middle-aged

Memory genes vary in protecting against age-related cognitive decline

November, 2011

New findings show the T variant of the KIBRA gene improves episodic memory through its effect on hippocampal activity. Another study finds the met variant of the BDNF gene is linked to greater age-related cognitive decline.

Previous research has found that carriers of the so-called KIBRA T allele have been shown to have better episodic memory than those who don’t carry that gene variant (this is a group difference; it doesn’t mean that any carrier will remember events better than any non-carrier). A large new study confirms and extends this finding.

The study involved 2,230 Swedish adults aged 35-95. Of these, 1040 did not have a T allele, 932 had one, and 258 had two.  Those who had at least one T allele performed significantly better on tests of immediate free recall of words (after hearing a list of 12 words, participants had to recall as many of them as they could, in any order; in some tests, there was a concurrent sorting task during presentation or testing).

There was no difference between those with one T allele and those with two. The effect increased with increasing age. There was no effect of gender. There was no significant effect on performance of delayed category cued recall tests or a visuospatial task, although a trend in the appropriate direction was evident.

It should also be noted that the effect on immediate recall, although statistically significant, was not large.

Brain activity was studied in a subset of this group, involving 83 adults aged 55-60, plus another 64 matched on sex, age, and performance on the scanner task. A further group of 113 65-75 year-olds were included for comparison purposes. While in the scanner, participants carried out a face-name association task. Having been presented with face-name pairs, participants were tested on their memory by being shown the faces with three letters, of which one was the initial letter of the name.

Performance on the scanner task was significantly higher for T carriers — but only for the 55-60 age group, not for the 65-75 age group. Activity in the hippocampus was significantly higher for younger T carriers during retrieval, but not encoding. No such difference was seen in the older group.

This finding is in contrast with an earlier, and much smaller, study involving 15 carriers and 15 non-carriers, which found higher activation of the hippocampus in non-T carriers. This was taken at the time to indicate some sort of compensatory activity. The present finding challenges that idea.

Although higher hippocampal activation during retrieval is generally associated with faster retrieval, the higher activity seen in T carriers was not fully accounted for by performance. It may be that such activity also reflects deeper processing.

KIBRA-T carriers were neither more nor less likely to carry other ‘memory genes’ — APOEe4; COMTval158met; BDNFval66met.

The findings, then, fail to support the idea that non-carriers engage compensatory mechanisms, but do indicate that the KIBRA-T gene helps episodic memory by improving the hippocampus function.

BDNF gene variation predicts rate of age-related decline in skilled performance

In another study, this time into the effects of the BDNF gene, performance on an airplane simulation task on three annual occasions was compared. The study involved 144 pilots, of whom all were healthy Caucasian males aged 40-69, and 55 (38%) of whom turned out to have at least one copy of a BDNF gene that contained the ‘met’ variant. This variant is less common, occurring in about one in three Asians, one in four Europeans and Americans, and about one in 200 sub-Saharan Africans.  

While performance dropped with age for both groups, the rate of decline was much steeper for those with the ‘met’ variant. Moreover, there was a significant inverse relationship between age and hippocampal size in the met carriers — and no significant correlation between age and hippocampal size in the non-met carriers.

Comparison over a longer time-period is now being undertaken.

The finding is more evidence for the value of physical exercise as you age — physical activity is known to increase BDNF levels in your brain. BDNF levels tend to decrease with age.

The met variant has been linked to higher likelihood of depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behavior and schizophrenia. It differs from the more common ‘val’ variant in having methionine rather than valine at position 66 on this gene. The BDNF gene has been remarkably conserved across evolutionary history (fish and mammalian BDNF have around 90% agreement), suggesting that mutations in this gene are not well tolerated.

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Obesity linked to better cognition in post-menopausal women

November, 2011
  • A new study suggests fat might help protect women from age-related cognitive decline.

Obesity has been linked to cognitive decline, but a new study involving 300 post-menopausal women has found that higher BMI was associated with higher cognitive scores.

Of the 300 women (average age 60), 158 were classified as obese (waist circumference of at least 88cm, or BMI of over 30). Cognitive performance was assessed in three tests: The Mini-Mental Statement Examination (MMSE), a clock-drawing test, and the Boston Abbreviated Test.

Both BMI and waist circumference were positively correlated with higher scores on both the MMSE and a composite cognitive score from all three tests. It’s suggested that the estrogen produced in a woman’s fat cells help protect cognitive function.

Interestingly, a previous report from the same researchers challenged the link found between metabolic syndrome and poorer cognitive function. This study, using data from a large Argentinean Cardiovascular Prevention Program, found no association between metabolic syndrome and cognitive decline — but the prevalence of metabolic syndrome and cognitive decline was higher in males than females. However, high inflammatory levels were associated with impairment of executive functions, and higher systolic blood pressure was associated with cognitive decline.

It seems clear that any connection between BMI and cognitive decline is a complex one. For example, two years ago I reported that, among older adults, higher BMI was associated with more brain atrophy (replicated below; for more recent articles relating obesity to cognitive impairment, click on the obesity link at the end of this report). Hypertension, inflammation, and diabetes have all been associated with greater risk of impairment and dementia. It seems likely that the connection between BMI and impairment is mediated through these and other factors. If your fat stores are not associated with such health risk factors, then the fat in itself is not likely to be harmful to your brain function — and may (if you’re a women) even help.

