middle-aged

Menopause ‘brain fog’ a product of poor sleep and depression?

May, 2012

A smallish study of women approaching and in menopause found that some experienced poorer working memory and attention, and these were more likely to have poorer sleep, depression, and anxiety.

A study involving 75 perimenopausal women aged 40 to 60 has found that those with memory complaints tended to show impairments in working memory and attention. Complaints were not, however, associated with verbal learning or memory.

Complaints were also associated with depression, anxiety, somatic complaints, and sleep disturbance. But they weren’t linked to hormone levels (although estrogen is an important hormone for learning and memory).

What this suggests to me is that a primary cause of these cognitive impairments may be poor sleep, and anxiety/depression. A few years ago, I reported on a study that found that, although women’s reports of how many hot flashes they had didn’t correlate with memory impairment, an objective measure of the number of flashes they experienced during sleep did. Sleep, as I know from personal experience, is of sufficient importance that my rule-of-thumb is: don’t bother looking for any other causes of attention and memory deficits until you have sorted out your sleep!

Having said that, depressive symptoms showed greater relationship to memory complaints than sleep disturbance.

It’s no big surprise to hear that it is working memory in particular that is affected, because what many women at this time of life complain of is ‘brain fog’ — the feeling that your brain is full of cotton-wool. This doesn’t mean that you can’t learn new information, or remember old information. But it does mean that these tasks will be impeded to the extent that you need to hold on to too many bits of information. So mental arithmetic might be more difficult, or understanding complex sentences, or coping with unexpected disruptions to your routine, or concentrating on a task for a long time.

These sorts of problems are typical of those produced by on-going sleep deprivation, stress, and depression.

One caveat to the findings is that the study participants tended to be of above-average intelligence and education. This would protect them to a certain extent from cognitive decline — those with less cognitive reserve might display wider impairment. Other studies have found verbal memory, and processing speed, impaired during menopause.

Note, too, that a long-running, large population study has found no evidence for a decline in working memory, or processing speed, in women as they pass through perimenopause and menopause.

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Genes, brain size, brain atrophy, and Alzheimer’s risk

May, 2012

A round-up of genetic news.

  • Several genes are linked to smaller brain size and faster brain atrophy in middle- & old age.
  • The main Alzheimer's gene is implicated in leaky blood vessels, and shown to interact with brain size, white matter lesions, and dementia risk.
  • Some evidence suggests early-onset Alzheimer's is not so dissimilar to late-onset Alzheimer's.

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.

 

Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.

http://www.eurekalert.org/pub_releases/2006-04/vfii-rda041906.php

Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao, X., & Südhof T. C.
(2001).  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60.
Science. 293(5527), 115 - 120.

http://www.eurekalert.org/pub_releases/2001-07/aaft-eta070201.php

Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.

http://www.eurekalert.org/pub_releases/2004-04/cp-ioa032904.php

Reference: 

[2858] Consortium, E N I G M-A(ENIGMA)., & Cohorts Heart Aging Research Genomic Epidemiology(charge)
(2012).  Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Nature Genetics. 44(5), 545 - 551.

[2909] Taal, R. H., Pourcain B S., Thiering E., Das S., Mook-Kanamori D. O., Warrington N. M., et al.
(2012).  Common variants at 12q15 and 12q24 are associated with infant head circumference.
Nature Genetics. 44(5), 532 - 538.

[2859] Cohorts Heart Aging Research Genomic Epidemiology,(charge), & Consortium E G G(EGG).
(2012).  Common variants at 6q22 and 17q21 are associated with intracranial volume.
Nature Genetics. 44(5), 539 - 544.

[2907] Stein, J. L., Medland S. E., Vasquez A A., Hibar D. P., Senstad R. E., Winkler A. M., et al.
(2012).  Identification of common variants associated with human hippocampal and intracranial volumes.
Nature Genetics. 44(5), 552 - 561.

[2925] Bell, R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al.
(2012).  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
Nature.

