* * * *
The Search for AD Genes
How does a researcher determine which genes might be involved in AD? They collect blood samples from large numbers of people with AD and compare their DNA with that from a large number of similar people who don't have it. Researchers then look at the relatively small number of genes that are different between the two groups, and try to determine which genes are really important.
In the 1990s, four genes were confirmed to be associated with AD. Mutations in each of these genes lead to increased production of Ab. Three were found by studying families with rare forms of early-onset AD: amyloid precursor protein (APP) gene on chromosome 21, presenilin 1 (PS1) gene on chromosome 14, and presenilin 2 (PS2) gene on chromosome 1. Less than 1% of AD patients have mutations in these genes.
The fourth is the only identified genetic risk factor for late-onset AD. About 50% of late-onset AD patients of European ancestry have the e4 allele of Apolipoprotein E gene (APOE4) on chromosome 19. However, many who have APOE4 live to a ripe old age without ever contracting AD.
No gene mutation associated with AD tangles has been identified, although two tau genes associated with frontotemporal dementia haves been found on chromosome 17 (tau and progranulin).
Since 2003, the Late-Onset AD Genetics Study (LOAD) has been collecting DNA via blood samples from 1000 families who have at least two living siblings diagnosed with late-onset AD in hopes of finding more AD-related genes. Researchers have identified over 100 potential AD-related genes, but none have been unanimously confirmed.
Human AD gene mutations have been injected into fertilized mouse eggs to create transgenic mice. They develop plaques indistinguishable from those in AD patients and develop the corresponding deficits in learning and memory. Transgenic mice exist for all known AD mutations. Interestingly, transgenic mice with Ab-associated genes do not form tangles or have the extensive neuron loss characteristic of AD. Transgenic mice that produce tangles are created using the frontotemporal dementia tau gene. Mice that display both plaques and tangles are created using combinations of APP, PS1, and tau genes.
Epigenetics, the study of changes to the genome that do not alter the DNA sequence, may hold promise for AD. Genes can be turned on and off through the attachment of acetyl or methyl groups in certain spots on chromatin, the combination of DNA and protein that makes up chromosomes. Research suggests epigenetic drift occurs with age and may increase the risk of developing AD. In one famous study, transgenic mice were taught a skill, then fed a chemical over a period of months to trigger a gene that causes significant brain atrophy. The mice lost the skill they'd learned. Mice who were allowed to play afterwards with a lot of cool toys recovered their long-term memory of the skill. Those mice were found to have new acetyl groups added to their chromatin and had developed new dendrites and nerve synapses.
* * * *
Related Physiologies
The vascular system is also a topic of AD research. Reduced blood flow interferes with protein metabolism, and severely reduced flow results in neuron death. Heart disease, high blood pressure that begins in midlife, and stroke are risk factors for AD, and vascular dementia is often found in AD patients. The question is: do vascular problems contribute to AD, or are they caused by it? Of particular interest is the blood-brain barrier(BBB), which allows desirable substances to cross into the brain from the circulatory system while barring foreign substances that might injure the organ. It's a complex array of specialized cells lining capillaries in the brain. Ab tends to accumulate on blood vessels and researchers are studying how different types of cells in the BBB interact with it.
Research with animal and humans suggests there may be a connection between high levels of blood cholesterol and development of AD. Statins are enzyme inhibitors that reduce elevated LDL cholesterol levels. A large clinical study is investigating whether statins can slow the progression of AD.
High levels of the amino acid homocysteine increase heart disease risk, and have been shown in mice to kill neurons. A recently concluded clinical study found that increasing intake of folic acid and vitamins B6 and B12 did indeed decrease homocysteine levels, but did not slow the progression of AD.
