risk factors

Alzheimer's risk gene disrupts brain function in older women, but not men

August, 2012

A new study indicates that carrying the ‘Alzheimer’s gene’ may be a significant risk factor for women only.

While the ‘Alzheimer’s gene’ is relatively common — the ApoE4 mutation is present in around 15% of the population — having two copies of the mutation is, thankfully, much rarer, at around 2%. Having two copies is of course a major risk factor for developing Alzheimer’s, and it has been thought that having a single copy is also a significant (though lesser) risk factor. Certainly there is quite a lot of evidence linking ApoE4 carriers to various markers of cognitive impairment.

And yet, the evidence has not been entirely consistent. I have been puzzled by this myself, and now a new finding suggests a reason. It appears there are gender differences in responses to this gene variant.

The study involved 131 healthy older adults (median age 70), whose brains were scanned. The scans revealed that in older women with the E4 variant, brain activity showed the loss of synchronization that is typically seen in Alzheimer’s patients, with the precuneus (a major hub in the default mode network) out of sync with other brain regions. This was not observed in male carriers.

The finding was confirmed by a separate set of data, taken from the Alzheimer's Disease Neuroimaging Initiative database. Cerebrospinal fluid from 91 older adults (average age 75) revealed that female carriers had substantially higher levels of tau protein (a key Alzheimer’s biomarker) than male carriers or non-carriers.

It’s worth emphasizing that the participants in the first study were all cognitively normal — the loss of synchronization was starting to happen before visible Alzheimer’s symptoms appeared.

The findings suggest that men have less to worry about than women, as far as the presence of this gene is concerned. The study may also explain why more women than men get the disease (3 women to 2 men); it is not (although of course this is a factor) simply a consequence of women tending to live longer.

Whether or not these gender differences extend to carriers of two copies of the gene is another story.

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Alzheimer’s biomarkers present decades before symptoms

July, 2012
  • People with a strong genetic risk of early-onset Alzheimer’s have revealed a progression of brain changes that begin 25 years before symptoms are evident.

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

Reference: 

[2997] Bateman, R. J., Xiong C., Benzinger T. L. S., Fagan A. M., Goate A., Fox N. C., et al.
(2012).  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease.
New England Journal of Medicine. 120723122607004 - 120723122607004.

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Immune system may protect against Alzheimer's

July, 2012

New studies involving genetically-engineered mice and older adult humans support a connection between the immune system and cognitive impairment in old age.

A number of studies have come out in recent years linking age-related cognitive decline and dementia risk to inflammation and infection (put inflammation into the “Search this site” box at the top of the page and you’ll see what I mean). New research suggests one important mechanism.

In a mouse study, mice engineered to be deficient in receptors for the CCR2 gene — a crucial element in removing beta-amyloid and also important for neurogenesis — developed Alzheimer’s-like pathology more quickly. When these mice had CCR2 expression boosted, accumulation of beta-amyloid decreased and the mice’s memory improved.

In the human study, the expression levels of thousands of genes from 691 older adults (average age 73) in Italy (part of the long-running InCHIANTI study) were analyzed. Both cognitive performance and cognitive decline over 9 years (according to MMSE scores) were significantly associated with the expression of this same gene. That is, greater CCR2 activity was associated with lower cognitive scores and greater decline.

Expression of the CCR2 gene was also positively associated with the Alzheimer’s gene — meaning that those who carry the APOE4 variant are more likely to have higher CCR2 activity.

The finding adds yet more weight to the importance of preventing / treating inflammation and infection.

Reference: 

[2960] Harries, L. W., Bradley-Smith R. M., Llewellyn D. J., Pilling L. C., Fellows A., Henley W., et al.
(2012).  Leukocyte CCR2 Expression Is Associated with Mini-Mental State Examination Score in Older Adults.
Rejuvenation Research. 120518094735004 - 120518094735004.

Naert, G. & Rivest S. 2012. Hematopoietic CC-chemokine receptor 2-(CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Molecular Medicine, 18(1), 297-313.

El Khoury J, et al. 2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine, 13, 432–8.

