early markers

Higher levels of copper in amyloid plaques associated with degree of neurodegeneration

Following on from the evidence that Alzheimer’s brains show higher levels of metals such as iron, copper, and zinc, a mouse study has found that amyloid plaques in Alzheimer’s-like brains with significant neurodegeneration have about 25% more copper than those with little neurodegeneration. This is consistent with a human study showing very high levels of copper in Alzheimer’s plaques.

Iron, though doubled in Alzheimer’s brains compared to controls, was not significantly different as a function of neurodegeneration, and zinc showed very little difference.

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Inhibitory control deficits common in those with MCI

January, 2013

Impairment in executive function is apparently far more common in those with MCI than previously thought, with the most common and severe impairment occurring in inhibitory control.

Providing some support for the finding I recently reported — that problems with semantic knowledge in those with mild cognitive impairment (MCI) and Alzheimer’s might be rooted in an inability to inhibit immediate perceptual information in favor of conceptual information — a small study has found that executive function (and inhibitory control in particular) is impaired in far more of those with MCI than was previously thought.

The study involved 40 patients with amnestic MCI (single or multiple domain) and 32 healthy older adults. Executive function was tested across multiple sub-domains: divided attention, working memory, inhibitory control, verbal fluency, and planning.

As a group, those with MCI performed significantly more poorly in all 5 sub-domains. All MCI patients showed significant impairment in at least one sub-domain of executive functioning, with almost half performing poorly on all of the tests. The sub-domain most frequently and severely impaired was inhibitory control.

The finding is in sharp contrast with standard screening tests and clinical interviews, which have estimated executive function impairment in only 15% of those with MCI.

Executive function is crucial for many aspects of our behavior, from planning and organization to self-control to (as we saw in the previous news report) basic knowledge. It is increasingly believed that inhibitory control might be a principal cause of age-related cognitive decline, through its effect on working memory.

All this adds weight to the idea that we should be focusing our attention on ways to improve inhibitory control when it declines. Although training to improve working memory capacity has not been very successful, specific training targeted at inhibitory control might have more luck. Something to hope for!

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Simple semantic task reveals early cognitive problems in older adults

January, 2013

A study finds early semantic problems in those with MCI, correlating with a reduced capacity to carry out everyday tasks.

A small study shows how those on the road to Alzheimer’s show early semantic problems long before memory problems arise, and that such problems can affect daily life.

The study compared 25 patients with amnestic MCI, 27 patients with mild-to-moderate Alzheimer's and 70 cognitively fit older adults (aged 55-90), on a non-verbal task involving size differences (for example, “What is bigger: a key or a house?”; “What is bigger: a key or an ant?”). The comparisons were presented in three different ways: as words; as images reflecting real-world differences; as incongruent images (e.g., a big ant and a small house).

Both those with MCI and those with AD were significantly less accurate, and significantly slower, in all three conditions compared to healthy controls, and they had disproportionately more difficulty on those comparisons where the size distance was smaller. But MCI and AD patients experienced their biggest problems when the images were incongruent – the ant bigger than the house. Those with MCI performed at a level between that of healthy controls and those with AD.

This suggests that perceptual information is having undue influence in a judgment task that requires conceptual knowledge.

Because semantic memory is organized according to relatedness, and because this sort of basic information has been acquired a long time ago, this simple test is quite a good way to test semantic knowledge. As previous research has indicated, the problem doesn’t seem to be a memory (retrieval) one, but one reflecting an actual loss or corruption of semantic knowledge. But perhaps, rather than a loss of data, it reflects a failure of selective attention/inhibition — an inability to inhibit immediate perceptual information in favor of more relevant conceptual information.

How much does this matter? Poor performance on the semantic distance task correlated with impaired ability to perform everyday tasks, accounting (together with delayed recall) for some 35% of the variance in scores on this task — while other cognitive abilities such as processing speed, executive function, verbal fluency, naming, did not have a significant effect. Everyday functional capacity was assessed using a short form of the UCSD Skills Performance Assessment scale (a tool generally used to identify everyday problems in patients with schizophrenia), which presents scenarios such as planning a trip to the beach, determining a route, dialing a telephone number, and writing a check.