Previous:

Overweight and obese elderly have smaller brains

Analysis of brain scans from 94 people in their 70s who were still "cognitively normal" five years after the scan has revealed that people with higher body mass indexes had smaller brains on average, with the frontal and temporal lobes particularly affected (specifically, in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus, in obese people, and in the basal ganglia and corona radiate of the overweight). The brains of the 51 overweight people were, on average, 6% smaller than those of the normal-weight participants, and those of the 14 obese people were 8% smaller. To put it in more comprehensible, and dramatic terms: "The brains of overweight people looked eight years older than the brains of those who were lean, and 16 years older in obese people." However, overall brain volume did not differ between overweight and obese persons. As yet unpublished research by the same researchers indicates that exercise protects these same brain regions: "The most strenuous kind of exercise can save about the same amount of brain tissue that is lost in the obese."

Reference: 

Zilberman, J.M., Del Sueldo, M., Cerezo, G., Castellino, S., Theiler, E. & Vicario, A. 2011. Association Between Menopause, Obesity, and Cognitive Impairment. Presented at the Physiology of Cardiovascular Disease: Gender Disparities conference, October 12, at the University of Mississippi in Jackson.

Vicario, A., Del Sueldo, M., Zilberman, J. & Cerezo, G.H. 2011. The association between metabolic syndrome, inflammation and cognitive decline. Presented at the European Society of Hypertension (ESH) 2011: 21st European Meeting on Hypertension, June 17 - 20, Milan, Italy.

[733] Thompson, P. M., Raji C. A., Ho A. J., Parikshak N. N., Becker J. T., Lopez O. L., et al.
(2010).  Brain structure and obesity.
Human Brain Mapping. 31(3), 353 - 364.

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Whether couple’s collaborative dialogue helps spouse's memory

September, 2011

A small study suggests that middle-aged couples are more likely to be effective than older couples in helping fill in each other’s memory gaps, but effective collaboration also depends on conversational style.

In my book on remembering what you’re doing and what you intend to do, I briefly discuss the popular strategy of asking someone to remind you (basically, whether it’s an effective strategy depends on several factors, of which the most important is the reliability of the person doing the reminding). So I was interested to see a pilot study investigating the use of this strategy between couples.

The study confirms earlier findings that the extent to which this strategy is effective depends on how reliable the partner's memory is, but expands on that by tying it to age and conversational style.

The study involved 11 married couples, of whom five were middle-aged (average age 52), and six were older adults (average age 73). Participants completed a range of prospective memory tasks by playing the board game "Virtual Week," which encourages verbal interaction among players about completing real life tasks. For each virtual "day" in the game, participants were asked to perform 10 different prospective memory tasks — four that regularly occur (eg, taking medication with breakfast), four that were different each day (eg, purchasing gasoline for the car), and two being time-check tasks that were not based on the activities of the board game (eg, check lung capacity at two specified times).

Overall, the middle-aged group benefited more from collaboration than the older group. But it was also found that those couples who performed best were those who were more supportive and encouraging of each other.

Collaboration in memory tasks is an interesting activity, because it can be both helpful and hindering. Think about how memory works — by association. You start from some point, and if you’re on a good track, more and more should be revealed as each memory triggers another. If another person keeps interrupting your train, you can be derailed. On the other hand, they might help you fill you in gaps that you need, or even point you to the right track, if you’re on the wrong one.

In this small study, it tended to be the middle-aged couples that filled in the gaps more effectively than the older couples. That probably has a lot to do with memory reliability. So it’s not a big surprise (though useful to be aware of). But what I find more interesting (because it’s less obvious, and more importantly, because it’s more under our control) is this idea that our conversational style affects whether memory collaboration is useful or counterproductive. I look forward to results from a larger study.

Reference: 

[2490] Margrett, J. A., Reese-Melancon C., & Rendell P. G.
(2011).  Examining Collaborative Dialogue Among Couples.
Zeitschrift für Psychologie / Journal of Psychology. 219, 100 - 107.

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Estrogen & Hormone therapy

Estrogen's effect on the brain is a complex story, one which we are only beginning to understand. We know it's important for women, but we're not sure about the details. One of the problems is that it appears to interact with stress. There are two aspects to estrogen's effects on women: normal monthly fluctuations in estrogen levels, and menopause.

It's also important to distinguish post-menopause (once you have completely stopped menstruating) from perimenopause (the years of menstrual irregularity leading up to this).

In general, the last few years of research seem to be coming to the conclusion that any cognitive problems women experience as they approach menopause is limited, both in time and in task, and depends in part on other factors. For example, those who experience many hot flashes may have poorer verbal memory, but the main cause for this may be the poorer sleep quality; those who are distressed or experience mood changes may find their memory and concentration affected for that reason.  These findings suggest the best approach to dealing with cognitive problems in perimenopause is to tackle the physical and/or emotional causes.

Post-menopause is different. Post-menopause is all about low estrogen levels, and the importance of estrogen for brain function. Nevertheless, estrogen therapy for postmenopausal women has had inconsistent results; there has even been some research suggesting it may increase the risk of later dementia. There is also some suggestion that it may not help those women who have cognitively stimulating environments, or are highly educated. And other indications that timing might be critical -- the age at which you begin hormone therapy. At the moment, we simply have too little clear evidence to warrant recommending hormone therapy for cognitive reasons (particularly in light of the possible cancer risk), or to know when it might be effective.

Excitingly, however (because there is no downside!), there is some evidence that physical exercise can counter the cognitive decline postmenopausal women may experience. There's also a study suggesting that the effect of low estrogen after menopause is not to impair cognition but simply to change it -- however, because women aren't prepared for, or understand, these changes, they perceive it as impairment. That would suggest that what is needed is an education program in how the brain changes (but first we have to understand exactly how it does change!).

