Sci. Aging Knowl. Environ., 29 October 2003
HOT TOPIC ORIENTATIONS
Detangling Alzheimer's Disease
New insights into the biological bases of the most common cause of dementia are pointing to better diagnostics and possible therapeutics
Abstract: Alzheimer's disease afflicts 4.5 million people in the United States, and the number is expected to rise to 16 million by the year 2050, as the population ages. Researchers are scrambling to find genetic risk factors, decipher disease mechanisms, and develop reliable diagnostic tests that detect the illness at its earliest, potentially most treatable stage. Using these findings, they hope to devise new therapeutic approaches. Current clinical trials are assessing novel techniques that stall or reverse Alzheimer-like neuropathology in mice.
"Alzheimer's is in fact like an insidious fog, barely noticeable until everything around has disappeared. After that, it is no longer possible to believe that a world without fog exists."
Introduction Back to TopAlzheimer's disease (AD) is one of the spookiest ailments around. It steals victims' memories, changes their personalities, and renders them speechless and unable to think coherently. But what makes the disease so frightening is not just its symptoms but its prevalence. One in 10 people older than 65 suffers from AD; above 85, by some estimates, the odds rise to almost 50%.
In contrast, research activity on AD is anything but spooky: Its rapid progress is demystifying the disease. Thanks to the past decade's insights into the genetics and underlying biological processes of the illness, "we can begin to think about doing something for [Alzheimer's patients], instead of just labeling them," says Donald Price of Johns Hopkins University School of Medicine in Baltimore. Indeed, several different strategies for alleviating or preventing some of the neuropathological symptoms of AD are being assessed in clinical trials now, and other lines of research are pointing to additional disease-fighting strategies.
Mountains of unanswered questions still loom, however. The field of AD research "has really blossomed," says Colin Masters of the University of Melbourne in Australia. "But it hasn't reached its peak yet. There's never been a better time for a young investigator since I've come into this area. There's just so much going on."
Diagnosis Back to TopAlzheimer's is tricky to diagnose. In its earliest stages, it can mimic depression, reactions to prescription drugs, a variety of other diseases, and normal aging. Some neuropsychological tests predict better than others who will develop more clear-cut symptoms of AD (1). Although subtle at first, "over time, the disease declares itself," says Donald Price. Memory, language, and decision-making skills decline steadily as confusion grows, sometimes accompanied by belligerence, anxiety, or hallucinations (see Honig and Chin Case Study and "When Does Normal Aging Become Abnormal?"). Excluding other causes and observing the rate and type of decline can allow a clinician to diagnose AD with as much as 90% accuracy. But because other dementias cause similar symptoms, ultimately only an autopsy can confirm that someone suffered from Alzheimer's. Using staining techniques and a microscope, a pathologist can spot the diagnostic plaques and tangles that riddle an AD patient's brain (Fig. 1). The so-called amyloid neuritic (or senile) plaques are found outside the cell and consist of -amyloid protein knotted up with tendrils of malformed brain cells; the neurofibrillary tangles are made of a protein called tau, and they bunch up inside neurons. Although plaques and tangles are still the defining characteristics of AD, the set of quantitative criteria used by neuropathologists to make the diagnosis is somewhat arbitrary and has changed in recent years. Sometimes the disease is called dementia of the Alzheimer's type (DAT) to reflect the uncertainties about how to define it as well as whether AD is a single disease rather than a collection of different ailments that cause similar symptoms.
As potential therapies snake through the drug-approval pipeline, better tools are needed to figure out who should get the therapies, says Donald Price. Ideally, treatments would reach people at risk for AD during the so-called preclinical stage--before they lose too many precious, largely irreplaceable neurons. If a benign treatment existed, he says, "when you joined AARP [the American Association of Retired Persons], you'd get your pill." The classic signs of AD--plaques and tangles--gunk up the brain well before people show symptoms of AD, according to autopsy studies that include nondemented people (2). Such studies imply that "the disease has already started before it can be clinically detected," says Joseph Price of Washington University School of Medicine in St. Louis, Missouri. And people who have been diagnosed with the mildest, early stage of AD already suffer from a substantial loss of neurons in memory areas of the brain (3), he adds.
