developing.  For that reason, we have a low threshold for prescribing Lexapro, Zoloft or Wellbutrin for older patients. 

Happiness is also to be at peace with the things that happen --  a calm temperament toward life and death, as they say in southwestern China.  But there is more to happiness than a stoical vision.  It is a life of purpose and meaning.  

Ask yourself, Is there a reason to stay alive?   It’s a question the Angel of Death ponders all the time.   He won’t be deterred if your answer is, I like it here, I don’t want to go or, There is still fun to be had.  Self-indulgence is human nature and we all need some now and then.  But it’s not a reason to live or a deterrent to our dark-winged friend.  Try this instead: I have something important to do, come back later.  And I know what that important thing is.  

I remember an old lady who brought her grandson to our clinic.  He was having problems at school, as his two older siblings had, and we were treating them, too.  She was 85 and looked tired.  She was raising four grandchildren; her daughter, their mother, had been addicted and now she was in prison.  The lady looked old and frail and the boy had been born with two strikes against them.  But the two older boys were doing pretty well, and I told her  what we were going to do for the third.  She gave me a weary but beatific smile and her eyes were determined.  She knew what she was going to do.  She told me she prayed every day but only for one thing: for the strength to continue doing God’s work.  

I remembered her when I read the Berlin Aging Study.  The investigators had interviewed older adults when they were, on average, 85 years old, and followed them for almost 20 years.  The ones who lived longest had one thing in common.  They were supporting their spouse, children or grandchildren.  Their health might be poor or their economic circumstances less than ideal, but the Angel was passing them by because they had something important to do. A similar survey of elderly Americans affirmed that providing care to an ill spouse predicted decreased mortality, whatever the caregiver’s own health or demographics.1 2

Meaning and purpose are where you find them, I suppose.  There are plutocrats who find meaning in their next acquisition and corporate raiders in their next target.  Many among us find meaning and purpose in acts of creation, in study, in worship or in Nature.  Some of us find meaning in the flow of an ordinary life, like Mr Canoglio, the cobbler on Avenue U.  

I have a bias.  I think the highest meaning is a life freely given in service.  Don’t pray for a long life.  Pray for the strength to devote your life someone who needs you.

I find myself saying the same things to my grandchildren that I said to my children and that my parents said to me.  For example, Enzo, who is seven, fell off the sink while he was brushing his teeth and banged his ankle on the toilet.  I picked him up, no small chore, and inspected the bruise.  Then I said, The only thing worse than physical pain, Enzo, is an additional increment of physical pain.  That sound advice is usually accompanied by the application of pressure to another part of the child’s anatomy, like poking him in the axilla.  

Why do I continue to do this?  IT NEVER WORKS.  None of my children ever responded favorably to my sound philosophy.  It would only add outrage to their evolving emotional breakdown.  Nor do I remember having ever felt solace when my father said it to me.  Even when I was a kid, I thought it was THE DUMBEST THING I EVER HEARD.  Yet here I am, at the height of my profession and learned in the psychology of children, saying the same dumb thing.

They say that insanity is doing the same thing over and over and expecting a different result.  My behavior, however, is not looking for a result.  Repeating what I heard long ago is like taking an old keepsake out of the display case and caressing it for a moment.  Except in this case, the old keepsake is a stercolith. 

Don’t scratch like that is something else I say, though when my mother said it to me, I remember thinking, Is there another way to scratch?  

Here is one more: Take your vitamins.  No one listens when I say that, of course.  Doctors say you don’t need to take vitamins every day if you eat a balanced diet.  Even the junk kids eat is fortified.  That vitamins make you smarter isn’t true either.  The brain has an active mechanism for extracting all the nutrients it needs from the blood.  It has priority in that regard over all the other body parts.  Nature gives priority to brain health, even if most humans don’t.

Well, those kids who took vitamins in the 1950s and 60s are old folk now and guess what?  They are SMARTER AND HEALTHIER THAN EVERYONE ELSE.  And guess what?  THEY STILL TAKE THEIR VITAMINS.  Even if they did spend years 18 to 50 doing without, disregarding their mothers’ good advice about drugs, alcohol, overwork, sleep deprivation and various other dissipations.

So, are vitamins good for you after all?  Old people think so, because they take more multivitamins, B Complex, vitamin D, zinc, selenium, biotin and even fish oil than young people do.  The ones who do live longer, are healthier and less prone to dementing disease.  Of course, it may not be the vitamins.  Vitamin eaters also tend to be better educated, financially secure and the offspring of conscientious mothers.  

It's the healthy person effect.  People who take supplements in reasonable amounts tend to be well-behaved and guard their health and vigor in many ways.  Because they do so many things right, it’s not possible to determine whether any one is determinative.  The Physicians’ Health Study, for example, was a ten-year follow-up of 14,641 US male physicians.  It was specifically concerned with vitamins and supplements, which were found to have no beneficial effect on cardiovascular health or cognition.1 2  

So, do the vitamins really do anything, or should we consign Take your vitamins to the dustbin of things no prudent parent should say?  Medical orthodoxy is decidedly in favor of the dustbin.  There is no unassailable evidence that multivitamins or any other vitamin or mineral serve a useful purpose in healthy people who eat a balanced diet.  

Undeterred by the mass of evidence, I continue to recommend that patients 50 and over take a multivitamin tablet and a fish oil capsule every day.  So, it seems, do many, if not most physicians.  They “use dietary supplements at least occasionally” and recommend them to their patients.

Fifty-seven percent of cardiologists said they use dietary supplements at least occasionally, as did 75% of dermatologists and 73% of orthopedists. The product most commonly reported to be used was a multivitamin, but over 25% in each specialty said they used omega-3 fatty acids and over 20% said they used some botanical supplements.  Seventy-two percent of cardiologists, 66% of dermatologists, and 91% of orthopedists reported recommending dietary supplements to their patients.3

All us doctors know that studies A, B and C show vitamins have no benefit on cognitive health.  But then there is study D that says they do.  We doctors also know that micronutrient inadequacies are widespread in the US and that multivitamins help fulfill nutrient requirements in adults and children.4  I take a vitamin tablet every day, and recommend it to patients.  It’s an easy decision.  The marginal cost is low and the marginal benefits are high.  

