MCI

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.

First, genetics.

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!

There was an alarming article recently in the Guardian newspaper. It said that in the UK, diabetes is now nearly four times as common as all forms of cancer combined. Some 3.6 million people in the UK are thought to have type 2 diabetes (2.8 are diagnosed, but there’s thought to be a large number undiagnosed) and nearly twice as many people are at high risk of developing it. The bit that really stunned me? Diabetes costs the health service roughly 10% of its entire budget. In north America, one in five men over 50 have diabetes. In some parts of the world, it’s said as much as a quarter of the population have diabetes or even a third (Nauru)! Type 2 diabetes is six times more common in people of South Asian descent, and three times in people of African and African-Caribbean origin.

Why am I talking about diabetes in a blog dedicated to memory and learning? Because diabetes, if left untreated, has a number of complications, several of which impinge on brain function.

For example, over half of those with type 2 diabetes will die of cardiovascular disease, and vascular risk factors not only increase your chances of heart problems and stroke (diabetes doubles your risk of stroke), but also of cognitive impairment and dementia.

Type 2 diabetes is associated with obesity, which can bring about high blood pressure and sleep apnea, both of which are cognitive risk factors.

Both diabetes and hypertension increases the chances of white-matter lesions in the brain (this was even evident in obese adolescents with diabetes), and the degree of white-matter lesions in the brain is related to the severity of age-related cognitive decline and increased risk of Alzheimer’s.

Mild cognitive impairment is more likely to develop into Alzheimer’s if vascular risk factors such as high blood pressure, diabetes, cerebrovascular disease and high cholesterol are present, especially if untreated. Indeed it has been suggested that Alzheimer’s memory loss could be due to a third form of diabetes. And Down syndrome, Alzheimer's, diabetes, and cardiovascular disease, have been shown to share a common disease mechanism.

So diabetes is part of a suite of factors that act on the heart and the brain.

But treatment of such risk factors (e.g. by using high blood pressure medicines, insulin, cholesterol-lowering drugs and diet control, giving up smoking or drinking) significantly reduces the risk of developing Alzheimer’s. Bariatric surgery has been found to improve cognition in obese patients. And several factors have been shown to make a significant difference as to whether a diabetic develops cognitive problems.

Older diabetics are more likely to develop cognitive problems if they:

• have higher (though still normal) blood pressure,
• have gait and balance problems,
• report themselves to be in bad health regardless of actual problems (this may be related to stress and anxiety),
• have higher levels of the stress hormone cortisol,
• don’t manage their condition (poor glucose control),
• have depression,
• eat high-fat meals.

Glucose control / insulin sensitivity may be a crucial factor even for non-diabetics. A study involving non-diabetic middle-aged and elderly people found that those with impaired glucose tolerance (a pre-diabetic condition) had a smaller hippocampus and scored worse on tests for recent memory. And some evidence suggests that a link found between midlife obesity and increased risk of cognitive impairment and dementia in old age may have to do with poorer insulin sensitivity.

Exercise and dietary changes are of course the main lifestyle factors that can turn such glucose impairment around, and do wonders for diabetes too. In fact, a recent small study found that an extreme low-calorie diet (don’t try this without medical help!) normalized pre-breakfast blood sugar levels and pancreas activity within a week, and may even have permanently cured some diabetics after a couple of months.

Diabetes appears to affect two cognitive domains in particular: executive functioning and speed of processing.

You can read all the research reports on diabetes that I’ve made over the years in my new topic collection.

Impaired vision is common in old age and even more so in Alzheimer’s disease, and this results not only from damage in the association areas of the brain but also from problems in lower-level areas. A major factor in whether visual impairment impacts everyday function is contrast sensitivity.

Contrast sensitivity not only slows down your perceiving and encoding, it also interacts with higher-order processing, such as decision-making. These effects may be behind the established interactions between age, perceptual ability, and cognitive ability. Such interactions are not restricted to sight — they’ve been reported for several senses.

In fact, it’s been suggested that much of what we regard as ‘normal’ cognitive decline in aging is simply a consequence of having senses that don’t work as well as they used to.

The effects in Alzheimer’s disease are, I think, particularly interesting, because we tend to regard any cognitive impairment here as inevitable and a product of pathological brain damage we can’t do anything much about. But what if some of the cognitive impairment could be removed, simply by improving the perceptual input?

That’s what some recent studies have shown, and I think it’s noteworthy not only because of what it means for those with Alzheimer’s and mild cognitive impairment, but also because of the implications for any normally aging person.

So let’s look at some of this research.

Let’s start with the connection between visual and cognitive impairment.

Analysis of data from the Health and Retirement Study and Medicare files, involving 625 older adults, found that those with very good or excellent vision at baseline had a 63% reduced risk of developing dementia over a mean follow-up period of 8.5 years. Those with poorer vision who didn’t visit an ophthalmologist had a 9.5-fold increased risk of Alzheimer disease and a 5-fold increased risk of mild cognitive impairment. Poorer vision without a previous eye procedure increased the risk of Alzheimer’s 5-fold. For Americans aged 90 years or older, 78% who kept their cognitive skills had received at least one previous eye procedure compared with 52% of those with Alzheimer’s disease.