Older news items (pre-2010) brought over from the old website

How does estrogen affect cognition?

Estrogen levels affect hippocampal wiring

Many studies have established the role of estrogen in female cognition. A rat study has now revealed the reason. It appears that the "wiring" in the hippocampus expands and retracts in relation to the amount of estrogen present during the estrous/menstrual cycle. The findings also suggest that “the brain's capacity for growth is well beyond anything we considered in the past”.
Routtenberg, A. 2005. Presented at the Society for Neuroscience's 35th Annual Meeting in Washington, D.C.
http://www.eurekalert.org/pub_releases/2005-11/nu-bma111405.php

How estrogen affects the brain

A new study involved cultured rat neurons has revealed how estrogen affects learning and memory. It appears that, in females, estrogen can activate particular glutamate receptors within the hippocampus. Glutamate is the primary excitatory neurotransmitter in the brain, allowing for fast communication between neurons.
[271] Boulware, M. I., Weick J. P., Becklund B. R., Kuo S. P., Groth R. D., & Mermelstein P. G.
(2005).  Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein.
J. Neurosci.. 25(20), 5066 - 5078.
http://www.eurekalert.org/pub_releases/2005-05/uom-uom051905.php

Estrogen effect on memory influenced by stress

The question of whether estrogen helps memory and cognition in women has proven surprisingly difficult to answer, with studies giving conflicting results. Now it seems the answer to that confusion is: it depends. And one of the things it depends on may be the level of stress the woman is experiencing. A rat study has found that the performance of female rats in a water maze was affected by the interaction of hormone level (whether the rat was estrous or proestrous) with water temperature (a source of physical stress). Those rats with high hormone levels did better when the water was warm, while those with low hormone levels did better when the water was cold. The researchers suggest both timing and duration of stress might be factors in determining the effect of hormones on cognition.
[384] Rubinow, M. J., Arseneau L. M., Beverly L. J., & Juraska J. M.
(2004).  Effect of the Estrous Cycle on Water Maze Acquisition Depends on the Temperature of the Water..
Behavioral Neuroscience. 118(4), 863 - 868.
http://www.eurekalert.org/pub_releases/2004-08/uoia-sss082704.php

Estrogen combines with stress to impair memory

A rat study has found that male and female rats performed equally well on a task involving the prefrontal cortex when under no stress, and when highly stressed, both made significant memory errors. But importantly, after exposure to a moderate level of stress, females were impaired, but males were not. When investigated further, it was found that female rats only showed this sensitivity when they were in a high-estrogen phase of their estrus cycle. The estrogen effect was confirmed in a further study using female rats who had had their ovaries removed, thus enabling the researchers to compare the effects of estrogen versus a placebo. These results suggest that high levels of estrogen can act to enhance the stress response, causing greater stress-related cognitive impairments, while providing reassurance that estrogen appears to have no effect on cognitive performance under non-stressful conditions.
[746] Shansky, R. M., Glavis-Bloom C., Lerman D., McRae P., Benson C., Miller K., et al.
(2003).  Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.
Mol Psychiatry. 9(5), 531 - 538.
http://www.eurekalert.org/pub_releases/2003-12/mp-epg112603.php

Why estrogen helps memory

Estrogen has been implicated as having a role in memory in a number of studies, although findings have been mixed as to the value of HRT for improving memory in post-menopausal women. A new study helps us understand why estrogen might be helpful. The study details how nerve cells in the hippocampus "grow in complexity" when exposed to estrogen, increasing connections among the nerve cells. It may be that, without estrogen, the connections that are there might not work as efficiently in storing and recalling certain types of memories. Previous studies have shown that the ability of women to remember word lists varies during their normal monthly cycle.
[1005] Akama, K. T., & McEwen B. S.
(2003).  Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway.
J. Neurosci.. 23(6), 2333 - 2339.
[880] Znamensky, V., Akama K. T., McEwen B. S., & Milner T. A.
(2003).  Estrogen Levels Regulate the Subcellular Distribution of Phosphorylated Akt in Hippocampal CA1 Dendrites.
J. Neurosci.. 23(6), 2340 - 2347.
http://www.eurekalert.org/pub_releases/2003-03/ru-rwc031403.php

Estrogen may dictate the problem-solving strategy chosen

Several studies have suggested estrogen may be beneficial for cognitive functioning in women. New research using rats suggests estrogen may be very specific in what types of learning it helps - and what types it may impair. In rats, it appeared to enhance place-learning, at the expense of response learning. It is suggested that postmenopausal women may experience a shift into a problem-solving mode more common to men. "Women may actually get better at performing a task from a different approach, but they are not used to doing it that way, so they view the change as an impairment."
[831] Korol, D. L., & Kolo L. L.
(2002).  Estrogen-induced changes in place and response learning in young adult female rats..
Behavioral Neuroscience. 116(3), 411 - 420.
http://www.eurekalert.org/pub_releases/2002-05/uoia-emd051502.php

Are you likely to develop cognitive problems in menopause?

