alzheimers causes

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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Discovery of more risky genes reveals more about the paths to Alzheimer’s

June, 2011

New genetic studies implicate myelin development, the immune system, inflammation, and lipid metabolism as critical pathways in the development of Alzheimer’s.

I commonly refer to ApoE4 as the ‘Alzheimer’s gene’, because it is the main genetic risk factor, tripling the risk for getting Alzheimer's. But it is not the only risky gene.

A mammoth genetic study has identified four new genes linked to late-onset Alzheimer's disease. The new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells, pointing to three new pathways that are critically related to the disease.

Genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of healthy older adults, plus additional data from another 32,000, has identified MS4A, CD2AP, CD33, and EPHA1 genes linked to Alzheimer’s risk, and confirmed two other genes, BIN1 and ABCA7.

A second meta-analysis of genetic data has also found another location within the MS4A gene cluster which is associated with Alzheimer's disease. Several of the 16 genes within the cluster are implicated in the activities of the immune system and are probably involved in allergies and autoimmune disease. The finding adds to evidence for a role of the immune system in the development of Alzheimer's.

Another study adds to our understanding of how one of the earlier-known gene factors works. A variant of the clusterin gene is known to increase the risk of Alzheimer’s by 16%. But unlike the ApoE4 gene, we didn’t know how, because we didn’t know what the CLU gene did. A new study has now found that the most common form of the gene, the C-allele, impairs the development of myelin.

The study involved 398 healthy adults in their twenties. Those carrying the CLU-C gene had poorer white-matter integrity in multiple brain regions. The finding is consistent with increasing evidence that degeneration of myelin in white-matter tracts is a key component of Alzheimer’s and another possible pathway to the disease. But this gene is damaging your brain (in ways only detectible on a brain scan) a good 50 years before any clinical symptoms are evident.

Moreover, this allele is present in 88% of Caucasians. So you could say it’s not so much that this gene variant is increasing your risk, as that having the other allele (T) is protective.

Reference: 

[2257] Naj, A. C., Jun G., Beecham G. W., Wang L-S., Vardarajan B. N., Buros J., et al.
(2011).  Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.
Nat Genet. 43(5), 436 - 441.

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at http://genomemedicine.com/content/3/5/33/abstract

[2254] Braskie, M. N., Jahanshad N., Stein J. L., Barysheva M., McMahon K. L., de Zubicaray G. I., et al.
(2011).  Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults.
The Journal of Neuroscience. 31(18), 6764 - 6770.

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High iron, copper levels block neuron repair

June, 2011

New findings help explain why too much copper and iron are bad for your brain, and why curry is good for it.

A new study finds out why curcumin might help protect against dementia, and links two factors associated with Alzheimer’s and Parkinson’s diseases: DNA damage by reactive oxygen species (ROS), and excessive levels of copper and iron in parts of the brain. It turns out that high levels of copper or iron help generate large numbers of ROS and interfere with DNA repair.

While small amounts of iron and copper are vital, these are normally bound by proteins. However, when there’s too much, it can overwhelm the proteins and the result is "free" iron or copper ions circulating in the blood, able to initiate chemical reactions that produce reactive oxygen species. Moreover, the free copper and iron also interferes with the activity of two enzymes that repair DNA, NEIL1 and NEIL2.

However, the curry spice curcumin binds to iron and copper and was extremely effective in protecting the NEIL enzymes from the metals.

Reference: 

Hegde, M.L., Hegde, P.M. , Rao, K.S.J. & Mitra, S. 2011. Oxidative Genome Damage and Its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword. Journal of Alzheimer's Disease , 25 (1), 183-198.

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Vascular disease underlies cognitive decline in healthy aging

December, 2010
  • New findings add to evidence that the key to not becoming cognitively impaired in old age is vascular health.

More evidence that vascular disease plays a crucial role in age-related cognitive impairment and Alzheimer’s comes from data from participants in the Alzheimer's Disease Neuroimaging Initiative.