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga, C., Chakraverty S., Mayo K., Vallania F. L. M., Mitra R. D., Faber K., et al.
(2012).  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families.
PLoS ONE. 7(2), e31039 - e31039.

Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

[2897] Pottier, C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., Rousseau S., et al.
(2012).  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
Molecular Psychiatry.

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

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Larger belly linked to memory problems in people with HIV

April, 2012

HIV-related cognitive impairment is significantly associated with a greater waist circumference, and in older adults, with diabetes.

A study involving 130 HIV-positive people has found that memory impairment was associated with a significantly larger waistline.

Some 40% of participants (average age 46) had impaired cognition. This group had an average waist circumference of 39 inches, compared to 35 inches for those without such problems. Memory impairment was also linked to diabetes in those older than 55 (15% of those with memory problems had diabetes compared to only 3% of those without memory problems).

Waistline was more important than BMI. Unfortunately, some anti-HIV drugs cause weight gain in this area.

The finding is consistent with evidence that abdominal weight is more important than overall weight for cognitive impairment and dementia in the general population.

For more about HIV-related cognitive impairment

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Alzheimer's protein may impair mental function even in healthy adults

March, 2012

The protein associated with Alzheimer's disease appears to impair cognitive function many years before symptoms manifest. Higher levels of this protein are more likely in carriers of the Alzheimer’s gene, and such carriers may be more affected by the protein’s presence.

Another study adds to the evidence that changes in the brain that may lead eventually to Alzheimer’s begin many years before Alzheimer’s is diagnosed. The findings also add to the evidence that what we regard as “normal” age-related cognitive decline is really one end of a continuum of which the other end is dementia.

In the study, brain scans were taken of 137 highly educated people aged 30-89 (participants in the Dallas Lifespan Brain Study). The amount of amyloid-beta (characteristic of Alzheimer’s) was found to increase with age, and around a fifth of those over 60 had significantly elevated levels of the protein. These higher amounts were linked with worse performance on tests of working memory, reasoning and processing speed.

More specifically, across the whole sample, amyloid-beta levels affected processing speed and fluid intelligence (in a dose-dependent relationship — that is, as levels increased, these functions became more impaired), but not working memory, episodic memory, or crystallized intelligence. Among the elevated-levels group, increased amyloid-beta was significantly associated with poorer performance for processing speed, working memory, and fluid intelligence, but not episodic memory or crystallized intelligence. Among the group without elevated levels of the protein, increasing amyloid-beta only affected fluid intelligence.

These task differences aren’t surprising: processing speed, working memory, and fluid intelligence are the domains that show the most decline in normal aging.

Those with the Alzheimer’s gene APOE4 were significantly more likely to have elevated levels of amyloid-beta. While 38% of the group with high levels of the protein had the risky gene variant, only 15% of those who didn’t have high levels carried the gene.

Note that, while the prevalence of carriers of the gene variant matched population estimates (24%), the proportion was higher among those in the younger age group — 33% of those under 60, compared to 19.5% of those aged 60 or older. It seems likely that many older carriers have already developed MCI or Alzheimer’s, and thus been ineligible for the study.

The average age of the participants was 64, and the average years of education 16.4.

Amyloid deposits varied as a function of age and region: the precuneus, temporal cortex, anterior cingulate and posterior cingulate showed the greatest increase with age, while the dorsolateral prefrontal cortex, orbitofrontal cortex, parietal and occipital cortices showed smaller increases with age. However, when only those aged 60+ were analyzed, the effect of age was no longer significant. This is consistent with previous research, and adds to evidence that age-related cognitive impairment, including Alzheimer’s, has its roots in damage occurring earlier in life.

In another study, brain scans of 408 participants in the Mayo Clinic Study of Aging also found that higher levels of amyloid-beta were associated with poorer cognitive performance — but that this interacted with APOE status. Specifically, carriers of the Alzheimer’s gene variant were significantly more affected by having higher levels of the protein.

This may explain the inconsistent findings of previous research concerning whether or not amyloid-beta has significant effects on cognition in normal adults.