Menopause transition may cause trouble learning

A four-year study of over 2,300 women, aged 42 to 52, has found evidence suggesting that during the early and late perimenopause women do not learn as well as they do during other menopause transition stages. Processing speed improved with repeated testing during premenopause, early perimenopause (menstrual irregularity but no "gaps" of 3 months), and postmenopause (no period for 12 months), but scores during late perimenopause (no period for three to 11 months) did not show the same degree of improvement. Improvements in processing speed were considerably reduced in late perimenopause, and improvement in verbal memory performance was reduced during both early and late perimenopause (and indeed almost non-existent during late perimenopause). These findings are consistent with self-reported memory difficulties — 60% of women state that they have memory problems during the menopause transition. The good news is that the effect seems to be temporary. Interestingly, although taking estrogen or progesterone hormones before menopause helped verbal memory and processing speed, taking them after the final period had a negative effect. This is consistent with other research indicating that the timing of hormone therapy is crucial to its effects.
[554] Greendale, G. A., Huang M. - H., Wight R. G., Seeman T., Luetters C., Avis N. E., et al.
(2009).  Effects of the menopause transition and hormone use on cognitive performance in midlife women.
Neurology. 72(21), 1850 - 1857.
http://www.eurekalert.org/pub_releases/2009-05/aaon-mtm051909.php

Hot flashes underreported and linked to forgetfulness

In the first study to explore the relationship between objectively measured hot flashes in menopausal women and memory performance, it’s been found that women dramatically underreport the number of hot flashes they experience (by about 43%), and that, with a clear measure of hot flashes, an association between number of hot flashes and poor verbal memory is evident. There was no relationship between the number of hot flashes women thought they had and memory performance. The average number of objective hot flashes was 19.5 per day. Unsurprisingly, poor sleep also predicted poorer memory, but it was also affected by the number of hot flashes during the night when a woman was sleeping. The researchers recommend treating women for their vasomotor symptoms.
An extended interview as MP3 audio file is at https://blackboard.uic.edu/bbcswebdav/institution/web/news/podcasts/PdCs...
[1128] Maki, P. M., Drogos L. L., Rubin L. H., Banuvar S., Shulman L. P., & Geller S. E.
(2008).  Objective hot flashes are negatively related to verbal memory performance in midlife women.
Menopause (New York, N.Y.). 15(5), 848 - 856.
http://www.eurekalert.org/pub_releases/2008-06/uoia-hfu061608.php

Memory problems at menopause

Findings from a study of 24 women approaching menopause have confirmed an earlier study involving over 800 women that found such women are no more likely than anyone else to suffer from memory retrieval problems. However, they did find that the women who complained more about problems with forgetfulness had a harder time learning or "encoding" new information, although they didn’t have actually have an impaired ability to learn new information. Although a larger study is needed to explore this link in more detail, the researchers suggest that stress and emotional upheaval may be responsible for attention failures that mean information isn’t encoded. The researchers did find that most of the women in their study had some sort of mood distress, including symptoms of depression or anxiety (note that this was not a random group, but women who were worried about their memory).
The study was reported at the annual meeting of the International Neuropsychological Society in Boston.
http://www.eurekalert.org/pub_releases/2006-02/uorm-mpa020206.php

Since 1996, 803 African American and white women aged 40 to 55 have been tested annually for loss of brain function. Performance was compared annually for women in premenopausal, during menopause, and postmenopausal groups. Small but significant increases in performance were found over time during the premenopausal and perimenopausal phases, leading the authors to conclude that transition through menopause is not accompanied by a decline in working memory and perceptual speed.
[1201] Meyer, P. M., Powell L. H., Wilson R. S., Everson-Rose S. A., Kravitz H. M., Luborsky J. L., et al.
(2003).  A population-based longitudinal study of cognitive functioning in the menopausal transition.
Neurology. 61(6), 801 - 806.
http://www.eurekalert.org/pub_releases/2003-09/aa-nss091803.php

Does estrogen help cognition?

For:

Hormone replacement therapy may improve visual memory of postmenopausal women
A study of 10 postmenopausal women (aged 50-60) found that those taking combined estrogen-progestin hormone therapy for four weeks showed significantly increased activity in the prefrontal cortex when engaged in a visual matching task, compared with those on placebo.
[1409] Smith, Y. R., Love T., Persad C. C., Tkaczyk A., Nichols T. E., & Zubieta J-K.
(2006).  Impact of combined estradiol and norethindrone therapy on visuospatial working memory assessed by functional magnetic resonance imaging.
The Journal of Clinical Endocrinology and Metabolism. 91(11), 4476 - 4481.
http://www.eurekalert.org/pub_releases/2006-11/uomh-hrt111606.php

Estrogen improves verbal memory in postmenopausal women

A study involving 60 postmenopausal women aged 32.8 to 64.9, found those receiving daily estrogen treatment (conjugated equine estrogens — Premarin) showed improved oral reading and verbal memory performance, compared to those receiving a placebo. This is consistent with brain imaging date indicating estrogen produces brain activations in the inferior parietal lobule, a region sensitive to phonological demands and implicated in reading.
[374] Shaywitz, S. E., Naftolin F., Zelterman D., Marchione K. E., Holahan J. M., Palter S. F., et al.
(2003).  Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen.
Menopause (New York, N.Y.). 10(5), 420 - 426.
http://www.eurekalert.org/pub_releases/2003-09/yu-eis092303.php

Hormone replacement therapy may have cognitive benefits for older women

A study of more than 2,000 women 65 or older, found that those who underwent hormone replacement therapy after menopause appeared to enjoy better mental functioning. Women 85 and older did especially well. The improvements were seen only in women free from dementia. However, the sample does not reflect the general population - most of the participants were Mormon, and the prohibition of alcohol and tobacco might be a significant factor.
[213] Carlson, M. C., Zandi P. P., Plassman B. L., Tschanz JA. T., Welsh-Bohmer K. A., Steffens D. C., et al.
(2001).  Hormone replacement therapy and reduced cognitive decline in older women: The Cache County Study.
Neurology. 57(12), 2210 - 2216.
http://tinyurl.com/i87m

