Saturday, February 25, 2006

Alzheimer's disease

Progress in understanding -- let alone treating -- Alzheimer's disease has been painfully slow. But a few interesting clues have turned up recently.

Alzheimer's Found To Be Mostly Genetic
Alzheimer disease has a genetic cause in up to 80 percent of cases, according to a USC-led study of nearly 12,000 twin pairs.

A twin study like this one involves analyzing data on identical twins. (Twin pairs that are not identical, and therefore do not have identical DNA, provide much less information about genetic effects). The study can give a statistical figure for the percentage of risk for some condition (Alzheimer's disease in this case) that is attributable to genetics. In this case, the risk is 79% (with 95% confidence). The implication is that in only about one fifth of identical twin pairs the disease will develop in one of the twins but not the other, presumably on account of some sort of environmental influence. In fact, in only about 45% of pairs where one twin has developed the disease has it appeared in the other also -- though it may well appear if the other twin lives long enough.

The general belief up to now has been that there are two types of Alzheimer's disease: "familial", or "early onset", (having a genetic basis) and "sporadic", or "late onset", (due more to random environmental factors). This study raises doubts about that assumption, although environmental factors may still play a role, such as by acting on genetic predispositions.

At least one genetic factor is already well known to indicate an increased risk for the disease: the so-called epsilon4 allele of the apolipoprotein E (ApoE) gene. (An allele is one variant of a gene that exists in several forms.) The ApoE protein is an interesting one, which normally regulates cholesterol metabolism. The epsilon4 allele has been associated with cardiovascular disease, such as atherosclerosis -- as well as Alzheimer's disease.

There is recent research indicating that the presence of ε4 ApoE is associated with differences in brain function that can be detected with an fMRI scan even before any other Alzheimer's disease symptoms are observable:

Epsilon4 allele carriers show altered brain activity before onset of Alzheimer’s symptoms
Healthy individuals who are at risk of Alzheimer’s disease show reduced activity in the hippocampal region of the brain when performing tasks related to forming new memories. In a study published today in the open access journal BMC Medicine, individuals carrying the apolipoprotein E (APOE) epsilon4 allele, which has previously been associated with high risk of developing Alzheimer’s disease (AD), showed altered brain activity compared to APOE epsilon3 homozygotes. According to the authors of the study, this supports the idea that certain regions of the brain exhibit functional decline associated with the AOPE epsilon4 allele, and this decline begins before the onset of AD symptoms.

What's new here is that changes in memory-related brain function associated with ApoE/ε4 show up before actual disease symptoms.

Given that the ApoE/ε4 allele is associated with abnormalities in the metabolism of lipoproteins, which assist in carrying fats in the bloodsteram, it's interesting that other recent research has shown a correlation between obesity and development of Alzheimer's:

Jefferson Scientists Discover Mechanism Tying Obesity to Alzheimer’s Disease
A team led by researchers at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and Edith Cowan University in Joondalup, Western Australia has shown that being extremely overweight or obese increases the likelihood of developing Alzheimer’s. They found a strong correlation between body mass index and high levels of beta-amyloid, the sticky protein substance that builds up in the Alzheimer’s brain and is thought to play a major role in destroying nerve cells and in cognitive and behavioral problems associated with the disease.

Of course, this does not necessarily mean that obesity "causes" Alzheimer's. It could be that ApoE/ε4 plays a role in promoting both conditions. It would be interesting to know whether this research took ApoE or other genetic factors into account. The only allusion to this in the press release is:
According to, Dr. Gandy, evidence has emerged over the last five years that many of the conditions that raise the risk for heart disease such as obesity, uncontrolled diabetes, hypertension and hypercholesterolemia also increase the risk for Alzheimer’s. Yet exactly how such factors made an individual more likely to develop Alzheimer’s remained a mystery.

What's the possible connection? Perhaps it's myelin, a substance that is an electrically insulating phospholipid (a type of fat) layer that surrounds the axons of many neurons. This covering of the axons is known as the myelin sheath. It is not present around young neurons, but builds up slowly in the process known as myelination. Myelination, and hence brain maturity, is not complete in humans until adulthood. Myelinated neurons conduct electrical signals much faster than unmyelinated ones. And so, anything that disrupts existing myelination can cause pathology. Yet another piece of recent research connects this to Alzheimer's:

Imaging Study Links Key Genetic Risk Factor for Alzheimer Disease to Breakdown of Myelin Insulation Coating Brain Cell Connections
A new UCLA imaging study shows that age-related breakdown of myelin, the fatty insulation coating the brain's internal wiring, correlates strongly with the presence of a key genetic risk factor for Alzheimer disease.

The findings are detailed in the January edition of the peer-reviewed journal Archives of General Psychiatry and add to a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life.

