middle-aged

Early surgical menopause linked to faster cognitive decline

February, 2013

Women who undergo surgical menopause at an earlier age may have an increased risk of cognitive decline.

The issue of the effect of menopause on women’s cognition, and whether hormone therapy helps older women fight cognitive decline and dementia, has been a murky one. Increasing evidence suggests that the timing and type of therapy is critical. A new study makes clear that we also need to distinguish between women who experience early surgical menopause and those who experience natural menopause.

The study involved 1,837 women (aged 53-100), of whom 33% had undergone surgical menopause (removal of both ovaries before natural menopause). For these women, earlier age of the procedure was associated with a faster decline in semantic and episodic memory, as well as overall cognition. The results stayed the same after factors such as age, education and smoking were taken into consideration.

There was also a significant association between age at surgical menopause and the plaques characteristic of Alzheimer's disease. However, there was no significant association with Alzheimer’s itself.

On the positive side, hormone replacement therapy was found to help protect those who had surgical menopause, with duration of therapy linked to a significantly slower decline in overall cognition.

Also positively, age at natural menopause was not found to be associated with rate of cognitive decline.

Reference: 

Bove, R. et al. 2013. Early Surgical Menopause Is Associated with a Spectrum of Cognitive Decline. To be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 21, 2013.

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Why learning gets harder as we get older

February, 2013

A mouse study shows that weakening unwanted or out-of-date connections is as important as making new connections, and that neurological changes as we age reduces our ability to weaken old connections.

A new study adds more support to the idea that the increasing difficulty in learning new information and skills that most of us experience as we age is not down to any difficulty in acquiring new information, but rests on the interference from all the old information.

Memory is about strengthening some connections and weakening others. A vital player in this process of synaptic plasticity is the NMDA receptor in the hippocampus. This glutamate receptor has two subunits (NR2A and NR2B), whose ratio changes as the brain develops. Children have higher ratios of NR2B, which lengthens the time neurons talk to each other, enabling them to make stronger connections, thus optimizing learning. After puberty, the ratio shifts, so there is more NR2A.

Of course, there are many other changes in the aging brain, so it’s been difficult to disentangle the effects of this changing ratio from other changes. This new study genetically modified mice to have more NR2A and less NR2B (reflecting the ratio typical of older humans), thus avoiding the other confounds.

To the researchers’ surprise, the mice were found to be still good at making strong connections (‘long-term potentiation’ - LTP), but instead had an impaired ability to weaken existing connections (‘long-term depression’ - LTD). This produces too much noise (bear in mind that each neuron averages 3,000 potential points of contact (i.e., synapses), and you will see the importance of turning down the noise!).

Interestingly, LTD responses were only abolished within a particular frequency range (3-5 Hz), and didn’t affect 1Hz-induced LTD (or 100Hz-induced LTP). Moreover, while the mice showed impaired long-term learning, their short-term memory was unaffected. The researchers suggest that these particular LTD responses are critical for ‘post-learning information sculpting’, which they suggest is a step (hitherto unknown) in the consolidation process. This step, they postulate, involves modifying the new information to fit in with existing networks of knowledge.

Previous work by these researchers has found that mice genetically modified to have an excess of NR2B became ‘super-learners’. Until now, the emphasis in learning and memory has always been on long-term potentiation, and the role (if any) of long-term depression has been much less clear. These results point to the importance of both these processes in sculpting learning and memory.

The findings also seem to fit in with the idea that a major cause of age-related cognitive decline is the failure to inhibit unwanted information, and confirm the importance of keeping your mind actively engaged and learning, because this ratio is also affected by experience.

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Menopause forgetfulness greatest early in postmenopause

January, 2013

A smallish study suggests that the cognitive effects of menopause are greatest in the first year after menopause.

Being a woman of a certain age, I generally take notice of research into the effects of menopause on cognition. A new study adds weight, perhaps, to the idea that cognitive complaints in perimenopause and menopause are not directly a consequence of hormonal changes, but more particularly, shows that early post menopause may be the most problematic time.

The study followed 117 women from four stages of life: late reproductive, early and late menopausal transition, and early postmenopause. The late reproductive period is defined as when women first begin to notice subtle changes in their menstrual periods, but still have regular menstrual cycles. Women in the transitional stage (which can last for several years) experience fluctuation in menstrual cycles, and hormone levels begin to fluctuate significantly.

Women in the early stage of post menopause (first year after menopause), as a group, were found to perform more poorly on measures of verbal learning, verbal memory, and fine motor skill than women in the late reproductive and late transition stages. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks.

Surprisingly, self-reported symptoms such as sleep difficulties, depression, and anxiety did not predict memory problems. Neither were the problems correlated with hormone levels (although fluctuations could be a factor).