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Effect of blood pressure on the aging brain depends on genetics

July, 2012
  • For those with the Alzheimer’s gene, higher blood pressure, even though within the normal range, is linked to greater brain shrinkage and reduced cognitive ability.

I’ve reported before on the evidence suggesting that carriers of the ‘Alzheimer’s gene’, APOE4, tend to have smaller brain volumes and perform worse on cognitive tests, despite being cognitively ‘normal’. However, the research hasn’t been consistent, and now a new study suggests the reason.

The e4 variant of the apolipoprotein (APOE) gene not only increases the risk of dementia, but also of cardiovascular disease. These effects are not unrelated. Apoliproprotein is involved in the transportation of cholesterol. In older adults, it has been shown that other vascular risk factors (such as elevated cholesterol, hypertension or diabetes) worsen the cognitive effects of having this gene variant.

This new study extends the finding, by looking at 72 healthy adults from a wide age range (19-77).

Participants were tested on various cognitive abilities known to be sensitive to aging and the effects of the e4 allele. Those abilities include speed of information processing, working memory and episodic memory. Blood pressure, brain scans, and of course genetic tests, were also performed.

There are a number of interesting findings:

  • The relationship between age and hippocampal volume was stronger for those carrying the e4 allele (shrinkage of this brain region occurs with age, and is significantly greater in those with MCI or dementia).
  • Higher systolic blood pressure was significantly associated with greater atrophy (i.e., smaller volumes), slower processing speed, and reduced working memory capacity — but only for those with the e4 variant.
  • Among those with the better and more common e3 variant, working memory was associated with lateral prefrontal cortex volume and with processing speed. Greater age was associated with higher systolic blood pressure, smaller volumes of the prefrontal cortex and prefrontal white matter, and slower processing. However, blood pressure was not itself associated with either brain atrophy or slower cognition.
  • For those with the Alzheimer’s variant (e4), older adults with higher blood pressure had smaller volumes of prefrontal white matter, and this in turn was associated with slower speed, which in turn linked to reduced working memory.

In other words, for those with the Alzheimer’s gene, age differences in working memory (which underpin so much of age-related cognitive impairment) were produced by higher blood pressure, reduced prefrontal white matter, and slower processing. For those without the gene, age differences in working memory were produced by reduced prefrontal cortex and prefrontal white matter.

Most importantly, these increases in blood pressure that we are talking about are well within the normal range (although at the higher end).

The researchers make an interesting point: that these findings are in line with “growing evidence that ‘normal’ should be viewed in the context of individual’s genetic predisposition”.

What it comes down to is this: those with the Alzheimer’s gene variant (and no doubt other genetic variants) have a greater vulnerability to some of the risk factors that commonly increase as we age. Those with a family history of dementia or serious cognitive impairment should therefore pay particular attention to controlling vascular risk factors, such as hypertension and diabetes.

This doesn’t mean that those without such a family history can safely ignore such conditions! When they get to the point of being clinically diagnosed as problems, then they are assuredly problems for your brain regardless of your genetics. What this study tells us is that these vascular issues appear to be problematic for Alzheimer’s gene carriers before they get to that point of clinical diagnosis.

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Type of fat, not amount of fat, linked to cognitive decline in old age

June, 2012

A large four-year study of older women has found high amounts of saturated fat were associated with greater cognitive decline, while higher amounts of monounsaturated fat were associated with better performance.

Data from the Women's Health Study, involving 6,183 older women (65+), has found that it isn’t the amount of fat but the type of fat that is associated with cognitive decline. The women were given three cognitive function tests at two-yearly intervals, and filled out very detailed food frequency surveys at the beginning of the study.

Women who consumed the highest amounts of saturated fat (such as that from animals) had significantly poorer cognitive function compared to those who consumed the lowest amounts. Women who instead had a high intake of monounsaturated fats (such as olive oil) had better cognitive scores over time. Total fat, polyunsaturated fat, and trans fat, were not associated with cognitive performance.

The findings are consistent with research associating the Mediterranean diet (high in olive oil) with lower Alzheimer’s risk, and studies linking diets high in saturated fats with greater cognitive decline.