The finding indicates that semantic memory problems are starting to occur early in the deterioration, and may be affecting general cognitive decline. However, if the problems reflect an access difficulty rather than data loss, it may be possible to strengthen these semantic processing connections through training — and thus improve general cognitive processing (and ability to perform everyday tasks).

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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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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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More evidence linking poor sleep to Alzheimer’s risk

March, 2012

Two recent studies add to the evidence linking sleep disorders to the later development of Alzheimer’s disease.

A small study of the sleep patterns of 100 people aged 45-80 has found a link between sleep disruption and level of amyloid plaques (characteristic of Alzheimer’s disease). The participants were recruited from the Adult Children Study, of whom half have a family history of Alzheimer’s disease.

Sleep was monitored for two weeks. Those who woke frequently (more than five times an hour!) and those who spent less than 85% of their time in bed actually asleep, were more likely to have amyloid plaques. A quarter of the participants had evidence of amyloid plaques.

The study doesn’t tell us whether disrupted sleep leads to the production of amyloid plaques, or whether brain changes in early Alzheimer's disease lead to changes in sleep, but evidence from other studies do, I think, give some weight to the first idea. At the least, this adds yet another reason for making an effort to improve your sleep!

The abstract for this not-yet-given conference presentation, or the press release, don’t mention any differences between those with a family history of Alzheimer’s and those without, suggesting there was none — but since the researchers made no mention either way, I wouldn’t take that for granted. Hopefully we’ll one day see a journal paper providing more information.

The main findings are supported by another recent study. A Polish study involving 150 older adults found that those diagnosed with Alzheimer’s after a seven-year observation period were more likely to have experienced sleep disturbances more often and with greater intensity, compared to those who did not develop Alzheimer’s.

Reference: 

Ju, Y., Duntley, S., Fagan, A., Morris, J. & Holtzman, D. 2012. Sleep Disruption and Risk of Preclinical Alzheimer Disease. To be presented April 23 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

Bidzan L, Grabowski J, Dutczak B, Bidzan M. 2011. [Sleep disorders in the preclinical period of the Alzheimer's disease]. Psychiatria Polska, 45(6), 851-60. http://www.ncbi.nlm.nih.gov/pubmed/22335128

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Walking speed and grip strength may predict dementia, stroke risk

March, 2012

More evidence comes for a link between lower physical fitness and increased risk of dementia in a large study that extends earlier findings to middle-aged and younger-old.

Following on from research showing an association between lower walking speed and increased risk of dementia, and weaker hand grip strength and increased dementia risk, a large study has explored whether this association extends to middle-aged and younger-old adults.

Part of the long-running Framingham study, the study involved 2,410 men and women with an average age of 62, who underwent brain scans and tests for walking speed, hand grip strength and cognitive function. During the follow-up period of up to 11 years, 34 people (1.4%) developed dementia (28 Alzheimer’s) and 79 people (3.3%) had a stroke.

Those who had a slower walking speed at the start of the study were one-and-a-half times more likely to develop dementia compared to people with faster walking speed, while stronger hand grip strength was associated with a 42% lower risk of stroke or transient ischemic attack in people over age 65.

Slower walking speed and weaker hand grip strength were also associated with lower brain volume and poorer cognitive performance. Specifically, those with slower walking speed scored significantly worse on tests of visual reproduction, paired associate learning, executive function, visual organization, and language (Boston Naming test). Higher hand grip strength was associated with higher scores on tests of visual reproduction, executive function, visual organization, language and abstraction (similarities test).

While the nature of the association is not yet understood, the findings do seem to support the benefits of physical fitness. At the least, these physical attributes can serve as pointers to the need for more investigation of an older person’s brain health. But they might also serve as a warning to improve physical fitness.

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Camargo, E.C., Beiser, A., Tan, Z.S., Au, R., DeCarli, C., Pikula, A., Kelly-Hayes, M., Kase, C., Wolf, P. & Seshadri, S. 2012. Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham Offspring Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

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Brain atrophy may predict risk for early Alzheimer's disease

January, 2012
  • Shrinking of certain brain regions predicts age-related cognitive decline and dementia, with greater brain tissue loss markedly increasing risk.