This seemingly contradicts earlier findings from the same researchers, who in a slightly smaller study found that those experiencing poorer working memory and attention were more likely to have poorer sleep, depression, and anxiety. That study, however, only involved women approaching and in menopause. Moreover, these aspects were not included in the abstract of the paper but only in the press release, and because I don’t have access to this particular journal, I cannot say whether there is something in the data that explains this. Because of this, I am not inclined to put too much weight on this point.

But we may perhaps take the findings as support for the view that cognitive problems experienced earlier in the menopause cycle are, when they occur, not a direct result of hormonal changes.

The important result of this study is the finding that the cognitive problems often experienced by women in their 40s and 50s are most acute during the early period of post menopause, and the indication that the causes and manifestations are different at different stages of menopause.

It should be noted, however, that there were only 14 women in the early postmenopause stage. So, we shouldn’t put too much weight on any of this. Nevertheless, it does add to the picture research is building up about the effects of menopause on women’s cognition.

While the researchers said that this effect is probably temporary — which was picked up as the headline in most media — this was not in fact investigated in this study. It would be nice to have some comparison with those, say, two or three and five years post menopause (but quite possibly this will be reported in a later paper).

Reference: 

[3237] Weber MT, Rubin LH, Maki PM. Cognition in perimenopause. Menopause: The Journal of The North American Menopause Society [Internet]. 2013 . Available from: http://journals.lww.com/menopausejournal/Abstract/publishahead/Cognition_in_perimenopause___the_effect_of.98696.aspx

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Social isolation decreases myelin

December, 2012

A mouse study demonstrates that prolonged social isolation can lead to a decrease in myelin, an effect implicated in a number of disorders, including age-related cognitive decline.

Problems with myelin — demyelination (seen most dramatically in MS, but also in other forms of neurodegeneration, including normal aging and depression); failure to develop sufficient myelin (in children and adolescents) — are increasingly being implicated in a wide range of disorders. A new animal study adds to that evidence by showing that social isolation brings about both depression and loss of myelin.

In the study, adult mice were isolated for eight weeks (which is of course longer for a mouse than it is to us) to induce a depressive-like state. They were then introduced to a mouse they hadn’t seen before. Although typically very social animals, those who had been socially isolated didn’t show any interest in interacting with the new mouse — a common pattern in human behavior as well.

Analysis of their brains revealed significantly lower levels of gene transcription for oligodendrocyte cells (the components of myelin) in the prefrontal cortex. This appeared to be caused by a lower production of heterochromatin (tightly packed DNA) in the cell nuclei, producing less mature oligodendrocytes.

Interestingly, even short periods of isolation were sufficient to produce changes in chromatin and myelin, although behavior wasn’t affected.

Happily, however, regardless of length of isolation, myelin production went back to normal after a period of social integration.

The findings add to the evidence that environmental factors can have significant effects on brain development and function, and support the idea that socializing is good for the brain.

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Brain training helps cognitive decline in many cancer survivors

November, 2012

A pilot study found that both training in memory strategies and processing speed training had significant benefits for breast cancer survivors with concerns about their memory and cognition.

Cancer survivors who underwent chemotherapy often suffer long-term cognitive problems. Until now, most research has been occupied with establishing that this is in fact the case, and studies investigating how to help have been rare. I recently reported on studies suggesting that help with sleep problems and stress can be beneficial. It has also been suggested that exercise can help. None of these suggestions are special to cancer survivors (although cancer survivors may well be one of several groups that derive particular benefit). Similarly, a new study investigates another familiar approach to improving cognitive decline.

The pilot study involved 82 post-menopausal breast cancer survivors (average age 56) who had received chemotherapy and who were worried about their cognitive abilities. The women were randomly assigned to one of three groups: one group received memory training adapted from the ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) trial; another received processing speed training using Posit Science’s Insight program (commercially available); the third was a wait-listed control group.

Training consisted of ten 1-hour small-group (3-5 people) sessions over 6-8 weeks. Memory training involved learning strategies and applying them to word lists, sequences, and texts. Strategies included mnemonic techniques, as well as instruction in principles of meaningfulness, organization, visualization, and association. Strategies were taught and practiced in the first five sessions, and further practiced in the remaining sessions.

In the Insight program, stimulus duration is progressively shortened during a series of progressively more difficult information-processing tasks, such as time-order judgment, discrimination, spatial-match, forward-span, instruction-following, and narrative-memory tasks. Exercises automatically adjust to maintain an 85% correct rate.

Both programs proved beneficial. The memory training group showed significant improvement in immediate and delayed memory, which was maintained at the two-month follow-up. There was of course individual variability: 39% showed significant improvement on immediate memory (compared to 18% of controls) and 42% on delayed memory (compared to 11% of controls). While the group as a whole didn’t show significant improvement in processing speed, some 73% of the group showed reliable improvement at the two-month follow-up.