The study involved more than 800 older adults (55-90), including around 200 cognitively normal individuals, around 400 people with mild cognitive impairment, and 200 people with Alzheimer's disease. The first two groups were followed for 3 years, and the Alzheimer’s patients for two. The study found that the extent of white matter hyperintensities (areas of damaged brain tissue typically caused by cardiovascular disease) was an important predictor of cognitive decline.

Participants whose white matter hyperintensities were significantly above average at the beginning of the study lost more points each year in cognitive testing than those whose white matter hyperintensities were average at baseline. Those with mild cognitive impairment or Alzheimer's disease at baseline had additional declines on their cognitive testing each year, meaning that the presence of white matter hyperintensities and MCI or Alzheimer's disease together added up to even faster and steeper cognitive decline.

The crucial point is that this was happening in the absence of major cardiovascular events such as heart attacks, indicating that it’s not enough to just reduce your cardiovascular risk factors to a moderate level — every little bit of vascular damage counts.

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How the Alzheimer’s gene works; implications for treatment

November, 2010

Research with genetically engineered mice shows why the apoE4 gene is so strongly associated with Alzheimer’s, and points to strategies for countering its effects.

Carriers of the so-called ‘Alzheimer’s gene’ (apoE4) comprise 65% of all Alzheimer's cases. A new study helps us understand why that’s true. Genetically engineered mice reveal that apoE4 is associated with the loss of GABAergic interneurons in the hippocampus. This is consistent with low levels of GABA (produced by these neurons) typically found in Alzheimer’s brains. This loss was associated with cognitive impairment in the absence of amyloid beta accumulation, demonstrating it is an independent factor in the development of this disease.

The relationship with the other major characteristic of the Alzheimer’s brain, tau tangles, was not independent. When the mice’s tau protein was genetically eliminated, the mice stopped losing GABAergic interneurons, and did not develop cognitive deficits. Previous research has shown that suppressing tau protein can also prevent amyloid beta from causing memory deficits.

Excitingly, daily injections of pentobarbital, a compound that enhances GABA action, restored cognitive function in the mice.

The findings suggest that increasing GABA signaling and reducing tau are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

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Compound in celery, peppers reduces age-related memory deficits

November, 2010

One precursor of age-related cognitive impairment and dementia is inflammation. Research suggests why that might be, and explains why the plant nutrient luteolin can help fight memory impairment.

Inflammation in the brain appears to be a key contributor to age-related memory problems, and it may be that this has to do with the dysregulation of microglia that, previous research has shown, occurs with age. As these specialized support cells in the brain do normally when there’s an infection, with age microglia start to produce excessive cytokines, some of which result in the typical behaviors that accompany illness (sleepiness, appetite loss, cognitive deficits and depression).

Now new cell and mouse studies suggests that the flavenoid luteolin, known to have anti-inflammatory properties, apparently has these benefits because it acts directly on the microglial cells to reduce their production of inflammatory cytokines. It was found that although microglia exposed to a bacterial toxin produced inflammatory cytokines that killed neurons, if the microglia were first exposed to luteolin, the neurons lived. Exposing the neuron to luteolin had no effect.

Old mice fed a luteolin-supplemented diet for four weeks did better on a working memory test than old mice on an ordinary diet, and restored levels of inflammatory cytokines in their brains to that of younger mice.

Luteolin is found in many plants, including carrots, peppers, celery, olive oil, peppermint, rosemary and chamomile.

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Low levels of omega-3 fatty acid may contribute to Alzheimer’s

October, 2010

A finding that the livers of Alzheimer’s patients have an impaired ability to make the omega-3 fatty acid DHA may suggest a new approach.