The positive effects of estrogen on memory

Postmenopausal women who take estrogen and young college-aged women performed more consistently on memory tests compared with postmenopausal women not taking the hormone. Consistency differs from overall memory ability and is a relatively new area in research about the neuropsychology of aging. Consistency measures memory capability on multiple administrations of the same test or on several related tests in a short period of time.
The study involved 48 postmenopausal women (aged 60 - 80), and 16 younger women (18 - 30). The older women were divided into three groups: 16 non-hormone users, 16 estrogen-users and 16 estrogen and progesterone-users. Younger women and older women taking estrogen performed more consistently than the older women not taking the hormone, as well as having higher overall memory scores. Women taking a combination of estrogen and progesterone did not perform as consistently as the estrogen-only users. This finding suggests progesterone may block some of the beneficial effects of taking estrogen alone.
Wegesin, D.J., Friedman, D., Varughese, N. & Stern, Y. 2001. Effects of estrogen-use and aging on intraindividual variability in recognition memory. Paper presented to the annual Society for Neuroscience meeting in San Diego, US.
http://www.eurekalert.org/pub_releases/2001-11/cuco-ssp111501.php

Against:

Combined hormone therapy doesn't boost memory

A study of 180 recently menopausal women found no effect of hormone therapy (a combination of estrogen and progesterone) on cognitive function. Previous research has indicated a positive benefit of estrogen on cognition, so it is speculated that progestin may counteract these positive effects.

[917] Maki, P. M., Gast M. J., Vieweg A. J., Burriss S. W., & Yaffe K.
(2007).  Hormone therapy in menopausal women with cognitive complaints: A randomized, double-blind trial.
Neurology. 69(13), 1322 - 1330.

http://www.eurekalert.org/pub_releases/2007-09/aaon-hti091807.php

Removing ovaries before menopause increases risk of cognitive impairment

A very long-running study of some 1,500 women who underwent the removal of one or both ovaries for non-cancer-related reasons, has found that women who had one or both ovaries removed before menopause were nearly two times more likely to develop cognitive problems or dementia compared to women who did not have the surgery. In addition, those women who were younger when their ovaries were removed were more likely to develop dementia than women who were older when their ovaries were removed. This finding adds to other research suggesting that there may be a critical age window for the protective effect of estrogen on the brain in women.

[1291] Rocca, W. A., Bower J. H., Maraganore D. M., Ahlskog J. E., Grossardt B. R., de Andrade M., et al.
(2007).  Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.
Neurology. 69(11), 1074 - 1083.

http://www.eurekalert.org/pub_releases/2007-08/aaon-rob082107.php

Estrogen-alone hormone therapy could increase risk of dementia in older women

A new report from the Women's Health Initiative Memory Study suggests that older women using estrogen-alone hormone therapy could be at a slightly greater risk of developing dementia, including Alzheimer's disease (AD), than women who do not use any menopausal hormone therapy. Among 10,000 women using conjugated equine estrogens, 37 could be expected to develop dementia, compared to 25 in 10,000 women using the placebo. Previous reports from the Study found a greater risk with hormone therapy involving both estrogen plus progestin: among 10,000 women over age 65 using estrogen plus progestin there might be 45 cases of dementia compared to 22 cases in 10,000 older women on placebo.
It was also reported that beginning estrogen-alone hormone therapy after age 65 can have a small negative effect on overall cognitive abilities and that this negative effect may be greater in women with existing cognitive problems.
[871] Lewis, C. E., Masaki K., Coker L. H., for the Women's Health Initiative Memory Study, Shumaker S. A., Legault C., et al.
(2004).  Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women's Health Initiative Memory Study.
JAMA. 291(24), 2947 - 2958.
[1309] Hays, J., Johnson K. C., Coker L. H., Dailey M., Bowen D., Rapp S. R., et al.
(2003).  Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2663 - 2672.
http://www.eurekalert.org/pub_releases/2004-06/nioa-eht062204.php
http://www.eurekalert.org/pub_releases/2004-06/wfub-etd061704.php

For women over 65, Combined Hormone Therapy increases risk of dementia

Much to the researchers’ surprise and disappointment, a four-year experiment involving 4,532 women at 39 medical centers, has found that combined hormone therapy (involving both estrogen and progestin) doubles the risk of Alzheimer's disease and other types of dementia in women who began the treatment at age 65 or older, although the risk is still small : for every 10,000 women 65 and older who take hormones, 23 of the predicted 45 cases of dementia a year, will be attributable to the hormones. The study also found that the combined hormone therapy produced no improvement in general cognitive function, and in fact had adverse effects on cognition among some women. This supports an earlier study suggesting that, while estrogen is helpful to cognitive function in postmenopausal women, the benefits can be cancelled out by progestin / progesterone. The study also confirmed previous research showing that the combination therapy increased the risk of stroke - previous research has indicated that risk factors for stroke are also risk factors for cognitive decline.
[918] Jackson, R. D., Morley Kotchen J., Wassertheil-Smoller S., Wactawski-Wende J., Shumaker S. A., Legault C., et al.
(2003).  Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2651 - 2662.
[1309] Hays, J., Johnson K. C., Coker L. H., Dailey M., Bowen D., Rapp S. R., et al.
(2003).  Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2663 - 2672.
[1194] Rossouw, J. E., Aragaki A., Safford M., Stein E., Laowattana S., Mysiw J. W., et al.
(2003).  Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's Health Initiative: A Randomized Trial.
JAMA. 289(20), 2673 - 2684.
http://www.eurekalert.org/pub_releases/2003-05/wfub-chr052203.php

When is estrogen therapy helpful?