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Eye health related to brain health in older adults

June, 2012
  • A large, long-running study has found cognitive decline and brain lesions are linked to mild retinal damage in older women.

Damage to the retina (retinopathy) doesn’t produce noticeable symptoms in the early stages, but a new study indicates it may be a symptom of more widespread damage. In the ten-year study, involving 511 older women (average age 69), 7.6% (39) were found to have retinopathy. These women tended to have lower cognitive performance, and brain scans revealed that they had more areas of small vascular damage within the brain — 47% more overall, and 68% more in the parietal lobe specifically. They also had more white matter damage. They did not have any more brain atrophy.

These correlations remained after high blood pressure and diabetes (the two major risk factors for retinopathy) were taken into account. It’s estimated that 40-45% of those with diabetes have retinopathy.

Those with retinopathy performed similarly to those without on a visual acuity test. However, testing for retinopathy is a simple test that should routinely be carried out by an optometrist in older adults, or those with diabetes or hypertension.

The findings suggest that eye screening could identify developing vascular damage in the brain, enabling lifestyle or drug interventions to begin earlier, when they could do most good. The findings also add to the reasons why you shouldn’t ignore pre-hypertensive and pre-diabetic conditions.

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Poor sleep in old age increases risk of cognitive impairment

May, 2012

Two recent studies add to evidence that sleeping poorly is a risk factor for several disorders in old age, including mild cognitive impairment, Parkinson’s, cardiovascular disease and diabetes.

Older adults who sleep poorly react to stress with increased inflammation

A study involving 83 older adults (average age 61) has found that poor sleepers reacted to a stressful situation with a significantly greater inflammatory response than good sleepers. High levels of inflammation increase the risk of several disorders, including cardiovascular disease and diabetes, and have been implicated in Alzheimer’s.

Each participant completed a self-report of sleep quality, perceived stress, loneliness and medication use. Around 27% were categorized as poor sleepers. Participants were given a series of tests of verbal and working memory designed to increase stress, with blood being taken before and after testing, as well as three more times over the next hour. The blood was tested for levels of a protein marker for inflammation (interleukin-6).

Poor sleepers reported more depressive symptoms, more loneliness and more perceived stress compared to good sleepers. Before cognitive testing, levels of IL-6 were the same for poor and good sleepers. However, while both groups showed increases in IL-6 after testing, poor sleepers showed a significantly larger increase — as much as four times larger and at a level found to increase risk for illness and death in older adults.

After accounting for loneliness, depression or perceived stress, this association remained. Surprisingly, there was no evidence that poor sleep led to worse cognitive performance, thus causing more stress. Poor sleepers did just as well on the tests as the good sleepers (although I note that we cannot rule out that poor sleepers were having to put in more effort to achieve the same results). Although there was a tendency for poor sleepers to be in a worse mood after testing (perhaps because they had to put in more effort? My own speculation), this mood change didn’t predict the increased inflammatory response.

The findings add to evidence that poor sleep (unfortunately common as people age) is an independent risk factor for cognitive and physical health, and suggest we should put more effort into dealing with it, rather than just accepting it as a corollary of age.

REM sleep disorder doubles risk of MCI, Parkinson's

A recent Mayo Clinic study has also found that people with rapid eye movement sleep behavior disorder (RBD) have twice the risk of developing mild cognitive impairment or Parkinson’s disease. Some 34% of those diagnosed with probable RBD developed MCI or Parkinson's disease within four years of entering the study, a rate 2.2 times greater than those with normal REM sleep.

Earlier research has found that 45% of those with RBD developed MCI or Parkinson's disease within five years of diagnosis, but these findings were based on clinical patients. The present study involved cognitively healthy older adults (70-89) participating in a population-based study of aging, who were diagnosed for probable RBD on the basis of the Mayo Sleep Questionnaire.