Diabetes Type 2 and insulin resistance are risk factors for AD and a hot topic of research. Insulin enables cells to use blood-borne glucose for energy. In insulin resistance, cells don't respond as well to insulin and require higher blood levels of it to be able to utilize glucose. Blood glucose levels rise and the pancreas produces more insulin to compensate. Abnormally high blood sugar levels damage blood vessels. If the insulin levels get too high, the BBB reduces transport of insulin into the brain, which makes brain cells less able to use glucose for energy. Starved cells don't work well. People who were given insulin nasally, which bypasses the BBB, improved performance on memory tests. High insulin levels also increase inflammation and gamma-secretase activity (which makes that enzyme snip more Ab from the APP protein). Researchers found the central nervous system in those with AD makes less insulin and insulin-like growth factors type I and II (IGF-I and IGF-II). IGF-I helps two proteins that bind Ab to cross the BBB, which may help clear Ab from the brain. New transgenic mouse models that combine plaque production with defects in insulin/IGF-I signaling are in development so these can be studied further. Given the strong association between insulin and AD, both insulin and diabetes drugs that reduce cell resistance to insulin are in AD clinical trials.
Early studies of estrogen suggested that it might help prevent AD in older women. Extensive clinical studies have not borne this out. In fact, it appears older women taking estrogen are at greater risk for dementia. However, a large clinical study of raloxifene (a selective estrogen-receptor modulator, or SERM, which is used to treat and prevent osteoporosis) found it lowered the risk of MCI among a group of postmenopausal women with osteoporosis. Raloxifene is now being tested to see if it slows the progression of AD.
A large number of studies document profound brain inflammation in AD. Along with plaque, this may generate freeradicals and oxidative injury to the brain. Many studies have shown people who take non-steroidal anti-inflammatory drugs (NSAIDs) have lower rates of dementia in late life. Unfortunately, in clinical trials NSAIDs did not improve cognitive function. Vitamins C, E, and other antioxidants that fight free radicals are in clinical studies to see if they can slow the progression of AD.
Exercise has been demonstrated to improve cognitive function and has a beneficial effect on several neurotransmitters. Rats trained with aerobic exercise actually grew new neurons in the hippocampus. Keeping the brain active by learning and doing also appears to lower AD risk.
Promising Therapies and Treatments
Neurotransmitters are the messengers nerves produce to communicate with each other. All drugs for AD approved by the FDA up through 2008 act to increase or decrease neurotransmitter activity. Aricept(TM), Exelon(TM), Razadyne(TM), and Cognex(TM) inhibit the enzyme acetylcholinesterase that breaks down the neurotransmitter acetylcholine, important in forming memories. Not everyone responds to these drugs, and cognitive improvement is limited to one or two years. A fifth US FDA-approved AD drug, memantine (Ebixa(TM), Namenda(TM)) blocks a receptor on nerve cells to prevent the body's main excitatory neurotransmitter glutamate from binding to the cells. Excessive glutamate appears to cause nerve cell degeneration or death.
Here are some tidbits from the more than 50 AD-targeted drugs, nutritional supplements, and other therapies in various stages of clinical trials.
Since plaque is a prime suspect in neuron death, many proposed therapies focus on preventing or removing plaque from the brain. Unfortunately, two promising Ab-fighting drugs failed in final clinical trials in 2007-08. Flurizan(TM), a selective amyloid-lowering agent (SALA), was expected to reduce Ab 42 by modulating gamma-secretase. Alzhemed(TM), based on the amino acid taurine, was expected to stop formation and deposition of Ab plaque and also bind soluble Ab to reduce brain inflammation. Neither made a significant improveme
nt in the cognitive abilities of human subjects. Alzhemed is now sold as a nutritional supplement under the brand name Vivimind(TM). We should note both drugs were developed using mice with familial AD genes that generated lots of plaque. The chemistry of human late-onset AD brains may be different enough that the drug did reduce Ab, just not enough to make a cognitive difference.