Cognitive benefit of estrogen minimal for the highly educated?
A mouse study sheds light on the mixed results coming from investigations into the cognitive effects of hormone replacement therapy. The study found no beneficial effect of estrogen in female mice who were raised in a stimulating environment. On the other hand, mice raised in standard conditions showed significant spatial and object memory improvement when treated with a high dose of estrogen (following removal of their ovaries). Among mice not treated with estrogen, an enriched environment alone significantly improved spatial memory. These results might help to explain why studies of hormone replacement therapy do not show beneficial effects for all women. Most studies of HRT use very well-educated women.
[1229] GRESACK, J. E., & Frick K. M.
(2004).  ENVIRONMENTAL ENRICHMENT REDUCES THE MNEMONIC AND NEURAL BENEFITS OF ESTROGEN.
Neuroscience. 128(3), 459 - 471.
http://www.eurekalert.org/pub_releases/2004-10/yu-eos102204.php

New insights into hormone therapy highlight when estrogen best aids brain

Several studies have been exploring some of the many variables that may be important in determining the effect of hormone replacement therapy.
A mouse study compared the effects of receiving daily estrogen injections (“continuous treatment”) with the effects of receiving it every four days (“cyclical treatment”). The treatment lasted three months. Ovariectomized mice receiving the continuous treatment performed better on memory tasks than those receiving cyclical treatment.
Another mouse study compared the brains of ovariectomized mice treated with continuous estrogen for 47 days with those not so treated, and found that, after five days on estrogen, estrogen-treated mice produced more of the proteins important for neuron repair and neuronal function. However, with prolonged, continuous estrogen treatment, this effect diminished, and by day 47 the estrogen-treated mice were similar to the non-estrogen-treated mice in levels of the repair proteins. Mice that did not receive estrogen showed an elevation of a brain protein associated with the negative aspects of brain aging, while estrogen-treated mice did not.
A rat study examined the effects of progesterone (a component of many hormone therapies), and found that ovariectomized rats receiving progesterone exhibited deficiencies in learning and memory, supporting the hypothesis that progesterone negatively affects memory during aging. It’s suggested that the negative outcome of several studies evaluating combined estrogen/progesterone HT may be due, in part, to unfavorable effects of progesterone.
Other rat studies have found that two established protective actions of estrogen with relevance to Alzheimer's are negatively affected by the presence of progesterone.
Another study using neurons in culture demonstrated the importance of timing. Neurons exposed to estrogen prior to exposure to beta-amyloid (the protein implicated in Alzheimers) had a significantly greater rate of survival than those exposed to estrogen after being exposed to beta-amyloid. The results are consistent with clinical studies in which women who received estrogen hormone therapy at the time of menopause, before cognitive degeneration becomes apparent, have a lower risk of developing Alzheimer's disease than women who never receive any sort of HT, while for women in their 60s and 70s, hormone therapy may make things worse.
Papers presented at the 34th Society for Neuroscience annual meeting in San Diego in late October 2004.
http://www.eurekalert.org/pub_releases/2004-10/sfn-nii102604.php

Dangers of hormone therapy

Getting the benefits of estrogen without the downside

We know estrogen helps learning and memory, but estrogen therapy also increases cancer risk. That’s why the results of a mouse study are exciting. The study found that estrogen acts through calpain, a protein crucial to learning and memory, and like adrenalin (which acts like a hormone in most of the body but as a neurotransmitter in the brain), it does so as a neurotransmitter, modulating synaptic transmission. The findings suggest drugs that target calpain directly may provide the same cognitive benefits of estrogen therapy, without the medical risks.
[299] Zadran, S., Qin Q., Bi X., Zadran H., Kim Y., Foy M. R., et al.
(2009).  17-β-Estradiol increases neuronal excitability through MAP kinase-induced calpain activation.
Proceedings of the National Academy of Sciences. 106(51), 21936 - 21941.
http://www.eurekalert.org/pub_releases/2009-12/uosc-cot120809.php

Other aids to help memory in menopausal women

Less cognitive impairment seen in women taking raloxifene

Raloxifene modulates the activity of the hormone estrogen and is one of the most widely prescribed drugs for the treatment of osteoporosis. A 3-year worldwide clinical trial involving 7705 postmenopausal women with osteoporosis found that those taking 120mg of raloxifene had a 33% less chance of developing mild cognitive impairment. There was no cognitive benefit from a 60mg dose. Note that, of the 5386 women participating in the cognitive part of this trial, only 3.4% had mild cognitive impairment, and 1% had dementia.
[757] Yaffe, K., Krueger K., Cummings S. R., Blackwell T., Henderson V. W., Sarkar S., et al.
(2005).  Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment in Older Women: The Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial.
Am J Psychiatry. 162(4), 683 - 690.
http://www.eurekalert.org/pub_releases/2005-04/uoc--lci040605.php

The estrogen drug raloxifene may help prevent cognitive decline in women over 70

The designer estrogen drug raloxifene has been prescribed to millions of postmenopausal women for osteoporosis, but its effects on the aging brain are unclear. A new study shows that although raloxifene does not affect the cognitive performance of most women, it may help prevent decline among women older than 70 and women whose cognitive performance is declining regardless of age.
Yaffe, K. et al. 2001. Cognitive Function in Postmenopausal Women Treated with Raloxifene. New England Journal of Medicine, 344, 1207-1213.Yaffe, K. et al. 2001. Cognitive Function in Postmenopausal Women Treated with Raloxifene. New England Journal of Medicine, 344, 1207-1213.
http://www.eurekalert.org/pub_releases/2001-04/UNKN-Derm-1704101.php