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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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Hypertension & Cognition

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

High blood pressure linked to memory problems in middle age

A study involving nearly 20,000 people age 45 and older, of whom nearly half were taking medication for high blood pressure, has found that those with high diastolic blood pressure (the bottom number of a blood pressure reading) were more likely to have cognitive impairment than those with normal diastolic readings. For every 10 point increase in the reading, the odds of a person having cognitive problems was 7% higher. There was no correlation with systolic blood pressure. The results were adjusted for age, smoking status, exercise level, education, diabetes and high cholesterol. High diastolic blood pressure is known to lead to weakening of small arteries in the brain.

[750] Tsivgoulis, G., Alexandrov A. V., Wadley V. G., Unverzagt F. W., Go R. C. P., Moy C. S., et al.
(2009).  Association of higher diastolic blood pressure levels with cognitive impairment.
Neurology. 73(8), 589 - 595.

http://www.eurekalert.org/pub_releases/2009-08/aaon-hbp081809.php

A diet that may reduce age-related cognitive decline

The Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure and is often recommended by physicians to people with high blood pressure or pre-hypertension. An 11-year study of over 3800 seniors found that those with higher DASH diet adherence scores had higher cognitive scores at the beginning of the study and increasingly so over time. Four of the nine food-group/nutrient components were independently associated with cognitive scores -- vegetables, whole grains, low-fat dairy, nut/legumes. When a score based on just these four components was used, the difference between those in the highest quintile and those in the lowest was even greater, particularly by the end of the study.

Wengreen, H.J. et al. 2009. DASH diet adherence scores and cognitive decline and dementia among aging men and women: Cache County study of Memory Health and Aging. Presented at the Alzheimer's Association International Conference on Alzheimer's Disease July 11-16 in Vienna.

Factors helping you maintain cognitive function in old age

An 8-year study of over 2,500 seniors in their 70s, has found that 53% showed normal age-related decline, 16% showed major cognitive decline, and an encouraging 30% had no change or improved on the tests over the years. The most important factors in determining whether a person maintained their cognitive health was education and literacy: those with a ninth grade literacy level or higher were nearly five times as likely to stay sharp than those with lower literacy levels; those with at least a high school education were nearly three times as likely to stay sharp as those who have less education. Lifestyle factors were also significant: non-smokers were nearly twice as likely to stay sharp as smokers; those who exercised moderately to vigorously at least once a week were 30% more likely to maintain their cognitive function than those who do not exercise that often; people working or volunteering and people who report living with someone were 24% more likely to maintain cognitive function.

[909] Ayonayon, H. N., Harris T. B., For the Health ABC Study, Yaffe K., Fiocco A. J., Lindquist K., et al.
(2009).  Predictors of maintaining cognitive function in older adults: The Health ABC Study.
Neurology. 72(23), 2029 - 2035.

http://www.eurekalert.org/pub_releases/2009-06/aaon-ssn060209.php

Hypertension in children linked to cognitive problems

A study of 32 newly diagnosed hypertensive children and adolescents (10 to 18 years old) plus 32 matched children with normal blood pressure has revealed that, according to parental assessment, those with high blood pressure scored significantly lower on executive function — that is, were poorer at planning, at complicated goal-directed tasks, and had more working memory problems. Additionally, more than half the children with both hypertension and obesity demonstrated clinically significant anxiety and depression.

Lande, M.B. et al. 2009. Parental Assessments of Internalizing and Externalizing Behavior and Executive Function in Children with Primary Hypertension. Journal of Pediatrics, 154 (2), 207-212.

http://www.eurekalert.org/pub_releases/2009-02/uorm-cwh022409.php

High blood pressure may make it difficult for the elderly to think clearly

A study involving 36 community-dwelling elderly (60-87 years old) whose blood pressure and cognitive functioning was monitored for 60 days has found that those with high blood pressure tended to perform more poorly on one of the three cognitive tasks, and this was particularly so when their blood pressure was higher than normal. The finding suggests that high blood pressure impacts on inductive reasoning, and thus the ability to work flexibly with unfamiliar information and find solutions. It also suggests that, for those with high blood pressure, such reasoning will be particularly difficult when they are stressed.