Low levels of DHA, an omega-3 fatty acid, have been found in the brains of those with Alzheimer's disease, but the reason has not been known. A new study has found that lower levels of DHA in the liver (where most brain DHA is manufactured) were correlated with greater cognitive problems in the Alzheimer’s patients. Moreover, comparison of postmortem livers from Alzheimer’s patients and controls found reduced expression of a protein that converts a precursor acid into DHA, meaning the liver was less able to make DHA from food.

The findings may explain why clinical trials in which Alzheimer's patients are given omega-3 fatty acids have had mixed results. They also suggest that it might be possible to identify at-risk persons using specific blood tests, and perhaps delay the development of Alzheimer’s with a chemically enhanced form of DHA.

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Cognitive decline is not simply a function of getting old

October, 2010
  • New research suggests that even “normal” cognitive decline with age reflects the type of brain damage that is (in greater amount) characteristic of dementia.

Findings from the long-running Religious Orders Study, from 354 Catholic nuns and priests who were given annual cognitive tests for up to 13 years before having their brains examined post-mortem, has revealed that even the very early cognitive impairments we regard as normal in aging are associated with dementia pathology. Although pathology in the form of neurofibrillary tangles, Lewy bodies, and cerebral infarctions were all associated with rapid decline, they were also associated with “normal” mild impairment. In the absence of any of these lesions, there was almost no cognitive decline.

Previous research has shown that white matter lesions are very common in older adults, and mild cognitive impairment is more likely in those with quickly growing white matter lesions; importantly, the crucial factor appears to be the rate of growth, not the amount of lesions. This new study extends the finding, suggesting that any age-related cognitive impairment reflects the sort of brain pathology that ultimately leads to dementia (if given enough time). It suggests that we should be more proactive in fighting such damage, instead of simply regarding it as normal.

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Link among Alzheimer's disease, Down syndrome, atherosclerosis and diabetes

January, 2010

New evidence suggests that Down syndrome, Alzheimer's, diabetes, and cardiovascular disease, all share a common disease mechanism.

It’s been suggested before that Down syndrome and Alzheimer's are connected. Similarly, there has been evidence for connections between diabetes and Alzheimer’s, and cardiovascular disease and Alzheimer’s. Now new evidence shows that all of these share a common disease mechanism. According to animal and cell-culture studies, it seems all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is characteristic of all the cells in people with Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer's. It now appears that amyloid protein is interfering with the microtubule transport system inside cells, essentially creating holes in the roads that move everything, including chromosomes, around inside the cells. Incorrect transportation of chromosomes when cells divide produces new cells with the wrong number of chromosomes and an abnormal assortment of genes. The beta amyloid gene is on chromosome 21; thus, having three copies produces extra beta amyloid. The damage to the microtubule network also interferes with the receptor needed to pull low-density lipoprotein (LDL — the ‘bad’ cholesterol) out of circulation, thus (probably) allowing bad cholesterol to build up (note that the ‘Alzheimer’s gene’ governs the low-density lipoprotein receptor). It is also likely that insulin receptors are unable to function properly, leading to diabetes.

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Alzheimer's memory problems originate with oligomers not plaques

April, 2010

While everyone agrees that amyloid-beta protein is part of the problem, not everyone agrees that amyloid plaques are the cause (or one of them) of Alzheimer’s. A new study provides convincing evidence that floating clumps called oligomers or ADDLs are the real problem.

While everyone agrees that amyloid-beta protein is part of the problem, not everyone agrees that amyloid plaques are the cause (or one of them) of Alzheimer’s. Other forms of amyloid-beta have been pointed to, including floating clumps called oligomers or ADDLs. A new study, using mice engineered to form only these oligomers, and never any plaques, throughout their lives, provides more support for this theory. Mice that never developed plaques were just as impaired by the disease as mice with both plaques and oligomers, and when a gene that converted oligomers into plaques was added to the mice, the mice were no more impaired than they had been before. This may explain why treatments aimed at removing plaques have not been successful, and offers a new approach to the treatment of Alzheimer’s.

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