Fitness counteracts cognitive decline from hormone-replacement therapy

A study of 54 postmenopausal women (aged 58 to 80) suggests that being physically fit offsets cognitive declines attributed to long-term hormone-replacement therapy. It was found that gray matter in four regions (left and right prefrontal cortex, left parahippocampal gyrus and left subgenual cortex) was progressively reduced with longer hormone treatment, with the decline beginning after more than 10 years of treatment. Therapy shorter than 10 years was associated with increased tissue volume. Higher fitness scores were also associated with greater tissue volume. Those undergoing long-term hormone therapy had more modest declines in tissue loss if their fitness level was high. Higher fitness levels were also associated with greater prefrontal white matter regions and in the genu of the corpus callosum. The findings need to be replicated with a larger sample, but are in line with animal studies finding that estrogen and exercise have similar effects: both stimulate brain-derived neurotrophic factor.
[375] Erickson, K. I., Colcombe S. J., Elavsky S., McAuley E., Korol D. L., Scalf P. E., et al.
(2007).  Interactive effects of fitness and hormone treatment on brain health in postmenopausal women.
Neurobiology of Aging. 28(2), 179 - 185.
http://www.eurekalert.org/pub_releases/2006-01/uoia-fcc012406.php

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Obesity in middle age increases dementia risk

May, 2011

A large Swedish study confirms earlier indications that excess weight in midlife increases your risk of dementia in old age.

Supporting earlier research, a study involving 8,534 older adults (65+; mean age 74.4) has found those who were obese in middle age had almost four times (300%) more risk of developing dementia. Those who were overweight in middle age had a 1.8 times (80%) higher risk of developing dementia.

Participants were drawn from the Swedish Twin Registry. Height and weight had been measured at a mean age of 43.3, and 29.8% were defined as overweight or obese. Dementia was diagnosed in 350 participants (4.1%), with a further 114 (1.33%) diagnosed as questionable.

Apart from the clear links between excess weight and risk factors such as cholesterol, diabetes, hypertension, inflammation, there are also correlational factors. Higher education (which helps protect against brain damage) was also associated with about 10% reduced risk of overweight and obesity.

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Adverse changes in sleep duration associated with cognitive decline in middle-aged adults

May, 2011

A large long-running study has found that middle-aged adults whose night’s sleep had decreased from 6-8 hours or increased from 7-8 hours performed worse on some cognitive tests.

From the Whitehall II study, data involving 5431 older participants (45-69 at baseline) has revealed a significant effect of midlife sleep changes on later cognitive function. Sleep duration was assessed at one point between 1997 and 1999, and again between 2002 and 2004. A decrease in average night’s sleep from 6, 7, or 8 hours was significantly associated with poorer scores on tests of reasoning, vocabulary, and the MMSE. An increase from 7 or 8 hours (but not from 6 hours) was associated with lower scores on these, as well as on tests of phonemic and semantic fluency. Short-term verbal memory was not significantly affected. The magnitude of these effects was equivalent to a 4–7 year increase in age.

Around 8% of participants showed an increase from 7-8 hours of sleep over the five-year period (7.4% of women; 8.6% of men), while around a quarter of women and 18% of men decreased their sleep amount from 6-8 hours. About 58% of men and 50% of women reported no change in sleep duration during the study period. Some 27% of the participants were women.

The optimal amount of sleep (in terms of highest cognitive performance) was 7 hours for women, closely followed by 6 hours. For men, results were similar at 6, 7 and 8 hours.

Analysis took into account age, sex, education and occupational status. The Whitehall II study is a large, long-running study involving British civil servants. Sleep duration was assessed simply by responses to the question "How many hours of sleep do you have on an average week night?"

A very large Chinese study, involving 28,670 older adults (50-85), of whom some 72% were women, also supports an inverted U-shaped association between sleep duration and cognitive function, with 7-8 hours sleep associated with the highest scores on a delayed word recall test.

I would speculate that this finding of an effect of short-term verbal memory (in contrast to that of the Whitehall study) may reflect a group distinction in terms of education and occupation. The Whitehall study is the more homogenous (mostly white-collar), with participants probably averaging greater cognitive reserve than the community-based Chinese study. The findings suggest that memory is slower to be affected, rather than not affected.

Reference: 

Ferrie JE; Shipley MJ; Akbaraly TN; Marmot MG; Kivimäki M; Singh-Manoux A. Change in sleep duration and cognitive function: findings from the Whitehall II study. SLEEP 2011;34(5):565-573.

Xu L; Jiang CQ; Lam TH; Liu B; Jin YL; Zhu T; Zhang WS; Cheng KK; Thomas GN. Short or long sleep duration is associated with memory impairment in older Chinese: the Guangzhou Biobank Cohort Study. SLEEP 2011;34(5):575-580.

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Long term exposure to pesticides linked to cognitive decline

April, 2011

A French study of vineyard workers points to lower cognitive performance and cognitive decline in those chronically exposed to pesticides.

A study involving 614 middle-aged vineyard workers has found that those who were exposed to pesticides were five times as likely to perform more poorly on cognitive tests compared to those not exposed, and twice as likely to show cognitive decline over a two-year period.

Participants were in their 40s and 50s and had worked for at least 20 years in the agricultural sector. One in five had never been exposed to pesticides as part of their job; over half had been directly exposed, and the remainder had been possibly or certainly indirectly exposed. Educational level, age, sex, alcohol consumption, smoking, psychotropic drug use and depressive symptoms were taken into account.

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Metabolic syndrome linked to memory loss in older people

March, 2011

Three more studies point to the increased risk of memory loss in older adults with cardiovascular problems.