The Insight group showed significant improvement on both memory and processing speed. Some 68% improved processing speed (compared to 43% of controls). But note that at the 2-month follow-up, the 67% of the Insight group is not that much greater than the 61% of the controls (demonstrating very clearly the benefits of even the small amount of practice received in testing) and is in fact less than the 73% of the memory group.

The Insight group also showed significant improvement in memory. At two-month follow-up, some 30% of the Insight group had improved immediate memory (compared to the 18% of controls), and 33% had improved delayed memory (vs 11%).

Both training programs had a positive effect on perceived cognitive functioning and symptom distress (mood, anxiety, fatigue), and there was no difference between the groups in terms of satisfaction with the training (both groups were very satisfied).

The researchers concluded that, while both training programs were promising, the dual effect of processing speed training (on memory as well as processing speed) argued for its broader benefits.

However, I note that, although the size of the effect of memory training on processing speed was too small to reach statistical significance, the fact that the number of participants showing reliable improvement was greater than that of the Insight group points to an equally broad effect of memory training. If the memory training was supplemented by a small amount of practice on tasks designed to boost processing speed, it would seem to me that this might produce greater cognitive benefits than the processing speed training. Indeed, the Insight program was, I believe, first developed in the context of the ACTIVE program, and I have, of course, talked before about the value of training that includes multiple domains.

Still, the main message of this study should not be overlooked: it demonstrates that many cancer survivors suffering from cognitive decline can improve their cognitive performance through training and practice.

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Why metabolic syndrome is linked to cognitive decline?

October, 2012

Preliminary results for a small study indicate metabolic syndrome is linked to significantly reduced blood flow in the brain, perhaps explaining its link to cognitive impairment.

I’ve reported before on the growing evidence that metabolic syndrome in middle and old age is linked to greater risk of cognitive impairment in old age and faster decline. A new study shows at least part of the reason.

The study involved 71 middle-aged people recruited from the Wisconsin Registry for Alzheimer's Prevention (WRAP), of whom 29 met the criteria for metabolic syndrome (multiple cardiovascular and diabetes risk factors including abdominal obesity, high blood pressure, high blood sugar and high cholesterol).

Those with metabolic syndrome averaged 15% less blood flow to the brain than those without the syndrome.

One tried and true method of increasing blood flow to the brain is of course through exercise.

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The study was presented at the Alzheimer's Association International Conference in Vancouver, Canada by Barbara Bendlin.

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Rapamycin makes young mice learn better and prevents decline in old mice

July, 2012

Further evidence from mice studies that the Easter Island drug improves cognition, in young mice as well as old.

I have reported previously on research suggesting that rapamycin, a bacterial product first isolated from soil on Easter Island and used to help transplant patients prevent organ rejection, might improve learning and memory. Following on from this research, a new mouse study has extended these findings by adding rapamycin to the diet of healthy mice throughout their life span. Excitingly, it found that cognition was improved in young mice, and abolished normal cognitive decline in older mice.

Anxiety and depressive-like behavior was also reduced, and the mice’s behavior demonstrated that rapamycin was acting like an antidepressant. This effect was found across all ages.

Three "feel-good" neurotransmitters — serotonin, dopamine and norepinephrine — all showed significantly higher levels in the midbrain (but not in the hippocampus). As these neurotransmitters are involved in learning and memory as well as mood, it is suggested that this might be a factor in the improved cognition.

Other recent studies have suggested that rapamycin inhibits a pathway in the brain that interferes with memory formation and facilitates aging.

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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 TC. A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60. Science [Internet]. 2001 ;293(5527):115 - 120. Available from: http://www.sciencemag.org/content/293/5527/115

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

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[2858] Consortium ENIGM-A (ENIGMA), Cohorts Heart Aging Research Genomic Epidemiology (charge). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics [Internet]. 2012 ;44(5):545 - 551. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2237.html

[2909] Taal RH, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics [Internet]. 2012 ;44(5):532 - 538. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2238.html

[2859] Cohorts Heart Aging Research Genomic Epidemiology (charge), Consortium EGG (EGG). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics [Internet]. 2012 ;44(5):539 - 544. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2245.html

[2907] Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics [Internet]. 2012 ;44(5):552 - 561. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2250.html

[2925] Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature [Internet]. 2012 . Available from: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11087.html?WT.ec_id=NATURE-20120517

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 FLM, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, et al. Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families. PLoS ONE [Internet]. 2012 ;7(2):e31039 - e31039. Available from: UR - http://dx.doi.org/10.1371/journal.pone.0031039,http://dx.doi.org/10.1371/journal.pone.0031039

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, Legallic S, Paquet C, Bombois S, Pariente J, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry [Internet]. 2012 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201215a.html

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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