Recommending a multivitamin to my patients is more than Pascal’s wager:  

• Micronutrient deficits are especially common in older adults and taking a daily vitamin improves the nutrient biomarker status of folate, iodine, selenium, and vitamins B6, B12, and D.  

• Nutrient intake is often suboptimal in old people.  The absorption and metabolism of vitamins is often impaired.  

• Small, subclinical nutritional deficiencies have unpredictable effects on health. 

• The ageing brain has unusual metabolic requirements as it struggles with all that entropy.  

• Multivitamins have beneficial effects on ageing markers such as cataracts, oxidative stress, the health of skin and bone, sour mood, and cognitive function.  Multivitamins seem to be general health promoters, just as your mother said.

• Most studies in the medical literature show no benefit for multivitamins against dementia, cardiovascular disease or cancer.  But there have also been well-conducted studies that indicate protection against ageing-related cognitive decline.  

• Taking vitamins may not help you if your micronutrient status is perfect, but do you know?

• Don’t argue.  Take your vitamins. 

A single multivitamin tablet is not very much – a bit less than the Recommended Daily Allowance.  That’s OK.  I recommend a daily vitamin because older people are prone to mild deficiencies of certain vitamins or minerals.  A daily vitamin is a good way to maintain the levels one needs.  It’s the first H: maintain good health.  

I don’t recommend multivitamin tablets because extra vitamins are good for you.  Every once in a while, there is flurry of news that vitamin, a vitamin combination or a vitaminoid, when given in high doses, will prevent or cure Alzheimer’s disease.  Or Parkinson’s disease, arthritis, cancer and upper respiratory infections.  If the arguments in favor are reasonable and the clamor is loud enough, there will be controlled studies.  Inevitably, the fad is debunked.  True believers will carry on for a while but then they, too, will lose interest.  Until the next fad comes along.

Vitamin E, for example, enjoyed a long run as a Parkinson’s disease preventer.  Alzheimer’s, too.  It is said to have  antioxidant, anti-inflammatory and anti-apoptotic powers that avert neurodegeneration.  It may well have all those powers, or even more, but they aren’t exercised in the service of dementia prevention, or anti-Parkinson’s.  It is probably effective for some patients with macular degeneration.  

Vitamin C is synergistic with Vitamin E.  One of its primary roles is the regeneration of oxidized tocopherols, recycling them to the reduced state that is essential for an antioxidant effect.  A patient who chooses to take vitamin E as a preventive antioxidant should also take vitamin C.  I don’t think you should take either, in high doses, anyway.  The oxidative stress theory of aging and degeneration is still with us.  We are even encouraged to eat vegetables with anti-oxidant powers.  It’s a lovely theory but there is no evidence whatever that anti-oxidant vitamins, supplements or vegetables do any good at all.  But you can eat all the broccoli you want.

If vitamin C protected you from cancer, heart disease, cataracts and arthritis, don’t you think your family doctor would have told you?  

Lower vitamin D concentrations are associated with poorer cognitive function and a higher risk of Alzheimer’s.  Your well-informed family doc has already taken care of that.

The B vitamins, B6, B12 and folate “are essential in several metabolic pathways in the CNS.. necessary for the production of monoamine transmitters, phospholipids, and nucleotides.”  Yes, they are, which is why they’re vitamins.  Vitamins are essential nutrients because they support one’s physiology.  That’s why we need to take our RDA.  The brain is the most metabolically active organ in the body and it needs its vitamins.  Brain doesn’t benefit from more than it needs.   

Serum levels of folate and B12 are customary in dementia workups because ageing affects the absorption of B12 and the metabolism of folic acid.  Vitamin B12 injections and tetrahydrofolic acid may be necessary to correct a deficiency.  Pyridoxine levels tend to be low in older people, too.  If you want to take a B complex tablet every day, go ahead, but a good multivitamin tablet usually is all you need.

My mother never said Take your fish oil because there was no such thing.  There was cod liver oil, usually administered for its punitive properties, but an excellent source of vitamins A and D as well as omega-3s.  It wasn’t encapsulated.  It was proffered by the tablespoon, smelled awful and tasted worse.  

There was no fish oil before 1980 because that was when three physicians from the University of Copenhagen told us that fish oil was good for the heart.  They took pains to answer a question no one had ever asked: why, despite living in the harshest climate imaginable, are Eskimos as healthy as they are. “Death from ischemic heart disease constitutes only 3.5% of all deaths in Greenland Eskimos despite a life span of more than 60 years,” they wrote.  The three Danes learned that Eskimos didn’t consume n-6 polyunsaturated fatty acids but only those belonging to the n-3 family.   The ratio of n-3 to n-6 polyunsaturated fatty acids was more than three times higher compared to mainland Danes because Greenlanders ate more fish. That fish are good for your heart came to the world’s attention and the world took note.1

In Brooklyn, my parents used to tell us that Fish is brain food although I don’t know how they knew.  (I haven’t tried that one on my grandchildren yet.)  We didn’t think about omega-3s in those days nor did we know that cod-liver oil might be good for your heart.  (It is.)  Not long after the Greenland report, fish oil became the number 1 dietary supplement in the USA. 

People take fish oil for heart health.  Omega-3s are antiarrhythmic and antihypertensive.  They decrease platelet aggregation and sometimes lower serum triglycerides.  They also have anti-inflammatory effects.  They are incorporated into cell membranes and affect membrane fluidity and signaling across membranes. They also modulate the function of membrane ion channels.  By virtue of these effects, omega-3s reduce heart attack, heart failure, stroke and thrombosis.  BTW they are good for weight  loss, type 2 diabetes, chronic kidney disease, depression, schizophrenia and COVID.  No wonder fish oil is number 1.  