A study involving 159 older adults (average age 76) has confirmed that the amount of brain tissue in specific regions is a predictor of Alzheimer’s disease development. Of the 159 people, 19 were classified as at high risk on the basis of the smaller size of nine small regions previously shown to be vulnerable to Alzheimer's), and 24 as low risk. The regions, in order of importance, are the medial temporal, inferior temporal, temporal pole, angular gyrus, superior parietal, superior frontal, inferior frontal cortex, supramarginal gyrus, precuneus.

There was no difference between the three risk groups at the beginning of the study on global cognitive measures (MMSE; Alzheimer’s Disease Assessment Scale—cognitive subscale; Clinical Dementia Rating—sum of boxes), or in episodic memory. The high-risk group did perform significantly more slowly on the Trail-making test part B, with similar trends on the Digit Symbol and Verbal Fluency tests.

After three years, 125 participants were re-tested. Nine met the criteria for cognitive decline. Of these, 21% were from the small high-risk group (3/14) and 7% from the much larger average-risk group (6/90). None were from the low-risk group.

The results were even more marked when less stringent criteria were used. On the basis of an increase on the Clinical Dementia Rating, 28.5% of the high-risk group and 9.7% of the average-risk group showed decline. On the basis of declining at least one standard deviation on any one of the three neuropsychological tests, half the high-risk group, 35% of the average risk group, and 14% (3/21) of the low-risk group showed decline. (The composite criteria required both of these criteria.)

Analysis estimated that every standard deviation of cortical thinning (reduced brain tissue) was associated with a nearly tripled risk of cognitive decline.

The 84 individuals for whom amyloid-beta levels in the cerebrospinal fluid were available also revealed that 60% of the high-risk group had levels consistent with the presence of Alzheimer's pathology, compared to 36% of those at average risk and 19% of those at low risk.

The findings extend and confirm the evidence that brain atrophy in specific regions is a biomarker for developing Alzheimer’s.

Reference: 

[2709] Dickerson, B. C., & Wolk D. A.
(2012).  MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults.
Neurology. 78(2), 84 - 90.

Dickerson BC, Bakkour A, Salat DH, et al. 2009. The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloidpositive individuals. Cereb Cortex;19:497–510.

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Brain starts shrinking long before Alzheimer's appears

June, 2011

A study following older adults for more than a decade has found that neural volume in specific brain regions markedly predicted later development of Alzheimer’s.

A long-term study of older adults with similar levels of education has found that those with the thinnest cerebral cortex in specific brain regions were the most likely to develop dementia. Among those in whom these signature brain areas were the thinnest at the beginning of the study, 55% developed dementia over the next decade, compared with 20% of those with average cortical thickness and none of those in whom cortical thickness was above average. Those with the thinnest cortical areas also developed Alzheimer's significantly faster.

The study involved two independent samples. In the first group, 33 people were followed for an average of 11 years, during which time eight developed Alzheimer's. In the second group, 32 people were followed for an average of seven years, and seven of them developed the disease. (So 23% developed Alzheimer’s in total.) Participants were divided into three groups based on cortical thickness in the key areas: 11 had the lowest levels, 9 had the highest, and 45 were average.

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Predicting memory loss in healthy older adults

February, 2011

Having the ‘Alzheimer’s gene’ and showing reduced brain activity during a mental task combined to correctly predict future cognitive decline in 80% of healthy elders.

In a study in which 78 healthy elders were given 5 different tests and then tested for cognitive performance 18 months later, two tests combined to correctly predict nearly 80% of those who developed significant cognitive decline. These tests were a blood test to identify presence of the ‘Alzheimer’s gene’ (APOE4), and a 5-minute fMRI imaging scan showing brain activity during mental tasks.

The gene test in itself correctly classified 61.5% of participants (aged 65-88; mean age 73), showing what a strong risk factor this is, but when taken with activity on the fMRI test, the two together correctly classified 78.9% of participants. Age, years of education, gender and family history of dementia were not accurate predictors of future cognitive decline. A smaller hippocampus was also associated with a greater risk of cognitive decline.

These two tests are readily available and not time-consuming, and may be useful in identifying those at risk of MCI and dementia.

Reference: 

Woodard, J.L.  et al. 2010. Prediction of Cognitive Decline in Healthy Older Adults using fMRI. Journal of Alzheimer’s Disease, 21 (3), 871-885.

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