Because it holds some personal resonance for me, my recent round-up of genetic news called to mind food allergies. Now food allergies can be tricky beasts to diagnose, and the reason is, they’re interactive. Maybe you can eat a food one day and everything’s fine; another day, you break out in hives. This is not simply a matter of the amount you have eaten, the situation is more complex than that. It’s a function of what we might call total allergic load — all the things you might be sensitive to (some of which you may not realize, because on their own, in the quantities you normally consume, they’re no or little problem). And then there are other factors which make you more sensitive, such as time of month (for women), and time of day. Perhaps, in light of the recent findings about the effects of environmental temperature on multiple sclerosis, temperature is another of those factors. And so on.
Now, I am not a medical doctor, nor a neuroscientist. I’m a cognitive psychologist who has spent the last 20 years reading and writing about memory. But I have taken a very broad interest in memory and cognition, and the picture I see developing is that age-related cognitive decline, mild cognitive impairment, late-onset Alzheimer’s, and early-onset Alzheimer’s, represent places on a continuum. The situation does not seem as simple as saying that these all have the same cause, because it now seems evident that there are multiple causes of dementia and cognitive impairment. I think we should start talking about Total Cognitive Burden.
Total Cognitive Burden would include genetics, lifestyle and environmental factors, childhood experience, and prenatal factors.
It is estimated that around a quarter of Alzheimer’s cases are familial, that is, they are directly linked to the possession of specific gene mutations. For the other 75%, genes are likely to be a factor but so are lifestyle and environmental factors. Having said that, the most recent findings suggest that the distinction between familial and sporadic is somewhat fuzzy, so perhaps it would be fairer to say we term it familial when genetics are the principal cause, and sporadic when lifestyle and environmental factors are at least as important.
While three genes have been clearly linked to early-onset Alzheimer’s, only one gene is an established factor in late-onset Alzheimer’s — the so-called Alzheimer’s gene, the e4 allele on the APOE gene (at 19q13.2). It’s estimated that 40-65% of Alzheimer’s patients have at least one copy of this allele, and those with two copies have up to 20 times the risk of developing Alzheimer’s. Nevertheless, it is perfectly possible to have this allele, even two copies of it, and not develop the disease. It is also quite possible — and indeed a third of Alzheimer’s patients have managed it — to develop Alzheimer’s in the absence of this risky gene variant.
A recent review selected 15 genes for which there is sufficient evidence to associate them with Alzheimer’s: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. Most of these are directly implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles, and indirectly in inflammatory response.
For example, five of these genes (APOE; LDLR; SORL1; CLU; TNF) are implicated in lipid metabolism (four in cholesterol metabolism). This is consistent with evidence that high cholesterol levels in midlife is a risk factor for developing Alzheimer’s. Cholesterol plays a key role in regulating amyloid-beta and its development into toxic oligomers.
Five genes (PICALM; SORL1; APOE; BIN1; LDLR) appear to be involved in the intracellular transport of APP, directly influencing whether the precursor proteins develop properly.
Seven genes (TNF; IL8; CR1; CLU; CCR2; PICALM; CHRNB2) were found to interfere with the immune system, increasing inflammation in the brain.
If you’re interested you can read more each of these genes in that review, but the point I want to make is that genes can’t be considered alone. They interact with each other, and they interact with other factors (for example, there is some evidence that SORL1 is a risk factor for women only; if you have always kept your cholesterol levels low, through diet and/or drugs, having genes that poorly manage cholesterol will not be so much of an issue). It seems reasonable to assume that the particular nature of an individual’s pathway to Alzheimer’s will be determined by the precise collection of variants on several genes; this will also help determine how soon and how fast the Alzheimer’s develops.
[I say ‘Alzheimer’s’, but Alzheimer’s is not, of course, the only path to dementia, and vascular dementia in particular is closely associated. Moreover, my focus on Alzheimer’s isn’t meant to limit the discussion. When I talk about the pathway to dementia, I am thinking about all these points on the continuum: age-related cognitive decline, mild cognitive impairment, senile dementia, and early dementia.]
It also seems plausible to suggest that the precise collection of relevant genes will determine not only which drug and neurological treatments might be most effective, but also which lifestyle and environmental factors are most important in preventing the development of the disease.
I have reported often on lifestyle factors that affect cognitive decline and dementia — factors such as diet, exercise, intellectual and social engagement — factors that may mediate risk through their effects on cardiovascular health, diabetes, inflammation, and cognitive reserve. We are only beginning to understand how childhood and prenatal environment might also have effects on cognitive health many decades later — for example, through their effects on head size and brain development.
You cannot do anything about your genes, but genes are not destiny. You cannot, now, do anything about your prenatal environment or your early years (but you may be able to do something about your children’s or your grandchildren’s). But you can, perhaps, be aware of whether you have vulnerabilities in these areas — vulnerabilities which will add to your Total Cognitive Burden. More easily, you can assess your lifestyle — over the course of your life — in these terms. Here are the sorts of questions you might ask yourself:
Do you have any health issues such as diabetes, cardiovascular disease, multiple sclerosis, positive HIV status?
Do you have a sleep disorder?
Have you, at any point in your life, been exposed to toxic elements (such as lead or severe air pollution) for a significant length of time?
Did you experience a lot of stress in childhood? Stress might come from a dangerous living environment (such as a violent neighborhood), warring parents, a dysfunctional parent, or a personally traumatic event (to take some examples).
Did you do a lot of drugs, or indulge in binge drinking, in college?
Have you spent many years eating an unhealthy diet — one heavy in fats and sugars?
Do you drink heavily?
Do you have ongoing stress in your life, or have experienced significant amounts of stress at some period during middle-age?
Do you rarely engage in exercise?
Do you spend most evenings blobbed out in front of the TV?
Do you experience little in the way of mental stimulation from your occupation or hobbies?
These questions are just off the top of my head, the ones that came most readily to mind. But they give you, I hope, some idea of the range of factors that might go to make up your TCB. The next step from there is to see what factors you can do something about. While you can’t do anything about your past, the good news is that, at any age, some benefit accrues from engaging in preventative strategies (such as improving your sleeping, reducing your stress, eating healthily, exercising regularly, engaging in mentally and socially stimulating activities). How much benefit will depend on how much effort you put into these preventative strategies, and on which and how many TCB factors are pushing you and how far you are along on the path. But it’s never too late to do something.
On the up-side, you might be relieved by such an exercise, realizing that your risk of dementia is smaller than you feared! If so, you might use this knowledge to motivate you to aspire to an excellent old age — with no cognitive decline. We tend to assume that declining faculties are an inevitable consequence of getting older, but this doesn’t have to be true. Some ‘super-agers’ have shown us that it is possible to grow very old and still perform as well as those decades younger. If your TCB is low, why don’t you make it even lower, and aspire to be one of those!