Gamaldo, A.A., Weatherbee, S.R. & Allaire, J.C. 2008. Exploring the Within-Person Coupling of Blood Pressure and Cognition in Elders. Journal of Gerontology: Psychological Science, 63, 386-389.

http://www.eurekalert.org/pub_releases/2008-12/ncsu-hbp121008.php

High blood pressure associated with risk for mild cognitive impairment

A study of nearly 1000 older adults (average age 76.3) without mild cognitive impairment at the start of the study found that over the follow-up period (average: 4.7 years), 334 individuals developed mild cognitive impairment, of which 160 were amnestic (reduced memory) and 174 were non-amnestic. Hypertension (high blood pressure) was associated with an increased risk of non-amnestic mild cognitive impairment; but not with amnestic mild cognitive impairment.

[712] Reitz, C., Tang M-X., Manly J., Mayeux R., & Luchsinger J. A.
(2007).  Hypertension and the Risk of Mild Cognitive Impairment.
Arch Neurol. 64(12), 1734 - 1740.

http://www.eurekalert.org/pub_releases/2007-12/jaaj-hbp120607.php

Memory tasks require more coordinated brain blood flow for people with high blood pressure

Previous studies have found an association between high blood pressure and cognitive decline in older adults, but the evidence hasn’t been entirely consistent. Now a new study helps explain why the situation is not entirely straightforward. It appears that people with high blood pressure required more blood flow to the parts of the brain that support memory function than those with normal blood pressure. Moreover, and surprisingly, it turned out that antihypertensive medication actually made it worse, increasing the inefficiency of the brain’s work during memory tasks.

The findings were reported at the American Heart Association’s 61st Annual Fall Conference of the Council for High Blood Pressure Research.

http://www.eurekalert.org/pub_releases/2007-09/aha-mtr092707.php

Lowering blood pressure doesn't prevent cognitive impairment, dementia

A review of three large-scale studies of patients with hypertension who were treated with either medication or lifestyle strategies found no convincing evidence that lowering blood pressure prevents the development of dementia or cognitive impairment in hypertensive patients without apparent prior cerebrovascular disease. However, there is some evidence that midlife hypertension but not late life hypertension is related to cognitive decline; these studies involved patients aged 60 and older.

McGuiness, B., et al. The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease. The Cochrane Database of Systematic Reviews 2006, Issue 2.

http://www.eurekalert.org/pub_releases/2006-05/cfta-lbp052306.php

Review supports link between lifestyle factors and cognitive function in older adults

A review of 96 papers involving 36 very large, ongoing epidemiological studies in North America and Europe looking at factors involved in maintaining cognitive and emotional health in adults as they age has concluded that controlling cardiovascular risk factors, such as reducing blood pressure, reducing weight, reducing cholesterol, treating (or preferably avoiding) diabetes, and not smoking, is important for maintaining brain health as we age. The link between hypertension and cognitive decline was the most robust across studies. They also found a consistent close correlation between physical activity and brain health. However, they caution that more research is needed before specific recommendations can be made about which types of exercise and how much exercise are beneficial. They also found protective factors most consistently reported for cognitive health included higher education level, higher socio-economic status, emotional support, better initial performance on cognitive tests, better lung capacity, more physical exercise, moderate alcohol use, and use of vitamin supplements. Psychosocial factors, such as social disengagement and depressed mood, are associated with both poorer cognitive and emotional health in late life. Increased mental activity throughout life, such as learning new things, may also benefit brain health.

[296] Wagster, M., Hendrie H., Albert M., Butters M., Gao S., Knopman D. S., et al.
(2006).  The NIH Cognitive and Emotional Health ProjectReport of the Critical Evaluation Study Committee.
Alzheimer's and Dementia. 2(1), 12 - 32.

http://www.eurekalert.org/pub_releases/2006-02/aa-nss021606.php

Uncontrolled high blood pressure means more cognitive problems in old age

A study involving a subset of men (average age 67 years) in the VA Normative Aging Study has found that those men with uncontrolled hypertension performed significantly worse on tests of verbal fluency and short-term memory. Those whose hypertension was controlled did as well as those with normal blood pressure. In the United States, hypertension affects 60% of adults age 60 and older, and a high proportion of these are untreated or inadequately treated.

