There's quite a bit of evidence now that socializing — having frequent contact with others — helps protect against cognitive impairment in old age. We also know that depression is a risk factor for cognitive impairment and dementia. There have been hints that loneliness might also be a risk factor. But here’s the question: is it being alone, or feeling lonely, that is the danger?

A large Dutch study, following 2173 older adults for three years, suggests that it is the feeling of loneliness that is the main problem.

At the start of the study, some 46% of the participants were living alone, and some 50% were no longer or never married (presumably the discrepancy is because many older adults have a spouse in a care facility). Some 73% said they had no social support, while 20% reported feelings of loneliness.

Those who lived alone were significantly more likely to develop dementia over the three year study period (9.3% compared with 5.6% of those who lived with others). The unmarried were also significantly more likely to develop dementia (9.2% vs 5.3%).

On the other hand, among those without social support, 5.6% developed dementia compared with 11.4% with social support! This seems to contradict everything we know, not to mention the other results of the study, but the answer presumably lies in what is meant by ‘social support’. Social support was assessed by the question: Do you get help from family, neighbours or home support? It doesn’t ask the question of whether help would be there if they needed it. So this is not a question of social networks, but more one of how much you need help. This interpretation is supported by the finding that those receiving social support had more health problems.

So, although the researchers originally counted this question as part of the measure of social isolation, it is clearly a poor reflection of it. Effectively, then, that leaves cohabitation and marriage as the only indices of social isolation, which is obviously inadequate.

However, we still have the interesting question re loneliness. The study found that 13.4% of those who said they felt lonely developed dementia compared with 5.7% of those who didn’t feel this way. This is a greater difference than that found with the ‘socially isolated’ (as measured!). Moreover, once other risk factors, such as age, education, and other health factors, were accounted for, the association between living alone and dementia disappeared, while the association with feelings of loneliness remained.

Of course, this still doesn’t tell us what the association is! It may be that feelings of loneliness simply reflect cognitive changes that precede Alzheimer’s, but it may be that the feelings themselves are decreasing cognitive and social activity. It may also be that those who are prone to such feelings have personality traits that are in themselves risk factors for cognitive impairment.

I would like to see another large study using better metrics of social isolation, but, still, the study is interesting for its distinction between being alone and feeling lonely, and its suggestion that it is the subjective feeling that is more important.

This is not to say there is no value in having people around! For a start, as discussed, the measures of social isolation are clearly inadequate. Moreover, other people play an important role in helping with health issues, which in turn greatly impact cognitive decline.

Although there was a small effect of depression, the relationship between feeling lonely and dementia remained after this was accounted for, indicating that this is a separate factor (on the other hand feelings of loneliness were a risk factor for depression).

A decrease in cognitive score (MMSE) was also significantly greater for those experiencing feelings of loneliness, suggesting that this is also a factor in age-related cognitive decline.

The point is not so much that loneliness is more detrimental than being alone, but that loneliness in itself is a risk factor for cognitive decline and dementia. This suggests that we should develop a better understanding of loneliness, how to identify the vulnerable, and how to help them.

The neurotransmitter dopamine is found throughout the brain and has been implicated in a number of cognitive processes, including memory. It is well-known, of course, that Parkinson's disease is characterized by low levels of dopamine, and is treated by raising dopamine levels.

A new study of older adults has now demonstrated the effect of dopamine on episodic memory. In the study, participants (aged 65-75) were shown black and white photos of indoor scenes and landscapes. The subsequent recognition test presented them with these photos mixed in with new ones, and required them to note which photos they had seen before. Half of the participants were first given Levodopa (‘L-dopa’), and half a placebo.

Recognition tests were given two and six hours after being shown the photos. There was no difference between the groups at the two-hour test, but at the six-hour test, those given L-dopa recognized up to 20% more photos than controls.

The failure to find a difference at the two-hour test was expected, if dopamine’s role is to help strengthen the memory code for long-term storage, which occurs after 4-6 hours.

Individual differences indicated that the ratio between the amount of Levodopa taken and body weight is key for an optimally effective dose.

The findings therefore suggest that at least part of the reason for the decline in episodic memory typically seen in older adults is caused by declining levels of dopamine.

Given that episodic memory is one of the first and greatest types of memory hit by Alzheimer’s, this finding also has implications for Alzheimer’s treatment.