A substance that does all that should be sung from the rooftops, figuratively speaking.  Or maybe it doesn’t do any of it at all.  It took 30 years, but finally the fish oil parade got rained on.  In 2014 a study of all the previous fish oil studies reported no clear benefit of omega-3s “to protect from coronary artery disease… Current evidence does not clearly support cardiovascular guidelines encouraging high consumption of omega-3s.”2  The authors might also have pointed out that life expectancy in Greenland is number 133 among all nations.

And then, and then… in 2020, yet another study of all the previous omega-3 studies.  It reported precisely the opposite.3  Fish oil is good for the heart, after all.

There is a lesson here.  Something like, You can’t believe everything you read, which is something my uncle Jack used to say.  He is also known for saying, Figures don’t lie but liars figure.  Two things I haven’t said to my grandchildren yet but I will before long.

Here is the lesson: the medical literature is so full and rich, you can find a study that supports just about any position you want to take, even some outlandish ones.  So, when you see an ad touting a new molecule to prevent heart attack, cancer, hair loss or Alzheimer’s disease, you will often see little numbers like 1 2 3… adorning the text.  The little numbers point to articles published in medical journals and give credence to the advertiser’s contentions.  That the cited articles are under-powered, irrelevant, self-serving,  flawed or downright deceptive is not something the consumer is likely to know.

Having immersed myself in the medical literature for almost 60 years, I have learned that approximately half the articles published in medical journals are either under-powered, irrelevant, self-serving,  flawed or downright deceptive.  The question is, which half?  How is one to know?

ONE READS BOOKS LIKE THIS ONE, that’s how.  A book written by someone you can trust.  You probably know the writer of this one and, if you do, you know his integrity is unimpeachable and his clinical judgment is trustworthy.  If you were warned to count your silverware after he comes to dinner, that is only a vile canard.  

This is what I think about fish oil: it may or may not be good for the heart but it’s probably good for the brain.  This is my reasoning, and I use it to guide recommendations about any supplement that is supposed to be good for heart attack, cancer, hair loss or Alzheimer’s disease:

1. The marginal cost must be low.  The more expensive an item is and the more heavily it is advertised, the less likely it is to be effective.

2. The marginal benefits must be high.  There have to at least some well-conducted studies by disinterested investigators to support its use.

3. There has to be a credible physiological mechanism to support the use of the substance.  Not just theoretical lab data that likely have no bearing on its impact in human beings, especially their brains.

4. A substance that is good for a given condition A ought to have beneficial effects on other, analogous conditions.  For example, omega-3s seem to promote brain development in fetuses and premature babies.  If they are good for developing brain, they should also be useful for declining brain, which is also contending with a state of extraordinary change.

I think that omega-3’s are good for brain health.  I take one a day, along with a Centrum Silver.  You should, too.

There is a raft of papers by disinterested physician-scientists to support that view.  Few, if any, are influenced by the prospect of financial gain.  Fish oil is cheap and no purveyor is going to pay a medical consultant to generate those little 1 2 3’s on its behalf.  There are proprietary versions of fish with some purported advantage and they cost a lot more.  I get my omega-3s at Walmart and they are just plain-old fish oil.    

The studies, so far, are positive.  At least 17 studies addressed the question, and fourteen showed a clear benefit of elevated omega-3 intake in reducing the risk of cognitive decline and dementia. The data favoring a positive effect of omega-3 on cognitive status has even been called “overwhelming.”4  On the other hand, omega-3 supplementation has not been effective in studies of patients who already had AD, except perhaps patients with very early signs of the disorder.  It’s likely that nutritional intervention with omega-3s fatty acids is preventive, rather than therapeutic. 

The use of omega-3s for brain health has a solid empirical base.  Omega-3s thin the blood.  They have anti-oxidant and anti-inflammatory effects.  Omega-3s, along with omega-6s, are essential components of the neuronal cell membrane, increase membrane fluidity and support neuronal communication. Between them they constitute 20% of one’s brain by weight.  The ideal consumption ratio for 6s and 3s is 1:1, but in modern societies the ratio is a high as 10:1 or even 50:1.

They say that our paleolithic enjoyed a diet that contained more-or-less equal amounts of the omega-6, linoleic acid and the omega-3, alpha-linolenic acid.  Mothers’ milk has a high fat content, mostly linoleic and alpha-linolenic acid in equal amounts, which is consistent with the idea of an ideal dietary ratio.  The proper balance of dietary omega-6 and omega-3 fatty acids is necessary for brain development and the loss of omega-3s is a feature of ageing, cognitive decline and Alzheimer’s disease.

The fatty acids are incorporated in large amounts into developing brain.  Deficiencies of omega-3s are associated with learning deficits in infants and children, and an abundance of omega-3s in the diet improves learning ability.  Learning deficits can be demonstrated in animals deficient in omega-3s. 

Much has made of the observation that eating fish is cardioprotective but fish oil is not.  No one has explained to me why that should be the case, although fish-eaters tend to be wealthier, healthier and better educated.  They also have higher blood levels of mercury.    

Fish oil and omega-3 fatty acids are well tolerated at doses of 1–2,000 mg/d and there is little evidence of toxicity. However, simultaneous consumption of fish liver oils which also contain vitamin A along with multivitamin supplements could result in hypervitaminosis A.  Fish oils and omega-3 fatty acid supplements may exacerbate anticoagulation and promote bleeding in patients taking anticoagulant medications such as warfarin.5  Stop your fish oil if you’re going to have surgery.