The new label of ‘metabolic syndrome’ applies to those having three or more of the following risk factors: high blood pressure, excess belly fat, higher than normal triglycerides, high blood sugar and low high-density lipoprotein (HDL) cholesterol (the "good" cholesterol). Metabolic syndrome has been linked to increased risk of heart attack.

A new French study, involving over 7,000 older adults (65+) has found that those with metabolic syndrome were 20% more likely to show cognitive decline on a memory test (MMSE) over a two or four year interval. They were also 13% more likely to show cognitive decline on a visual working memory test. Specifically, higher triglycerides and low HDL cholesterol were linked to poorer memory scores; diabetes (but not higher fasting blood sugar) was linked to poorer visual working memory and word fluency scores.

The findings point to the importance of managing the symptoms of metabolic syndrome.

High cholesterol and blood pressure in middle age tied to early memory problems

Another study, involving some 4800 middle-aged adults (average age 55), has found that those with higher cardiovascular risk were more likely to have lower cognitive function and a faster rate of cognitive decline over a 10-year period. A 10% higher cardiovascular risk was associated not only with increased rate of overall mental decline, but also poorer cognitive test scores in all areas except reasoning for men and fluency for women.

The cardiovascular risk score is based on age, sex, HDL cholesterol, total cholesterol, systolic blood pressure and whether participants smoked or had diabetes.

Memory problems may be sign of stroke risk

A very large study (part of the REGARDS study) tested people age 45 and older (average age 67) who had never had a stroke. Some 14,842 people took a verbal fluency test, and 17,851 people took a word recall memory test. In the next 4.5 years, 123 participants who had taken the verbal fluency test and 129 participants who had taken the memory test experienced a stroke.

Those who had scored in the bottom 20% for verbal fluency were 3.6 times more likely to develop a stroke than those who scored in the top 20%. For the memory test, those who scored in the bottom 20% were 3.5 times more likely to have a stroke than those in the top quintile.

The effect was greatest at the younger ages. At age 50, those who scored in the bottom quintile of the memory test were 9.4 times more likely to later have a stroke than those in the top quintile.

 

Together, these studies, which are consistent with many previous studies, confirm that cardiovascular problems and diabetes add to the risk of greater cognitive decline (and possible dementia) in old age. And point to the importance of treating these problems as soon as they appear.

Reference: 

[2147] Raffaitin, C., Féart C., Le Goff M., Amieva H., Helmer C., Akbaraly T. N., et al.
(2011).  Metabolic syndrome and cognitive decline in French elders.
Neurology. 76(6), 518 - 525.

The findings of the second and third studies are to be presented at the American Academy of Neurology's 63rd Annual Meeting in Honolulu April 9 to April 16, 2011

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Steep cholesterol decline in older women linked to Alzheimer's risk

February, 2011

A long-running study has found cholesterol levels at in mid-life were not linked to later dementia in women, but marked decline in cholesterol level over the study period was.

Research into the link, if any, between cholesterol and dementia, has been somewhat contradictory. A very long-running Swedish study may explain why. The study, involving 1,462 women aged 38-60 in 1968, has found that cholesterol measured in middle or old age showed no link to dementia, but there was a connection between dementia and the rate of decline in cholesterol level. Those women whose cholesterol levels decreased the most from middle to older age were more than twice as likely to develop dementia as those whose cholesterol levels increased or stayed the same (17.5% compared to 8.9%).After 32 years, 161 women had developed dementia.

Later in life, women with slightly higher body mass index, higher levels of cholesterol and higher blood pressure tend to be healthier overall than those whose weight, cholesterol and blood pressure are too low. But it is unclear whether "too low" cholesterol, BMI and blood pressure are risk factors for dementia or simply signs that dementia is developing, for reasons we do not yet understand.

On the other hand, a recent rat study has found that consuming a high cholesterol diet for five months caused memory impairment, cholinergic dysfunction, inflammation, enhanced cortical beta-amyloid and tau and induced microbleedings — all of which is strikingly similar to Alzheimer's pathology. And this finding is consistent with a number of other studies. So it does seem clear that the story of how exactly cholesterol impacts Alzheimer’s is a complex one that we are just beginning to unravel.

In light of other research indicating that the response of men and women to various substances (eg caffeine) may be different, we should also bear in mind that the results of the Swedish study may apply only to women.

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Heavy smoking in midlife associated with dementia in later years

November, 2010

A very large long-running study has found smoking over two packs per day in middle age more than doubled the chances of developing dementia in later life.

Data from 21,123 people, surveyed between 1978 and 1985 when in their 50s and tracked for dementia from 1994 to 2008, has revealed that those who smoked more than two packs per day in middle age had more than twice the risk of developing dementia, both Alzheimer's and vascular dementia, compared to non-smokers.

A quarter of the participants (25.4%) were diagnosed with dementia during the 23 years follow-up, of whom a little over 20% were diagnosed with Alzheimer's disease and nearly 8% with vascular dementia.

Former smokers, or those who smoked less than half a pack per day, did not appear to be at increased risk. Associations between smoking and dementia did not vary by race or sex.

Smoking is a well-established risk factor for stroke, and is also known to contribute to oxidative stress and inflammation.

Reference: 

[1934] Rusanen, M., Kivipelto M., Quesenberry C. P., Zhou J., & Whitmer R. A.
(2010).  Heavy Smoking in Midlife and Long-term Risk of Alzheimer Disease and Vascular Dementia.
Arch Intern Med. archinternmed.2010.393 - archinternmed.2010.393.

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