Caffeine improves recognition of positive words

Another recent study also demonstrates, rather more obliquely, the benefits of dopamine. In this study, 200 mg of caffeine (equivalent to 2-3 cups of coffee), taken 30 minutes earlier by healthy young adults, was found to improve recognition of positive words, but had no effect on the processing of emotionally neutral or negative words. Positive words are consistently processed faster and more accurately than negative and neutral words.

Because caffeine is linked to an increase in dopamine transmission (an indirect effect, stemming from caffeine’s inhibitory effect on adenosine receptors), the researchers suggest that this effect of caffeine on positive words demonstrates that the processing advantage enjoyed by positive words is driven by the involvement of the dopaminergic system.

In a large Mayo Clinic study, self-reported diet was found to be significantly associated with the risk of seniors developing mild cognitive impairment or dementia over a four-year period.

The study involved 1,230 older adults (70-89) who completed a 128-item food-frequency questionnaire about their diet during the previous year. Of these, around three-quarters (937) showed no signs of cognitive impairment at the beginning of the study period, and were asked to return for follow-up cognitive assessments. These assessments took place every 15 months. After about four years, 200 (21%) had developed mild cognitive impairment (MCI) or dementia.

The likelihood of cognitive deterioration was significantly affected by the type of diet. Those with the highest carbohydrate intake were nearly twice as likely to develop cognitive impairment compared to those with the lowest carbohydrate consumption, and when total fat and protein intake were taken into account, they were 3.6 times likelier to develop impairment.

Those with the highest sugar intake were 1.5 times more likely to develop cognitive impairment.

But — a finding that will no doubt surprise many — those with the highest fat consumption were 42% less likely to develop cognitive impairment, compared to those with the lowest level of fats.

Less surprisingly, those with highest intake of protein had a reduced risk of 21%.

In other words, the worst diet you can have, if you want to keep your brain healthy, is one that receives most of its calories from carbohydrates and sugar, and relatively little from fats and protein.

The findings about carbs, sugar, and protein are consistent with other research. The finding regarding fats is somewhat more surprising. The inconsistency may lie in the type of fat. Research implicating high-fat diets as a risk factor in Alzheimer’s have used saturated fats. Diets high in olive oil, on the other hand, have been found to be beneficial.

It seems likely that the danger of carbs and too much sugar lies in the effects on glucose and insulin metabolism. Saturated fats also interfere with glucose metabolism. Alzheimer’s has sometimes been called Type 3 diabetes, because of its association with insulin problems.

Caffeine has been associated with a lower of developing Alzheimer's disease in some recent studies. A recent human study suggested that the reason lies in its effect on proteins involved in inflammation. A new mouse study provides more support for this idea.

In the study, two groups of mice, one of which had been given caffeine, were exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow. When re-oxygenated, caffeine-treated mice recovered their ability to form a new memory 33% faster than the other mice, and the caffeine was observed to have the same anti-inflammatory effect as blocking interleukin-1 (IL-1) signaling.

Inflammation is a key player in cognitive impairment, and IL-1 has been shown to play a critical role in the inflammation associated with many neurodegenerative diseases.

It was found that the hypoxic episode triggered the release of adenosine, the main component of ATP (your neurons’ fuel). Adenosine is released when a cell is damaged, and this leakage into the environment outside the cell begins a cascade that leads to inflammation (the adenosine activates an enzyme, caspase-1, which triggers production of the cytokine IL-1β).

But caffeine blocks adenosine receptors, stopping the cascade before it starts.

The finding gives support to the idea that caffeine may help prevent cognitive decline and impairment.

I reported a few months ago on some evidence of a link between disturbed sleep and the development of Alzheimer’s. Now a mouse study adds to this evidence.

The mouse study follows on from an earlier study showing that brain levels of amyloid beta naturally rise when healthy young mice are awake and drop after they go to sleep, and that sleep deprivation disrupted this cycle and accelerated the development of amyloid plaques. This natural rhythm was confirmed in humans.

In the new study, it was found that this circadian rhythm showed the first signs of disruption as soon as Alzheimer’s plaques began forming in the mice’s brains. When the genetically engineered mice were given a vaccine against amyloid beta, the mice didn’t develop plaques in old age, the natural fluctuations in amyloid beta levels continued, and sleep patterns remained normal.

Research with humans in now underway to see whether patients with early markers of Alzheimer’s show sleep problems, and what the nature of these problems is.

Just to make it clear: the point is not so much that Alzheimer’s patients are more likely to have sleep problems, but that the sleep problems may in fact be part of the cause of Alzheimer’s disease development. The big question, of course, is whether you can prevent its development by attacking the dysfunction in circadian rhythm. (See more on this debate at Biomed)