Vitamins and fish oil are for everyone.  Now, the drugs we recommend for patients with mild cognitive impairment and early Alzheimer’s disease, and also for people who are at serious risk of developing Alzheimer’s:  an acetylcholinesterase inhibitor like Aricept, low dose lithium and, sometimes, an antidepressant or an NMDA antagonist (memantine).  

First, the acetylcholinesterase inhibitors (ACI).  There are three:

• Donepezil (Aricept)  Start 5 mg/day for one month, then increase to 10 mg/day.  Benefits on the 23 mg/day ER are no greater than on 10 mg/day, and benefits on the 10 mg/day dose are marginally larger than 5 mg.

• Galantamine (Reminyl)  4 mg twice daily for 4 weeks, then 8 mg twice daily for 4 weeks, then 12 mg twice daily.

• Rivastigmine (Exelon)  1.5 mg twice daily. At 14-day intervals the dose may be increased by increments of 1.5 mg twice daily up to a maximum dosage of 6 mg twice daily.

The ACI inhibit the enzyme, acetylcholinesterase.  It is an enzyme that breaks down acetyl choline.  

Acetyl choline is a neuromodulator like dopamine, norepinephrine and serotonin.  It is essential for a number of mental functions, including learning and memory, effortful attention and detection of significant stimuli.  Levels of acetyl choline go down as one ages, and go down much more as dementia develops, especially Alzheimer’s.  There is a theory that low acetyl choline is central to the development of Alzheimer’s disease.

Inhibiting the enzyme, acetylcholinesterase, means there is more acetyl choline available in brain to do its vital work.

Almost all of the acetyl choline in the brain originates in a small nucleus in the basal forebrain, the nucleus basalis of Meynert.  The neurons of that basal nucleus provide acetyl choline to the entire neocortex and limbic lobe.  Damage to the neurons occurs very early in the course of Alzheimer’s and Parkinson’s disease and Lewy Body dementia.  Losing cholinergic neurons impairs cognitive functions, especially memory and attention.  The ACI maintain higher levels of acetyl choline and protect those vital functions.  They may even protect cholinergic neurons from deteriorating.

The ACI are approved for patients with “mild to moderate” Alzheimer’s disease, but physicians usually prescribe Aricept as soon as older patients begin to complain of memory weakness.  They are mild cognitive stimulants that are useful for several other dementias and sometimes for brain injury and stroke.  They are even effective for ADHD and Down syndrome patients.  Children, though, are particularly sensitive to nausea caused by ACI.

Nausea is the main problem in adults, too, and about a third of patients can’t take the drugs for that reason.  Otherwise, they are remarkably safe, and treatment can continue for years.

The ACI are indicated for mild to moderate dementia, where they may improve cognition, energy, mood and behavior.  They are probably more effective if begun earlier, before the symptoms of dementia emerge.  They seem to work better in patients who are not medically fragile or on a lot of other drugs.

Of the three ACI, Aricept may be the most effective and least prone to side effects.  

The ACI are considered to be symptomatic treatments.  That is, they alleviate the symptoms of mild cognitive impairment or dementia, but don’t change the course of the disorder.   However, they may do exactly that.  We have been using the drugs for a long time now and have a better idea of what they really do.  Recent large-scale studies indicate the cognitive benefits of the ACI persist over time.  (A word of advice: you meet a patient on Aricept and no one thinks the drug is doing any good.  So, assiduous physician as you are, you stop the drug.  The patient deteriorates and you re-start it, but the patient doesn’t return to baseline.  He goes downhill faster than ever.  It’s the paint-on-the-walls-is-holding-up-the-house theory of dementia.  The ACI is keeping those withered pre- and post-synaptic neurons alive and without it, they just collapse.)

More to the point, mortality is lower in patients treated with ACI and progression to severe dementia seems to be slowed.1 2  We may just be holding up the walls with a thick layer of paint, but the whole point of dementia treatment is to prevent disability, and however we can do it is all right with me.

There are theoretical arguments that support ACI as neuroprotectants.  They point to the antioxidant, anti-inflammatory, anti-amyloid and pro-mitochondrial effects of the ACI.  Of course, we read those arguments all the time, and with reference to just about every molecule with purported anti-ageing effects.  

My confidence in the ACI for dementia prevention is not based on their effects in vitro but is based on a principal; that Alzheimer’s pathology is first seen in the small nuclei that generate dopamine, norepinephrine, serotonin and acetyl choline. (The basal forebrain nuclei reside in the paleocortex, at the confluence of the limbic lobes and the isodendritic core.)  Virtually all the dementia risk factors are associated with stress to those nuclei.  Keeping them healthy or at least active is a proper goal of dementia prevention. They do seem to respond favorably to a small degree of stimulation, and that’s what we are doing with the ACI.  

THEN THERE IS HUPERZINE A

For those of you who don’t like drugs and prefer ‘natural’ treatments, there is Qian Ceng Ta, a traditional Chinese medicine produced from the club moss, Huperzia serrata.  The moss contains a molecule, huperzine A, that is sold in China as a treatment for Alzheimer’s and in the USA as a supplement.  Huperzine A is a specific, and reversible inhibitor of acetylcholinesterase (AChE), almost as potent as donepezil and less likely to cause nausea.  It is said to have better penetration through the blood–brain barrier, higher oral bioavailability, and longer duration of acetylcholinesterase inhibition.3 4   As you might guess, it has antioxidant, anti-inflammatory, anti-amyloid and pro-mitochondrial effects.  If you can’t tolerate one of the ACIs, Huperzine A is probably a good substitute.

The other Alzheimer’s drug is memantine (Namenda).  It’s approval is for patients with moderate-to-severe Alzheimer’s disease, who are said to be more stable when they take the drug.  It is said to delay cognitive decline and loss of independence.  The recent literature suggests a positive effect on survival.(Oquendo et al., 2024)  It is supposed to be a neuroprotectant as well, with all the obligate antioxidant, anti-inflammatory, anti-amyloid and pro-mitochondrial effects.  

