Cognitive Labs

Insulin growth factor 1

Sometimes research leads to unexpected results. For example, stimulating growth hormone secretion in Alzheimer's patients did not help clear protein-containing beta-amyloid plaques or halt disease progression, as was hypothesized, particularly in APOEe4 carriers. Researchers used an experimental growth hormone secretion booster known as MK-677.

While the growth hormone dramatically increased levels of insulin-like growth factor-1 (IGF-1), which in animal studies had been shown to increase clearance of beta-amyloid, there was no incipient trend of beta-amyloid clearance in a subgroup of patients.

"Given that multiple pathways contribute to the clinical Alzheimer's disease phenotype," the scientists wrote, "it is possible that selectively altering the IGF-1 system alone is insufficient to slow the overall rate of disease progression."

563 patients age 50 or older were analyzed at 45 sites. Participants were randomized to double-blind treatment with the growth hormone-stimulating agent MK-677 at a dose of 25 mg or placebo for 12 months.

Growth hormone secretagogue therapy had the expected effect on serum IGF-1 levels -- a 60.1% increase at six weeks and a 72.9% increase at 12 months -- that were significantly greater than in the placebo group (difference 61.4 ng/mL at 12 months, P<0.001).

But the researchers noted that the effect was small and substantially less than reported for FDA-approved cholinesterase inhibitors.

The only subgroup that appeared to potentially benefit from growth hormone treatment were noncarriers of the apolipoprotein E (APOE) epsilon (e) 4 allele gene, that is, individuals with APOE2 or APOE3 biomarkers. (the link provides a general overview of APOE)

This group had a marginally significant improvement in global clinical status measured by CIBIC-plus (P≤0.05) and some numerical but nonsignificant effects on the other efficacy outcomes.

The researchers noted that this was not a prespecified subgroup analysis and should be interpreted with caution.

Source reference:

Sevigny JJ, et al "Growth hormone secretagogue MK-677: No clinical effect on AD progression in a randomized trial" Neurology 2008; 71:1702-1708.

Note: The research was funded by Merck and the authors have been financially supported by, and/or own stock-options of Merck, Inc.

Labels: apoe, hgh, igf1, merck, mk677

A new study at UCSD has found that APOE positive individuals perform poorly on cognitive tests in the presence of the stress hormone cortisol in their saliva.

The researchers analyzed a large population of 962 individuals. Research concerning the mechanisms by which chronic stress influences pathological aging and cognitive decline is important for determining interventions, either pharmacological or behavioral.

The growing evidence of significant relationships between chronic stress and cognitive changes may be particularly important in the study of Alzheimer’s disease. Recent animal studies have shown associations between chronic stress and neuropathological changes associated with Alzheimer’s disease, including synapse loss, increases in amyloid-β peptide, and tau accumulation and phosphorylation. Clearly, there are many factors that lead to the pathology and symptoms of Alzheimer’s disease, including environmental and genetic factors.

full paper

Labels: alzheimers, apoe, cognitive, cortisol, Peavy, UCSD

A paper on APOEe4, a genetic indicator of increased Alzheimer's propensity, cognitive speed, and the Cognitive Labs technology has been published in paper format.

The reference is here

O'hara R, Sommer B, Way N, Kraemer HC, Taylor J, Murphy G "Slower speed-of-processing of cognitive tasks is associated with presence of the apolipoprotein epsilon4 allele." Journal of Psychiatric Research, (2008)February; 42(3) 199-204

Previously it existed in as an e-publication (2007)

Labels: apoe, apoee4, cognitive, Cognitive Labs, genes, o'hara

Gladstone Institute at UCSF and University of Texas researchers have found the APOEe4 genetic marker, known as the most significant genetic risk determinant of Alzheimer's Disease and a factor in heart disease and stroke, also may play a role in the severity of HIV in people who have the disease. Results were published in the Proceedings of the National Academy of Sciences.

A seemingly trifling sequence difference of just one amino acid has profound implications for the structure and function of the APoE4 protein. ApoE4 has an extra intra-molecular bond that results in a more compact structure, and it also is more likely to be unstable, linked to its deleterious effects. Although the apoE3 gene is the most prevalent in all human populations, with frequencies of 50%, the genetic variant that leads to production of apoE4 is also widely distributed; its prevalence is 15.% (Some sources estimate at 20% or more of all humans)

Those with two copies of APOEe4, the homogeneous zygote, had a much more rapid progressions of HIV, leading to death, than those with two copies APOEe3.