The press release continues:
Myelin is a sheet of lipid, or fat, with very high cholesterol content — the highest of any brain tissue. The high cholesterol content allows myelin to wrap tightly around axons, speeding messages through the brain by insulating these neural "wire" connections.

As the brain continues to develop in adulthood and as myelin is produced in greater and greater quantities, cholesterol levels in the brain increase and eventually promote the production of a toxic protein that attacks the brain. The protein attacks myelin, disrupts message transfer through the axons and eventually can lead to the brain/mind-destroying plaques and tangles visible years later in the cortex of Alzheimer patients.

The Apolipoprotein E (ApoE) genotype is the second most influential Alzheimer risk factor, after only advanced age. The study used MRI to assess myelin breakdown in 104 healthy individuals between ages 55 and 75 and determine whether the shift in the age at onset of Alzheimer disease caused by the ApoE genotype is associated with age-related myelin breakdown.

The results show that in later-myelinating regions of the brain, the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.

Looks like the case that ApoE/ε4 is implicated with Alzheimer's is getting pretty convincing, no? But wait. We're not done yet. There's also this:

Region of DNA strongly associated with Alzheimer's disease
An international team of researchers, led by investigators at Washington University School of Medicine in St. Louis, are zeroing in on a gene that increases risk for Alzheimer's disease. They have identified a region of chromosome 10 that appears to be involved in risk for the disease that currently affects an estimated 4.5 million Americans.

"There are a few genes that have been implicated in the development of early-onset Alzheimer's disease, but other than APOE, no genes have been found that increase risk for the more common, late-onset form of the disease," says principal investigator Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry at Washington University. "The region of DNA identified in our study showed evidence of replication in four independent series of experiments. I haven't seen a putative risk factor show such consistent results since the e4 variant of the APOE gene was identified as a risk factor for late-onset Alzheimer's disease more than 10 years ago."

What these researchers have found is different from ApoE, because their results come from a search for single-nucleotide polymorphisms (SNPs) -- i. e., gene variations -- on chromosome 10. They found only a single SNP on chromosome 10 that was consistently associated with Alzheimer's. It isn't related to ApoE, which is on chromosome 19.
"The region of DNA implicated in our study contains six genes," Goate says. "We don't know which of those genes is most likely to harbor this particular risk factor for Alzheimer's disease, but we're getting closer. We're now trying to nail down which one of these six genes is the most likely to be involved."

Goate expects between five and 10 genes eventually will be implicated as possible risk factors for late-onset Alzheimer's disease, and she says it's possible that more than one of those genes is located on chromosome 10.

"One thing we're trying to do at a functional level is to see whether any of the six genes that we've identified might be involved in pathways that we already know are related to Alzheimer's disease," she says. "For example, we know amyloid-beta peptide plays a role, so we want to see whether any of these genes might have a role in amyloid-beta metabolism.

"We don't really know the nature of this risk factor yet. What we can say is that we believe we know where it's located, and we know there are six genes in that region. But there also could be other regulatory elements within that strand of DNA that don't directly produce a protein but may somehow affect proteins produced elsewhere in the genome. At this point, we can say that there is a variant in this region of DNA that is increasing risk for Alzheimer's disease, but we can't yet say how," Goate says.

There's one more piece of recent research which has nothing (apparently) to do with ApoE, but might implicate whatever gene the preceding research seems to have found on chromosome 10:

Fruit Fly Reveals A Potential Connection Between Dementia And Cancer
Neurons in the brain generally do not divide. It is therefore perplexing that in Alzheimer's disease, and other dementias associated with a protein called tau, dying neurons actually re-express proteins normally seen during cell division or in cancer. It has previously been unclear whether such cell-division proteins cause neuronal death, protect neurons from death, or are irrelevant.

In the present work, the researchers used a fruit-fly model of Alzheimer's disease to examine the relationship of cell-division proteins to neurodegeneration. The power of this model, which recapitulates key features of the human disease, lies in the ability to use genetic tools to establish a causal connection between a molecular pathway and neuronal death. Khurana and colleagues found that, as in human disease, abnormal expression of cell-cycle proteins accompanied neuronal death in their fly model. Most importantly, loss of neurons could be prevented when the cell cycle was genetically blocked or when flies were fed anticancer drugs. Cell-cycle activation depended upon a hyperactive cell growth molecule, TOR (target of rapamycin), also known to be abnormally activated in Alzheimer's disease.

Is there a connection here? At this point it's anyone's guess. But there certainly seem to be signs of progress here.

What would be really, really interesting to know is how any of these results are related to the pathological conditions that have long been known to be associated with Alzheimer's. Namely the presence of plaques outside the neurons consisting of beta amyloid protein fragments, and neurofibrillary tangles inside of neurons consisting of tau protein.


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