In other words, if you leave poor vision untreated, you greatly increase your risk of cognitive impairment and dementia.

Similarly, cognitive testing of nearly 3000 older adults with age-related macular degeneration found that cognitive function declined with increased macular abnormalities and reduced visual acuity. This remained true after factors such as age, education, smoking status, diabetes, hypertension, and depression, were accounted for.

And a study comparing the performance of 135 patients with probable Alzheimer’s and 97 matched normal controls on a test of perceptual organization ability (Hooper Visual Organization Test) found that the VOT was sensitive to severity of dementia in the Alzheimer’s patients.

So let’s move on to what we can do about it. Treatment for impaired vision is of course one necessary aspect, but there is also the matter of trying to improve the perceptual environment. Let’s look at this research in a bit more detail.

A 2007 study compared the performance of 35 older adults with probable Alzheimer’s, 35 healthy older adults, and 58 young adults. They were all screened to exclude those with visual disorders, such as cataracts, glaucoma, or macular degeneration. There were significant visual acuity differences between all 3 groups (median scores: 20/16 for young adults; 20/25 for healthy older adults; 20/32 for Alzheimer’s patients).

Contrast sensitivity was also significantly different between the groups, although this was moderated by spatial frequency (normal contrast sensitivity varies according to spatial frequency, so this is not unexpected). Also unsurprisingly, the young adults outperformed both older groups at every spatial frequency, except at the lowest, where it was matched by that of healthy older adults. Similarly, healthy older adults outperformed Alzheimer’s patients at every frequency bar one — the highest frequency.

For Alzheimer’s patients, there was a significant correlation between contrast sensitivity and their cognitive (MMSE) score (except at the lowest frequency of course).

Participants carried out a number of cognitive/perceptual tasks: letter identification; word reading; unfamiliar-face matching; picture naming; pattern completion. Stimuli varied in their perceptual strength (contrast with background).

Letter reading: there were no significant differences between groups in terms of accuracy, but stimulus strength affected reaction time for all participants, and this was different for the groups. In particular, older adults benefited most from having the greatest contrast, with the Alzheimer’s group benefiting more than the healthy older group. Moreover, Alzheimer’s patients seeing the letters at medium strength were not significantly different from healthy older adults seeing the letters at low strength.

Word reading: here there were significant differences between all groups in accuracy as well as reaction time. There was also a significant effect of stimulus strength, which again interacted with group. While young adults’ accuracy wasn’t affected by stimulus strength, both older groups were. Again, there were no differences between the Alzheimer’s group and healthy older adults when the former group was at high stimulus strength and the latter at medium, or at medium vs low. That was true for both accuracy and reaction time.

Picture naming: By and large all groups, even the Alzheimer’s one, found this task easy. Nevertheless, there were effects of stimulus strength, and once again, the performance of the Alzheimer’s group when the stimuli were at medium strength matched that of healthy older adults with low strength stimuli.

Raven’s Matrices and Benton Faces: Here the differences between all groups could not in general be ameliorated by manipulating stimulus strength. The exception was with the Benton Faces, where Alzheimer’s patients seeing the medium strength stimuli matched the performance of healthy older adults seeing low strength stimuli.

In summary, then, for letter reading (reaction time), word reading (identification accuracy and reaction time), picture naming, and face discrimination, manipulating stimulus strength in terms of contrast was sufficient to bring the performance of individuals with Alzheimer’s to a level equal to that of their healthy age-matched counterparts.

It may be that the failure of this manipulation to affect performance on the Raven’s Matrices reflects the greater complexity of these stimuli or the greater demands of the task. However, the success of the manipulation in the case of the Benton Faces — a similar task with stimuli of apparently similar complexity — contradicts this. It may that the stimulus manipulation simply requires some more appropriate tweaking to be effective.

It might be thought that these effects are a simple product of making stimuli easier to see, but the findings are a little more complex than I’ve rendered them. The precise effect of the manipulation varied depending on the type of stimuli. For example, in some cases there was no difference between low and medium stimuli, in others no difference between medium and high; in some, the low contrast stimuli were the most difficult, in others the low and medium strength stimuli were equally difficult, and on one occasion high strength stimuli were more difficult than medium.

The finding that Alzheimer’s individuals can perform as well as healthy older adults on letter and word reading tasks when the contrast is raised suggests that the reading difficulties that are common in Alzheimer’s are not solely due to cognitive impairment, but are partly perceptual. Similarly, naming errors may not be solely due to semantic processing problems, but also to perceptual problems.