Brady, C.B., Spiro, A. III & Gaziano, J.M. 2005. Effects of Age and Hypertension Status on Cognition: The Veterans Affairs Normative Aging Study. Neuropsychology, 19 (6).

http://www.eurekalert.org/pub_releases/2005-12/apa-uhb113005.php

High blood pressure has stronger effect on cognitive function in African-Americans

Analysis of a large longitudinal study (the Maine-Syracuse Longitudinal Study 1976—2002) has found significant associations of high blood pressure to lower cognitive performance in the areas of abstract reasoning, psychomotor skills and visual organization skills. This association, moreover, was significantly greater for African-Americans, although it should be noted that there were only 147 African-Americans among the 1,563 participants. The effect was independent of age.

[795] Robbins, M. A., Elias M. F., Elias P. K., & Budge M. M.
(2005).  Blood pressure and cognitive function in an African-American and a Caucasian-American sample: the Maine-Syracuse Study.
Psychosomatic Medicine. 67(5), 707 - 714.

http://www.eurekalert.org/pub_releases/2005-09/cfta-hbp092205.php

High blood pressure may be a factor in "senior moments"

An imaging study of seniors (average age 60) found that those with high blood pressure showed reduced blood flow to active brain areas when performing various everyday memory tasks, such as looking up a phone number then walking to another room to pick up the phone and dial the number. The diminished blood flow correlated to slightly worse scores on the memory tests. The differences weren’t large, but may help account for "senior moments" - memory problems commonly associated with age. It’s estimated that as many as a third of those with high blood pressure are not aware they have it.

Jennings, J.R., Muldoon, M.F., Meltzer, C.C., Ryan, C. & Price, J. 2003. Human Cerebral Blood Flow Responses to Information Processing Tasks are Decreased in Hypertensives Relative to Normotensives. Report presented at the American Heart Association's 57th Annual High Blood Pressure Research Conference, September 23.

http://www.eurekalert.org/pub_releases/2003-09/aha-hbp091703.php

Effects of high blood pressure on cognition may have been overstated

Epidemiological studies have suggested hypertensive patients perform worse than individuals with normal blood pressure on cognition tests. A new study has investigated performance on specific cognitive tasks (visual and memory search involving computer displays) by those with high blood pressure who were not on medication and had no detectable cardiovascular disease. Participants ranged in age from 20 to 80. Contrary to expectation, high blood pressure slowed performance only in the middle-aged group (40-59), not in those younger or older.

Madden, D., Langley, L., Thurston, R., Whiting, W. & Blumenthal, J. 2003. Interaction of Blood Pressure and Adult Age in Memory Search and Visual Search Performance. Aging, Neuropsychology and Cognition, 10 (4), 241-54.

http://www.eurekalert.org/pub_releases/2003-09/dumc-hbp092503.php

Treatment to lower blood pressure reduces risk of cognitive decline in stroke patients

High blood pressure and stroke are associated with increased risks of dementia and cognitive impairment. In a study aimed to determine whether blood pressure lowering would reduce the risks of dementia and cognitive decline among individuals with cerebrovascular disease, 6105 people with prior stroke or transient ischemic attack were given either active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). Over some 4 years, dementia was found in 6.3% of those given active treatment and 7.1% of those in the placebo group. Cognitive decline occurred in 9.1% of the actively treated group and 11.0% of the placebo group. The researchers concluded that blood pressure lowering with perindopril and indapamide therapy was helpful for those with cerebrovascular disease, in terms of reduced risks of dementia and cognitive decline.