Other Ab-fighting drugs are in current trials. Several drugs designed to inhibit beta-secretase (BACE1) activity are in various stages of development. A different approach focuses on a protein called Receptor for Advanced Glycation Endproducts (RAGE) that helps Ab cross the BBB and bind on the surface of brain and its blood vessels. A human study of a RAGE inhibitor started in December 2007.
Reducing tau tangles is another therapeutic approach. Methylthioninium chloride (MTC) in the test tube dissolves tau tangle filaments and prevented formation of tangles. In clinical trials it appears to improve cognitive function and blood flow to the hippocampus and prevent further decline.
Immunotherapy developments for AD are in the works. A synthetically engineered A b antibody that generated an active immune response cleared Ab from the brain in APP mice. In 2001, researchers began a clinical trial of the vaccine with humans, but the study was halted after a number of participants developed inflammation of the brain and spinal cord. A passive Ab-fighting immunotherapy entered Phase 3 clinical trials in 2007.
Human gene therapy trials using nerve growth factor(NGF) are in process after 12 years of successful animal studies. NGF directs how nerve cells outside the central nervous system regrow or regenerate after an injury. In the trials, human skin cells modified to secrete NGF are implanted directly into the person's brain. Preliminary results have seen brain cell growth, and cognitive decline slowed significantly.
Another gene therapy approach engineered mice skin cells to make neprilysin, an enzyme that degrades Ab and has lower-than-normal blood levels in AD patients. Researchers then injected the cells into the hippocampus of mouse brains and nearby plaque, even some further away, disappeared. A Herpes simplex virus has also been used to deliver neprilysin across the BBB with encouraging results. Researchers are currently trying to determine whether neprilysin gene therapy improves cognition in mice.
SouvenaidTM is a medical food designed to improve synapse formation and synaptic transmissionclaimed to be useful in AD. In pre-clinical models it also reduced amyloid production. Its combination of uridine monophosphate, choline, omega-3 fatty acids (EPA, DHA), phospholipids, B vitamins, and antioxidants appears to be improving cognition in proof-of-concept human trials.
Therapies based on stem cells arein their infancy. Stem cells implanted in live mice brains whose neurons had been intentionally damaged generated new neuron growth and improved memory after a few months. The complex environment of the AD brain can affect both where stem cells end up and what cell type they become. In many brain regions, implanted stem cells don't become neurons, although they may become other kinds of beneficial cells. In one study, transplanting human umbilical cord blood stem cells into transgenic mouse brains resulted in a 62% reduction in Ab accumulation.
No proven therapies are ready yet, but work continues. The first disease-modifying drugs might be available in the 2010-2015 time frame.
However, we're still not sure what truly causes AD. Some have criticized AD research for overemphasizing plaques and tangles without proof they cause neuron death. At times the field seems divided into cliques of “tauists,” “baptists” who concentrate on Ab, and everybody else. Perhaps recent findings have brought new perspective so that researchers can refocus on the lives they hold in trust: ours.n Copyright © 2009 Janet Freeman
* * * *
References for Readers:
www.alzforum.org/
Current research news, forums with researchers, info on approved and experimental Alzheimer's medicines and treatments.
www.nia.nih.gov/Alzheimers/
Alzheimer's Disease Education and Referral Center website has current, comprehensive AD information and resources from the National Institute on Aging
www.ncbi.nlm.nih.gov/pubmed/
Search for abstracts of published research papers, with links to complete papers (usually for a fee). University libraries may have free access.
www.mayoclinic.com/
Search on Alzheimer's for access to info on diagnosis, treatments, caregiving, and many other AD topics.
* * * *
About the Author
Janet Freeman is an MIT- and Caltech-trained engineer with a passion for learning about Alzheimer's disease. A lifetime love of space, gadgets, and science fiction led her to work in aerospace business development until leaving at age 42 to care for both parents and an aunt, all afflicted with dementia. She has a son who has Asperger's, which fuels an interest in autism and learning disabilities. After many years writing fiction for industry, she's now trying her hand at writing for herself.