Memantine and its close cousin amantadine have been around for a long time.  Amantadine was first used as an antiviral drug, and then for Parkinson’s disease; memantine was once used as an antispasmodic.  Occasionally, they would be prescribed to patients with “senile dementia of the Alzheimer type.”  In both conditions, they were helpful, sometimes.  Memantine subsequently gained FDA approval; amantadine is too prone to side effects for routine use. 

In our clinics, we use amantadine for dementia patients with prominent frontal lobe symptoms or agitation or hyperactivity, just as we do for patients with similar problems who are intellectually disabled or have had brain injuries.  Memantine is used mostly as the acetylcholinesterase inhibitors (ACI) are, as a somewhat routine stimulant in patients with different dementias; its use is not confined to  Alzheimer’s.  There is no reason not to use memantine in patients with mild cognitive impairment or mild dementia, especially when it is combined with an ACI.  The combination of memantine with an ACI is said to have increased effect, but if it does, you need a strong light to see it.  

That’s the problem with memantine.  It’s effective for depression, OCD, catatonia, autism, migraine, cardiac arrhythmias and osteoarthritis.  It prevents radiation damage to brain in oncology patients.  The medical literature suggests it has neuroprotective powers equivalent to Sanctifying Grace.  One wonders, then, why its clinical utility is so meager.

One does meet dementia and MCI patients who have improved a lot on memantine, with or without an ACI.  The drug is safe (although it can cause bradycardia), it’s generic and there is seldom a reason not to give it a try.  It’s just not likely to help much. (Knorz & Quante, 2022)

Starting dosage: 5 mg once daily

Target dosage: 20 mg once daily

Titration: Dosage increased by 5 mg daily in weekly intervals as tolerated

Immediate-release (IR) 10 bid is equivalent to extended-release (ER) 28 mg daily.

Memantine and amantadine are NMDA antagonists.  Memantine has clinical effects because it mitigates glutamine hyperactivity, which causes excitotoxic damage to neurons.  Amantadine, ketamine and dextromethorphan are also NMDA antagonists, but they have different effects, probably because they act on so many other brain systems as well.

Very low doses of lithium are believed to prevent dementia.  And if you happen to have a dementing condition, lithium may delay its advance.  How do we know?  It’s an interesting story.

For 2000 years humans have immersed themselves in pools and drunk water suffused with sodium, iron, sulfur, alum, uranium and other such fruits of the Earth’s crust.    There are towns called Mineral Springs, Hot Springs, Thermal Springs and Bath all over the English-speaking world, and there must be places in other countries with equivalent names.  The idea is that small quantities of minerals are good for you.  It’s mostly myth, but there happens to one mineral, and a small one at that, that is really helpful.  It is found places called Lithium Springs, and also in a few happy places where there are high concentrations in the ground water that people drink every day.  In such places, we are told, the locals enjoy good health, longevity and a calm disposition.  

Lithium is a metal, atomic number 3, the third most common element in the universe.  It is one of three primordial elements created during the Big Bang and is still manufactured by certain stars.  They, too, must be happy stars.  On Earth, lithium is a most useful element, good for paving roads and manic-depression, and used in grease, batteries and thermonuclear weapons.  One hopes we won’t run out soon.  

In 1947, John Cade, an Australian psychiatrist, discovered that lithium was a cure for manic-depression.  It took about 30 years for other psychiatrists to warm to the idea and it is still the best drug for that condition as well as certain forms of depression.  Then, in 1970, three chemists from the University of Texas discovered that Texas counties with higher levels of lithium in drinking water had lower rates of mental hospital admissions.   It was pure serendipity, just as Cade’s discovery was.  The three chemists took this to mean that lithium was a trace element essential to human health, or at least mental health.1  No one believed them.  It was Texas, after all.  Besides, counties with high lithium in groundwater were also the farthest away from mental hospitals.

The three chemists, Dawson, Moore and McGinity, repeated the study in 1972, controlling for distance from mental hospitals and all the other potential confounders.  Doing so, they found that, in addition to mental illness, rates of homicide and other violent crimes were lower in lithium-enriched counties.  More studies were done, and in other places.  Higher concentrations of lithium were found to be associated with lower rates of suicide and drug addiction.  In Japan, lithium in groundwater increased longevity.2  More to the point, Alzheimer’s disease rates were lower, not only in Texas, but in Japan, Austria and Lithuania.  Think of all the disease, death and destruction that may have been averted had the nations of the world lithiated their waters in 1972.  

Regions with higher levels of lithium in drinking water have lower rates of Alzheimer’s disease as well as other diseases.  As of 2014, nine out of 11 epidemiological studies, usually of drinking water sources, affirmed the association between trace dose lithium and low dementia and mortality rates, not to mention lower suicide and violent crime.3 4 5 6 7  All four clinical trials of lithium for Alzheimer’s patients have found at least some clinical or biological benefits.8  

Lithium promotes neurogenesis in the hippocampus and prevents neuronal changes induced by stress in experimental animals.  It increases the protective proteins, BDNF and CREB.  Patients treated with lithium have larger cortical and hippocampal volumes.  Lithium is antioxidant and anti-inflammatory, and there are a number of other explanations for its extraordinary healing powers.

Having read this far, you know that even the most compelling theoretical arguments on behalf of a purported new treatment don’t prove that it really works as a treatment.  Small doses of lithium, for example, increase the life span of C elegans, the roundworm, by 50%.  That’s not a reason to treat Alzheimer’s with lithium, any more than observational studies are, or small clinical trials.  The very fact that low doses of lithium are good for so many different conditions should be enough to rouse one’s suspicion.  Nevertheless, that lithium is neuroprotective  has become, in some circles, an item of faith.  