[603] The PROGRESS Collaborative Group*
(2003).  Effects of Blood Pressure Lowering With Perindopril and Indapamide Therapy on Dementia and Cognitive Decline in Patients With Cerebrovascular Disease.
Arch Intern Med. 163(9), 1069 - 1075.

http://archinte.ama-assn.org/cgi/content/abstract/163/9/1069

Age-related changes in the brain's white matter affect cognitive function

From around age 60, "white-matter lesions" appear in the brain, significantly affecting cognitive function. But without cognitive data from childhood, it is hard to know how much of the difference in cognitive abilities between elderly individuals is due to aging. A longitudinal study has been made possible by the Scottish Mental Survey of 1932, which gave 11-year-olds a validated cognitive test. Scottish researchers have tracked down healthy living men and women who took part in this Survey and retested 83 participants. Testing took place in 1999, when most participants were 78 years old.
It was found that the amount of white-matter lesions made a significant contribution to general cognitive ability differences in old age, independent of prior ability. The amount of white-matter lesions contributed 14.4% of the variance in cognitive scores; early IQ scores contributed 13.7%. The two factors were independent.
Although white-matter lesions are viewed as a normal part of aging, they are linked with other health problems, in particular to circulatory problems (including hypertension, diabetes, heart disease and cardiovascular risk factors).

[442] Deary, I. J., Leaper S. A., Murray A. D., Staff R. T., & Whalley L. J.
(2003).  Cerebral white matter abnormalities and lifetime cognitive change: a 67-year follow-up of the Scottish Mental Survey of 1932.
Psychology and Aging. 18(1), 140 - 148.

http://www.eurekalert.org/pub_releases/2003-03/apa-aci031703.php

Sunflower seeds helpful in reducing hypertension and associated cognitive impairment

Research in rats has found that linoleic acid improved not only blood pressure, but also hypertension-induced memory decline, suggesting that the early incorporation of linoleic acid in the diet, may not only help in controlling hypertension, but may also improve hypertension-induced cognitive impairment. Linoleic acid is found in vegetable seed oils, such as safflower, sunflower, and hemp seed.

Holloway, V. 2002. Effects of early nutritional supplementation of linoleic acid in Hypertension. Paper presented at an American Physiological Society (APS) conference, "The Power of Comparative Physiology: Evolution, Integration and Application", August 24-28 in San Diego, CA.

http://www.eurekalert.org/pub_releases/2002-08/aps-mk082602.php

High blood pressure increases risk of cognitive decline in older adults

A large-scale six-year study of people aged 40 to 70 years old found that people with diabetes and high blood pressure are more likely to experience cognitive decline. Diabetes was associated with greater cognitive decline for those younger than 58 as well as those older than 58, but high blood pressure was a risk factor only for the 58 and older group.

[2534] Knopman, D. S., Boland L. L., Mosley T., Howard G., Liao D., Szklo M., et al.
(2001).  Cardiovascular risk factors and cognitive decline in middle-aged adults.
Neurology. 56(1), 42 - 48.

http://www.eurekalert.org/pub_releases/2001-01/MC-Nsld-0701101.php
http://www.eurekalert.org/pub_releases/2001-01/AAoN-Dahb-0801101.php

Untreated hypertension linked to severe cognitive decline in older adults

A large-scale study of French people aged 59 to 71 found that, after four years, 21.7% of those with untreated high blood pressure experienced severe cognitive decline. Of those with high blood pressure whose treatment didn't bring the blood pressure down to normal, 12.5% had severe cognitive decline. Of those whose high blood pressure was successfully treated, 7.8% had severe cognitive decline. Only 7.3% of those with normal blood pressure had severe cognitive decline.

Tzourio, C., Dufouil, C., Ducimetière, P., Alpérovitch, A. and for the EVA Study Group. 1999. Cognitive decline in individuals with high blood pressure: A longitudinal study in the elderly. Neurology, 53, 1948.

http://www.eurekalert.org/pub_releases/1999-12/AAoN-Hbpi-091299.php

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Low levels of omega-3 fatty acids linked to brain aging

April, 2012
  • A large study has found that older adults with low levels of omega-3 fatty acids had greater brain atrophy and more white matter damage.

A study involving 1,575 older adults (aged 58-76) has found that those with DHA levels in the bottom 25% had smaller brain volume (equivalent to about 2 years of aging) and greater amounts of white matter lesions. Those with levels of all omega-3 fatty acids in the bottom quarter also scored lower on tests of visual memory, executive function, and abstract thinking.

The finding adds to the evidence that higher levels of omega-3 fatty acids reduce dementia risk.

For more about omega-3 oils and cognition

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