The APOEe4 protein is smaller and more compact, but more unstable - than the APOEe2 and APOEe3. The reason for the APOEe4 mutation, it is hypothesized, helped people metabolize a lean, scarce diet and avoid starvation and possibly lowered the chance of child mortality. It also may be linked to colder temperatures, or possibly to those groups with the mutation who migrated into northern latitudes - it is more prevalent in Finland as a percentage of the population than anywhere else on earth, and also amongst relatively homogeneous ethnic groups (for example, German Russians) where increased APOEe4 risk has followed such groups even after migrating to North America where it is seen in distinct family histories of Alzheimer's Disease.

Labels: apoe, apoee3, apoee4, gladstone, homogeneous, texas, ucsf, zygote

Larry Page talked to the AAAS in San Francisco about DNA and its small footprint. (an OS smaller than Windows or Linux)

The programming language of humans, if you will, would include the workings of your brain, said Page, who offered his hypothesis Friday night during a plenary lecture here at the annual American Association for the Advancement of Science conference. His guess, he said, was that the brain's algorithms weren't all that complicated and could be approximated, eventually, with a lot of computational power.

"We have some people at Google (who) are really trying to build artificial intelligence and to do it on a large scale," Page said to a packed Hilton ballroom of scientists. "It's not as far off as people think."

Page, the director of products at the 8-year-old search giant, described several of his areas of interest in science and technology during the hour-long talk, which was a rare engagement for the nerdy billionaire. But the common thread in the lecture seemed to be enthusiasm for what Page (and co-founder Sergey Brin) managed to do well with Google: good old-fashioned entrepreneurialism while solving a single problem.

Here's a response.

Labels: apoe, cnet, cognitivelabs.com, dna, page

...Scientists said on Sunday they have pinpointed a new gene linked to
Alzheimer's disease, the incurable brain disorder that is the top cause of dementia in the elderly.

Abnormalities in a gene called SORL1 increased the risk for the disease, and this finding could help scientists develop new treatments, the researchers reported in the journal Nature Genetics.

The researchers looked at DNA samples from 6,000 people from four ethnic groups: Caribbean-Hispanics, North Europeans, black Americans and Israeli-Arabs. They found certain variations of SORL1 more often in people with late-onset Alzheimer's disease than in healthy people.

The late-onset form, affecting people age 65 and up, represents about 90 percent of Alzheimer's cases. The rarer early-onset form affects people from about age 30 to 65.

Only one other gene, called ApoE4, has been identified as a risk factor for late-onset Alzheimer's. It was identified in 1993.

Several genes are linked with early Alzheimer's, and study of both types might lead to better understanding of how the disease begins and how to tackle it.

Many scientists think Alzheimer's begins with the buildup in the brain of a gooey material called amyloid that clumps together to form plaques. That material stems from a protein called amyloid precursor protein, or APP.

SORL1 controls the distribution of APP inside nerve cells of the brain. When working normally, the gene prevents APP from being degraded into a toxic byproduct called amyloid beta peptide. When SORL1 is deficient, it allows more of the bad amyloid beta peptide to accumulate, fostering amyloid plaques.

Alzheimer's is a complex disease that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. Scientists have struggled to understand the biology of the disease and its genetic and environmental causes.

'PIECE OF THE PUZZLE'

"It's another clue to the way in which this disease comes about, another piece of the puzzle," Dr. Peter St. George-Hyslop, director of the Center for Research in Neurodegenerative Diseases at the University of Toronto and one of the key researchers, said in a telephone interview.

"Every time you get a piece of the puzzle and you can relate it to something else in the puzzle, you're that much closer to knowing what the picture on the puzzle is," he added.

St. George-Hyslop said it is premature to say what percentage of cases of late-onset Alzheimer's disease can be attributed to SORL1. ApoE4, which also may be involved in the production of amyloid plaques, has been linked to about 20 percent of late-onset Alzheimer's cases.

"This appears to be the fifth Alzheimer's disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete," Dr. Richard Mayeux of Columbia University Medical Center in New York, also involved in the research, said in a statement.

The disease first affects parts of the brain controlling memory and thinking, but as it advances it kills cells elsewhere in the brain. Eventually, if the patient has no other serious illness, the loss of brain function will prove fatal.

Researchers from Boston University and the Mayo Clinic College of Medicine in Jacksonville, Florida, also took part in the five-year study.

Labels: alzheimers, apoe, gene, sorl