If lithium is, in fact, neuroprotective in vivo, it would be a blockbuster drug for all time.  Someone ought to try to prove it.  But lithium is an atom, not a drug, and it is dug out of the ground.  No pharmaceutical company is going to invest a billion dollars to prove that it works for Alzheimer’s or any other condition.  That is a shame, because a recent analysis suggests that lithium is safer and more effective than the wildly expensive anti-amyloid infusions, donanemab, lecanemab and aducanumab.9

Absent definitive proof, one relies on the weight of the evidence, and the evidence points to low dose lithium as a safe treatment that is likely to prevent Alzheimer’s, delay its onset or slow its progression.  The only other such treatment are the ACI.  

Most of the evidence in favor of lithium is observational or correlative, and the controlled studies are comparatively small, but the concordance of evidence from multiple sources is impressive.  The evidence in support of anti-amyloid infusions is not nearly so impressive and the rationale for such treatments is weaker.

We know that lithium, at therapeutic doses, is an incredibly effective treatment for bipolar disorder, for antidepressant augmentation and as a suicide-preventer.  We also know that subtherapeutic doses of lithium have similar effects.  We’re not dealing with sawdust here, or jellyfish extract.  The tiny atom has physiological effects, and it probably is an essential trace element.  

Lithium has a narrow therapeutic window, and many patients can’t tolerate therapeutic doses for one reason or another.  Therapeutic doses can impair renal function although, remarkably, they don’t cause renal failure.  Very low doses of lithium may have acute side effects, like nausea or muscle stiffness, so some people can’t take it.  But low doses are safe, with none of the toxicity of the doses needed for bipolar patients.

What is a low dose?  In our clinics, we prescribe 150 mg tablets, and patients can take a half-tablet every day, or a full tablet.  The advantage of 75 or 150 mg is to assuage an irritable disposition or reinforce the effects of a concomitant antidepressant.  Very low dose lithium supplements are available without a prescription, and they may be preventive, too, but I don’t know.

The only problem with low-dose lithium is that, like that of vitamins and fish oil, its beneficial effects are invisible.  All you see is what doesn’t happen.  The patients don’t decline so much.  I can’t prove it, but it seems so.  Also, they are less likely to commit homicide.

I don’t take lithium myself, nor do I recommend it for people who are not at risk for dementia.  Perhaps we all ought to.  But for people who are at risk, perhaps because of their ApoE status or because their mother had Alzheimer’s, it is the only supplement likely to delay the inevitable.  The only supplement, that is, aside from vitamins and fish oil. 

If you want your spouse or parent to stay healthy and happy, not commit murder or suicide, and not be admitted to a mental hospital again, you can try low dose lithium.  Your family doc may disapprove of lithium, and many do, though they shouldn’t.  If so, you can buy lithia water.  You have to drink a lot of it to get 150 mg of lithium, but it is likely that a neuroprotective dose is lower than that.   What is the right dose, anyway?  Lithium-rich hot springs around the world have concentrations of 1-10 mg/Liter.1  The fortunate counties in Texas had 70-160 mg/L while the Japanese prefectures were only as high as 0.59 µg/L (that’s micrograms, a thousandth of a milligram).2 3  San Pellegrino is the only popular mineral water I know that contains lithium, about 200 µg/L.  You might get by, then, if you drink a Liter of Pellegrino every day.  That’s dementia protection, Japan style.  I prescribe 150 mg, Texas-sized dementia protection. 

You may not need Pellegrino because the concentration of lithium in groundwater is increasing as we speak, mainly because of batteries dumped in landfills.  Environmental insouciance in the service of longevity and dementia prevention, you could say.  I say this: ONLY 40% OF BATTERIES ARE RECYCLED.  GET WITH IT, PEOPLE.  

Enough! you must be thinking.  I know, I know, enough about groundwater, but you do need to think about what you are drinking.  San Pellegrino, for one, and my wife serves it at her fabulous restaurant in Chapel Hill.  If you can’t afford San Pellegrino, drink water.  As we age, our bodies dry out.  Children are 60% water, but older adults are 20% drier.  The old brain loses a lot of water-weight, too.  Dehydration is not uncommon among the elderly and causes cognitive impairment among other things.  So, stay hydrated.(Altman, 1961;Friis-Hansen et. al., 1951;Greenleaf, 1998;Olde Rikkert et. al., 1997) 5

Here is something else you should drink: green tea.  Especially freshly brewed green tea, because the beneficial polyphenols degrade quickly after it is brewed.  The heavily sugared green tea you buy in Seven-Elevens has no nutritional value.  I know that plain green tea tastes like grass, but you get used to it.  Add a bit of honey or elderberry syrup.  Drinking green tea is associated with lower all-cause mortality.  It is a cancer and stroke preventive and, of course, a neuroprotectant.

Black tea is good, too, and so is coffee, but green tea is best.  I love this study: they compared tea and coffee drinkers in Japan, and evaluated the odds of a low score on the MMSE as an indicator of ageing-related cognitive decline.6  Two cups of green tea every day lowers one’s risk of cognitive impairment by more than half.

BEVERAGE CONSUMPTION AND ODDS RATIO FOR COGNITIVE IMPAIRMENT

Consum.            Green Tea Black Tea  Coffee

3 or fewer cups/wk   1.00    1.00         1.00

4-6 cups/wk                  0.62    0.60         1.16

2 or more cups/d         0.46   0.87         1.03

Green tea, black tea and coffee are good things to drink.  Green and black tea are better because they are acetylcholinesterase inhibitors, like Aricept.  Coffee is not.  But coffee is no slouch.  It has more caffeine and caffeine seems to be beneficial, too.  Studies in a number of different countries show less cognitive impairment and Alzheimer’s disease in coffee drinkers, and the optimal dose is three cups per day.

WHAT NOT TO DRINK IS ALCOHOL.  