Alzheimer’s individuals have been shown to do better recognizing stimuli the closer the representation is to the real-world object. Perhaps it is this that underlies the effect of stimulus strength — the representation of the stimulus when presented at a lower strength is too weak for the compromised Alzheimer’s visual system.

All this is not to say that there are not very real semantic and cognitive problems! But they are not the sole issue.

I said before that for Alzheimer’s patients there was a significant correlation between contrast sensitivity and their MMSE score. This is consistent with several studies, which have found that dementia severity is correlated with contrast sensitivity at some spatial frequencies. This, and these experimental findings, suggests that contrast sensitivity is in itself an important variable in cognitive performance, and contrast sensitivity and dementia severity have a common substrate.

It’s also important to note that the manipulations of contrast were standard across the group. It may well be that individualized manipulations would have even greater benefits.

Another recent study comparing the performance of healthy older and younger adults and individuals with Alzheimer's disease and Parkinson's disease on the digit cancellation test (a visual search task used in the diagnosis of Alzheimer’s), found that increased contrast brought the healthy older adults and those with Parkinson’s up to the level of the younger adults, and significantly benefited Alzheimer’s individuals — without, however, overcoming all their impairment.

There were two healthy older adults control groups: one age-matched to the Alzheimer’s group, and one age-matched to the Parkinson’s group. The former were some 10.5 years older to the latter. Interestingly, the younger control group (average age 64) performed at the same level as the young adults (average age 20), while the older old control group performed significantly worse. As expected, both the Parkinson’s group and the Alzheimer’s group performed worse than their age-matched controls.

However, when contrast was individually tailored at the level at which the person correctly identified a digit appearing for 35.5 ms 80% of the time, there were no significant performance differences between any of the three control groups or the Parkinson’s group. Only the Alzheimer’s group still showed impaired performance.

The idea of this “critical contrast” comparison was to produce stimuli that would be equally challenging for all participants. It was not about finding the optimal level for each individual (and indeed, young controls and the younger old controls both performed better at higher contrast levels). The findings indicate that poorer performance by older adults and those with Parkinson’s is due largely to their weaker contrast sensitivity, but those with Alzheimer’s are also hampered by their impaired ability to conduct a visual search.

The same researchers demonstrated this in a real-world setting, using Bingo cards. Bingo is a popular activity in nursing homes, senior centers and assisted-living facilities, and has both social and cognitive benefits.

Varying cards in terms of contrast, size, and visual complexity found that all groups benefited from increasing stimulus size and decreasing complexity. Those with mild Alzheimer’s were able to perform at levels comparable to their healthy peers, although those with more severe dementia gained little benefit.

Contrast boosting has also been shown to work in everyday environments: people with dementia can navigate more safely around their homes when objects in it have more contrast (e.g. a black sofa in a white room), and eat more if they use a white plate and tableware on a dark tablecloth or are served food that contrasts the color of the plate.

There’s a third possible approach that might also be employed to some benefit, although this is more speculative. A study recently reported at the American Association for the Advancement of Science annual conference revealed that visual deficits found in individuals born with cataracts in both eyes who have had their vision corrected can be overcome through video game playing.

After playing an action video game for just 40 hours over four weeks, the patients were better at seeing small print, the direction of moving dots, and the identity of faces.

The small study (this is not, after all, a common condition) involved six people aged 19 to 31 who were born with dense cataracts in each eye. Despite these cataracts being removed early in life, such individuals still grow up with poorer vision, because normal development of the visual cortex has been disrupted.

The game required players to respond to action directly ahead of them and in the periphery of their vision, and to track objects that are sometimes faint and moving in different directions. Best results were achieved when players were engaged at the highest skill level they could manage.

Now this is quite a different circumstance to that of individuals whose visual system developed normally but is now degrading. However, if vision worsens for some time before being corrected, or if relevant activities/stimulation have been allowed to decline, it may be that some of the deficit is not due to damage as such, but more malleable effects. In the same way that we now say that cognitive abilities need to be kept in use if they are not to be lost, perceptual abilities (to the extent that they are cognitive, which is a great extent) may benefit from active use and training.

In other words, if you have perceptual deficits, whether in sight, hearing, smell, or taste, you should give some thought to dealing with them. While I don’t know of any research to do with taste, I have reported on several studies associating hearing loss with age-related cognitive impairment or dementia, and similarly olfactory impairment. Of particular interest is the research on reviving a failing sense of smell through training, which suggested that one road to olfactory impairment is through neglect, and that this could be restored through training (in an animal model). Similarly, I have reported, more than once, on the evidence that music training can help protect against hearing loss in old age. (You can find more research on perception, training, and old age, on the Perception aggregated news page.)

For more on the:

Bingo study: https://www.eurekalert.org/pub_releases/2012-01/cwru-gh010312.php

Video game study:

https://www.guardian.co.uk/science/2012/feb/17/videogames-eyesight-rare-eye-disorder

https://medicalxpress.com/news/2012-02-gaming-eyesight.html