[Back to Table of Contents]
Novella: FAILURE TO OBEY by John G. Henry
* * * *
Illustrated by Mark Evans
* * * *
Certain situations require a kind of discipline that we would not accept in everyday life. But they may need something else even more....
* * * *
Perhaps it was some instinct born of experience that made Lieutenant Jen Shen jerk awake in the middle of the night, the voices of dead shipmates echoing in her fading dreams, and lunge for the survival suit kept in a ready locker right next to her bunk. She was halfway into the suit before the structure of Benjamin Franklin Naval Space Station shuddered twice, and fastening the last seals before the blare of the general quarters alarm began resounding urgently.
No one was in sight as Jen slammed shut the door to the closet-sized room that made up her personal quarters and began pelting down the passageway toward main engineering control. Heading in toward the hollow center of the vast rotating disc which was Franklin, Jen was going uphill against the rotation-induced gravity, taking ladders two steps at a time as she tried to cover ground before airtight hatches closed and made progress much slower. As she approached the armored survival bulkhead between her and engineering control, the massive hatch at the end of the passageway began sliding shut as its own warning alert added to the clamor. Jen managed to slide through sideways just in time, feeling the station jerk several times again as unknown forces slammed the structure.
Another ladder up, then another hatch loomed before her, this one sealed tight. She rammed her palm against the reader next to the hatch, punching the “open” button repeatedly as Jen waited for the reader to identify her from the chip embedded in her hand.
The hatch swung open, Jen hurled herself inside, and the hatch slammed behind her. It took two more passageways, ladders, and hatches before she reached her objective.
She finally paused, then, to take in the scene in main engineering control. At this hour, only the watch standers were present, five enlisted sailors led by Chief Petty Officer Carreras, all of whom were already in survival suits as well. “What's going on?” Jen demanded.
Carreras looked at her, his expression impossible to read through the faceplate of his suit. “Damned if I know, Lieutenant. We've got system failures cascading through part of the station inboard from here and it feels like there are explosions in that area, but the sensors are dead. We've all been ordered to stay here while command central tries to find out what's going on."
Typical. Too many people depended on remote sensors for information and didn't know what to do if those sensors failed. Eventually command central would order investigators into the area, but experience had proven to Jen just how critical time was in responding to emergencies. “I haven't been ordered to stay here.” Fighting off a flashback to the devastating explosion on her old ship the Maury, Jen punched open the hatch leading toward the affected areas.
She ran again, up a ladder and down the narrow passageway leading to the area of the station where supplies and the
water tanks were warehoused near the hollow core, yanking open the hatch at the far end. Once again, some instinct made her pause before dashing through, and she saw two figures in survival suits moving toward her from the damaged area. Wind whistled past, warning of breaches in the hull where atmosphere was venting. “What's—” she started to ask them.
Both of the figures raised weapons and began running toward her. Jen just stared in disbelief for a moment, then slammed her fist onto the “close” button as one of the figures opened fire, metal slugs rattling off of the closing hatch in a deafening hail. Punching in a code, she locked the hatch against anyone without the proper access. She had a sinking suspicion that anyone who had blown their way inside the station could also get through interior hatches, but it might slow down whoever the attackers were.
This time Jen ran even faster, half sliding, half falling down the ladder and reaching the hatch to engineering central as Franklin's structure shuddered again. Looking back, she saw the hatch she'd sealed falling inward, its edges glowing with intense heat, figures in survival suits coming through quickly, all carrying weapons.
Jen sealed and locked this hatch, too, calling out orders to the watch standers in engineering central. “We're under attack! Notify command central! It's people wearing survival suits like ours. Numbers unknown.” As a stunned Chief Carreras called command central, Jen rushed to one of the control consoles. “Shut everything down! Shift all controls to secondary stations! Do it now! Those guys are right behind me!"
Analog SFF, July-August 2009 Page 18