This is quite a reversal for medical science.  For more than 50 years we maintained that light-to-moderate alcohol drinking was protective against coronary heart disease, stroke and vascular dementia, and might also reduce the risk of Alzheimer’s.  Red wine was thought to be particularly beneficial, because it contains resveratrol and because Italians and the French are the longest-living Europeans, in spite of their other bad habits.  The flavonoids in wine are powerful antioxidant substances, and similar compounds are found in tea, fruits and vegetables, Ginkgo biloba extract and curcumin.  

Well, we got it wrong, or so medical science tells us now.  The latest belief is that any amount of alcohol is bad for your health, let alone your brain.  “There is a linear relationship between the amount of alcohol consumed and mortality risk. No risk-free dose of alcohol exists.” 7  Alcohol, it seems, causes cancer, especially breast cancer.  However, the data continue to suggest a beneficial effect for low-to-moderate alcohol on cardiovascular health.

I don’t have a dog in this fight.  The evidence for and against low-to-moderate drinking is based on observational and epidemiological studies.  The reader has learned how far one can trust such research.  It is never definitive.  

Let’s assume that low-to-moderate drinking is neither particularly harmful nor healthful.  Even if you believe the data, the risks and benefits are quite small.  Let us also agree that heavy drinking and frequent binging are bad things.

Here is my dog: the older you get, the less you should drink.  Alcohol tolerance decreases with age, especially in women.  And if you are developing cognitive symptoms as you age, you shouldn’t drink at all.  Low-to-moderate drinking is not good for a declining brain.

Many of my healthy old patients with incipient cognitive decline have had the habit of a cocktail or two, and wine with dinner.  It’s an agreeable custom, alcohol is a reliable old friend, and it’s hard to hear one should stop.  Cutting back to 3-5 small drinks per week is the upper limit, I tell them.  Or go California sober.            

Not really. I don’t advise those patients to substitute a tiny nibble on a cannabis gummy, but alcohol may be worse for the ageing brain than cannabis.  The risk of falling is higher with cannabis, I think.

Did I just say that caffeine was good for the ageing brain?  Let me check my notes…

IT GROWS ON PLANTS

Nature must have had something in mind.  Molecules that give you energy and make you feel better are ubiquitous.  They grow on plants for gosh sake.  

Plants aren’t dumb.  They learned how to produce molecules to influence the behavior of insects and animals and other plants, too.  Most of the time, they do it for protection.  They make defensive chemicals to keep from being devoured or nibbled to death.  Coffee plants, for example, use caffeine to ward off undesirable insects that would otherwise feast on the leaves and beans.  At high doses, caffeine can be toxic to insects.  In response, insects evolved taste receptors to avoid caffeine, but that’s the point, isn’t it?  The coffee bush has a way to discourage competition from other plants, too.  When its leaves fall to the ground, they contaminate the soil with caffeine, which makes it difficult for other plants to germinate.  So, you can throw your coffee grounds into the compost pile, but not bags full of grounds from the local coffee shop.    

The coffee bush is also an example of how plants use chemicals for propagation.  It wants to energize pollinators and the birds and goats and who eat the beans and spread seeds far and wide.1  To that end, low doses of caffeine are stimulating to insects and animals.2  There are other examples, like nicotine, which increases the activity of fruit-flies and cocaine, which “forager bees overestimate the value of the floral resources they collected”.  The bees advertise the location of coca plants to their nest-mates and one assumes the other bees are suitably impressed.3 4

Insects, animals and human beings are attracted to stimulating chemicals.  Plants evolved to accommodate their wishes.  But they don’t want to be stripped bare, so the stimulants they make have come with this warning: a little bit is good for you but a bit more is too much.  So, in high doses, stimulants are cardiotoxic and brain-toxic.   

So it is with caffeine.  If you take it coffee, it is good for you up to 400 mg per day; in pregnant women, up to 300 mg.  More than that, as you know, the effects are nasty.

Caffeine is a stimulant because it inhibits adenosine, a sleep molecule.  Doing so, it increases the activity of dopamine and other monoamines.  In the lab, caffeine protects neurons against dysfunction and death in animal models of stroke, Alzheimer’s disease and Parkinson’s disease.  Theoretically, then, caffeine is neuroprotective; thus its use in premature infants.5  Why it may be protective, we don’t know, although it may be because it activates the monoamines.  Other theories round up the usual suspects; caffeine is anti-inflammatory, an antioxidant, etc.  Thus, presumably, the benefits of drinking coffee.  

Whatever the mechanism, stimulants like caffeine are good because they affect the second H, hactivity or hexercise.  Insects, animals and humans like to be alert and energetic because they have important stuff to do.  Their brains, little or big, like to be stimulated.  It’s the way we are all built.  Plants want us to be that way, too, but not too much, and where would be all be without plants?

The rule of the narrow therapeutic index holds for all the stimulants.  Nicotine prevents Parkinson’s disease and not just because you’re likely to die before you have a chance to get it.  In low doses it seems to protect dopaminergic neurons.  Indians in the Andes chew coca leaves, which have a number of medicinal uses, but purified cocaine is wildly neurotoxic.  So, too, are the powerful stimulants, methamphetamine and Ecstasy, while low doses of stimulant drugs behave like caffeine.

Are low doses of milder stimulants, like methylphenidate (Ritalin) or amphetamine (Adderall, Vyvanse) good for your brain?  They follow the rule, after all.  High doses are cardiotoxic and neurotoxic.  Low doses are good for recovery from brain injury and sometimes from stroke.

I addressed this topic in an earlier book.  I described a 78 year old patient called Howard who took low doses of dextro-amphetamine several times a week to increase productivity and also because he thought that stimulating his monoamine system would keep his brain healthy.  His name wasn’t really Howard, though, but he was my old friend Miles Standwich whom I have known since college days.  One has to resort to such subterfuges when recounting one’s encounters with patients.  