As the researchers of the first study point out, what’s needed is information on the long-term course of these brain changes, and they are planning to follow these participants.

In the meantime, all in all, the findings do provide more strength to the argument that your lifestyle in mid-life (and perhaps even younger) may have long-term consequences for your brain in old age — particularly for those with a genetic susceptibility to Alzheimer’s.

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Cognitive decline begins in middle age

February, 2012

A large ten-year study of middle-aged to older adults (45-70) has found that cognitive decline begins in the 45-55 decade, with reasoning ability the most affected by age.

The age at which cognitive decline begins has been the subject of much debate. The Seattle longitudinal study has provided most of the evidence that it doesn’t begin until age 60. A more recent, much larger study that allows both longitudinal and cross-sectional analysis suggests that, depressingly, mid-to-late forties might be closer to the mark.

A long-term British study known as Whitehall II began in 1985, when all civil servants aged 35-55 in 20 London-based departments were invited to participate. In 1997-9, 5198 male and 2192 female civil servants, aged 45-70 at this point, were given the first of three rounds of cognitive testing. The second round took place in 2002-4, and the third in 2007-9.

Over these ten years, all cognitive scores except vocabulary declined in all five age categories (45-49, 50-54, 55-59, 60-64, and 65-70 at baseline). Unsurprisingly, the decline was greater with increasing age, and greatest for reasoning. Men aged 45-9 at baseline showed a 3.6% decline in reasoning, compared to a 9.6% decline for those aged 65-70. Women were less affected by age: while showing the same degree of decline when younger, the oldest showed a 7.4% decline.

None of the other cognitive tasks showed the same age-related deterioration as reasoning, which displayed a consistently linear decline with advancing age. The amount of decline over ten years was roughly similar for each age group for short-term memory and phonemic and semantic fluency (although the women displayed more variability in memory, in a somewhat erratic pattern which may perhaps reflect hormonal changes — I’m speculating here). Moreover, the amount of decline in each decade for these functions was only about the same as reasoning’s decline in the younger decades — about -4% in each decade.

Men and women differed significantly in education (33% of men attended university compared to 21% of women; 57% of women never finished secondary school compared to 39% of men). It is therefore unsurprising that men performed significantly better on all cognitive tests except memory (noting that the actual differences in score were mostly quite small: 16.9/35 vs 16.5 for phonemic fluency; 16.7/35 vs 15.8 for semantic fluency; 25.7/33 vs 23.1 for vocabulary; 48.7/65 vs 41.6 for reasoning).

The cognitive tests included a series of 65 verbal and mathematical reasoning items of increasing difficulty (testing inductive reasoning), a 20-word free recall test (short-term verbal memory), recalling as many words as possible beginning with “S” (phonemic fluency) and recalling members of the animal category (semantic fluency), and a multi-choice vocabulary test.

The design of the study allowed both longitudinal and cross-sectional analyses to be carried out. Cross-sectional data, although more easily acquired, has been criticized as conflating age effects with cohort differences. Generations differ on several relevant factors, of which education is the most obvious. The present study semi-confirmed this, finding that cross-sectional data considerably over-estimated cognitive decline in women but not men — reflecting the fact that education changed far more for women than men in the relevant time periods. For example, in the youngest group of men, 30% had less than a secondary school education and 42% had a university degree, and the women showed a similar pattern, with 34% and 40%. However, for those aged 55-59 at baseline, the corresponding figures were 38% and 29% for men compared to 58% and 17% for women.

The principal finding is of course that measurable cognitive decline was evident in the youngest group, meaning that at some point during that 45-55 decade, cognitive faculties begin to decline. Of course, it should be emphasized that this is a group effect — individuals will vary in the extent and timing of any cognitive decline.

(A side-note: During the ten year period, 305 participants died. The probability of dying was higher in those with poorer cognitive scores at baseline.)

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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.

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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."

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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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tags lifestyle: 

tags problems: 

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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