This is what I told Howard:

I told Howard (i.e., my friend Miles) that  I agreed with him, stimulants are probably underused in older people.  They are useful for treating late life depression and problems associated with early dementia.   Meaningful activities, such as those he pursued, gave one a reason to live.  And old folk can usually do well with an energy jolt now and then.  Stimulants are also mild pain relievers, or at least they divert one’s attention from all the aches and pains that come with living 79 years.  Be careful on a hot Carolina day; you’ll stay in the garden too long and get heat stroke.  A small dose of amphetamine, once or twice a week, might be OK, I said, but there are side effects.  Older people are at particular risk for stimulant-induced hypertension, cardiac arrhythmia and heart attack.

For those reasons, we seldom prescribe stimulants to old people.

Nevertheless, the rationale for stimulants is obvious.  It’s so obvious, I’m going to tell you what it is.  Or what they are.  Ageing is entropy, right?  We are losing energy.  Our mitochondria get older faster than we do.  Instead of their cute oblong shape, they turn into donuts, for gosh sake.  But the little fellows live longer if they stay in shape.  That’s why they like to be stimulated, and that’s what I mean by the second H.  Exercise and activity are good for your mitochondria.  Inactivity and loneliness are not good for your mitochondria, they accelerate ageing and lead to dementia.  Stimulating drugs activate mitochondria, which is great, but they also stimulate the monoamines, dopamine, norepinephrine and serotonin, which energize our body, brain and mood.  

The stimulants, however, including caffeine, have time-limited effects and a narrow therapeutic window.  There is, however, a class of drugs that are mildly stimulating and increase the activity of your monoamine system in a safer and more lasting way.  They are antidepressants, especially Bupropion ( Wellbutrin), sertraline (Zoloft) and escitalopram (Lexapro).    

The modern antidepressants are for many of us the key to healthy ageing.  Not only because they treat anxiety and depression but because they alleviate so many problems we old people have (more often than we like to admit): loss of interest, low motivation and fatigue, bitterness and irritability, a negative outlook, obsessive worry or regret, personal rigidity, social withdrawal, fearfulness, stress intolerance, noise intolerance, people intolerance.  Antidepressants are good for all those things, although I have met people who fail to respond and are irrepressibly indolent, bitter and irritable, obsessive, rigid and intolerant, but you must hate it when I talk about my family all the time.

Antidepressants also affect dopamine, norepinephrine and serotonin.  They have an indirect effect on the monoamines.  They don’t squeeze monoamines out from the neuron as stimulants do, but block the recycling mechanism that sucks them back up into the neuron they came from.  Thus, the biogenic amines stay longer in the synapse and the intracellular space.  The energizing effects of antidepressants are more subtle than those of stimulants but they are more sustained. 

All the antidepressants, even the old tricyclics and monoamine inhibitors, are known to be neuroprotective in preclinical studies.  They can reduce inflammation, enhance oxidant defenses and improve the efficiency of mitochondrial enzymes.6 7  They stimulate the activity of neurotrophic molecules like BDNF and CREB that support the health and plasticity of neurons.,  In humans, antidepressants increase the rate of neurogenesis in the hippocampus and reverse the hippocampal atrophy that sometimes accompanies depression.8 9  They also affect gene expression “in tens if not hundreds of genes”.  The genes, in turn, strengthen synaptic efficiency and neural connectivity.  

Observational studies are mostly in favor of beneficial antidepressant effects, especially SSRIs, on ageing-related diseases, including diabetes, cancer, cardiovascular disease and Alzheimer’s.  The benefits are direct, not indirect.10 11 12 13 14  15 16 17 18  An indirect effect would be if patients were less depressed because they were taking an SSRI and thus took better care of themselves and dealt with ageing in a better frame of mind.  In contrast, a direct effect would be a change in the individual’s physiology.  For example, the SSRI, citalopram, decreases the formation of amyloid-Beta.  The studies have been done in ‘mouse models’ of Alzheimer’s disease and also in humans, using a PET scanner.  The SSRI lowers Aβ in a dose-dependent manner.  Five milligrams of citalopram reduced Aβ by 16%, while 10 mg of the same SSRI reduced β‐amyloid by 26%.  In a study from Washington-St Louis, 186 older people, all of whom were cognitively sound, were scanned.  Fifty-two of them had been treated with antidepressants, and they had fewer amyloid plaques.  The longer they had been treated with antidepressants, the lower their amyloid burden.19

We have mentioned a few times that the incidence of dementia has been going down and disability caused by dementia is decreasing.  It’s been happening in developed countries for about 30 years, that is, since modern antidepressants were introduced.  In 2018, the rate of antidepressant use in US adults was over 13%, and in older adults, 19%.   

SHOULD I DO IT?

I have no idea.  It depends, I think, on who you are and why you may want to take a stimulant or an SSRI. And also what happens if you do.  If you are in tip-top good health, exercise regularly, eats lots of fresh fruit and vegetables and have a calm temperament toward life and death, there’s no reason to believe that an additional increment of any compound is likely to extend your life or prevent your mitochondria from wearing out. (Except, of course, fish oil and multivitamins.)  However, if you have a good reason to try a stimulant or, better, an antidepressant, you should probably do so.  The good reason doesn’t have to be depression, either, or disabling panic attacks.  Older people, even healthy ones, can be given to worry, a rigid disposition, a reluctance to venture forth and be engaged or a negative attitude, especially about the many ways the world is going to hell in a handbasket and young people get stupider all the time.  You may be pleasantly surprised at how a low dose of Lexapro or Zoloft can make your life-view a bit lighter.  You may even appreciate that young people aren’t nearly so stupid as you (and I) were at their age.  There is something about positive energy that’s really good even if you don’t live an additional 4.8 years to enjoy it.  

Whether you choose to try an antidepressant or not, you may not have a choice.  Antidepressants are finding their way into the water table.  So are the stimulants. 20 21 22  At this rate, we are going to live forever.