Both Prices (who are unrelated) point out that several approaches might yield decent diagnostics for Alzheimer's. Blood or spinal fluid might carry legible signatures of the proteins that compose plaques and tangles, for instance. As yet, brain imaging isn't used to diagnose AD, but many research teams are furiously tinkering with existing technologies to tune them to the disease. Magnetic resonance imaging (MRI) scans, for instance, create crisp images of the brain. By comparing a patient's current MRI with one taken a year or two earlier, researchers can look for the distinctive pattern of brain shrinkage seen in AD patients (4). A quicker diagnosis might come from the Technicolor lens of positron emission tomography scans, which monitor radioactive tracers in the brain. Researchers are developing tags for amyloid, the main ingredient in plaques (see "Plaques Aglow") (5).
At the 2002 International Conference on Alzheimer's Disease and Related Disorders in Stockholm, Sweden, William Klunk, Chester Mathis, and colleagues from the University of Pittsburgh in Pennsylvania and Henry Engler of Uppsala University in Sweden reported preliminary results from a clinical trial with nine patients suffering from mild AD. The patients and several controls received injections of a radioactive tracer targeted to amyloid. In healthy people, the tracer sailed through the brain; in the AD patients, it appeared to lodge in regions where plaques accumulate (Fig. 2) (6).
The search continues for another type of diagnostic: genes that predict someone's risk of Alzheimer's. So far, three genes--Presenilin 1 (PS1), Presenilin 2 (PS2), and APP--have been linked to rare, early-onset forms of the disease that usually strike people before they reach age 60; each child of such a patient stands a 50% chance of inheriting the gene and thus succumbing to the disease if he or she lives long enough (7-12). And one version of a fourth gene, ApoE, increases a person's risk of AD but doesn't impose an absolute sentence as the others do (13).
But the early-onset genes account for less than 5% of Alzheimer's patients. A strong genetic component contributes to the common type of illness that hits people when they're older, but that form of the disease isn't due to a single gene's defect. As a result, it's harder to study than the rare, early-onset form.
The hunt for AD genes is still on. "To me, the genetics [of AD] is just starting," says Rudolph Tanzi of Harvard Medical School in Boston. "The tools are in place," including the human genome sequence, identification of single-nucleotide polymorphisms (SNPs), and studies of families with a high incidence of Alzheimer's. Researchers hope that new genes will hint at the disease's etiology, which molecular pathways it hijacks, and where drugs might aim to block it. Tanzi's team and others have identified a region of chromosome 10 linked to sporadic, late-onset AD (14-16). No one has pinpointed the exact spot in this neighborhood that increases risk of AD, but the bet right now is on a gene called IDE. The enzyme produced by IDE is better known for degrading insulin, but it also escorts amyloid out of the brain (see "Double Duty") (17). Ellen Wijsman of the University of Washington (UW), Seattle, estimates that at least five or six genes that predict a person's risk of AD at least as reliably as does ApoE remain to be found (18).
Pathology Back to TopDuring much of the 1990s, great rhetorical battles rumbled between two camps of Alzheimer's researchers. Hoisters of the -amyloid flag held senile plaques primarily responsible for AD neuropathology. Their rivals insisted that neurofibrillary tangles, composed of the protein tau, caused the nervous system more significant damage. That battle, still commonly known as the battle of the aptists (for -amyloid protein) versus the Tauists, has subsided somewhat, although it has left plenty of questions (19) (see Lee Science Article).
amyloid, the active ingredient in neuritic plaques (20), is a fragment sliced out of the middle of a protein called -amyloid precursor protein (APP), which weaves in and out of the cell membrane. Two enzymes, -secretase and -secretase, snip amyloid free from APP and allow it to float away from the cell (Fig. 3). This process usually doesn't cause trouble; amyloid shows up in many healthy body tissues, although no one knows what it does. But when amyloid is overproduced in the brains of people with AD, it bands together first in fibrils and then in plaques. These clumps probably irritate nearby neurons in a variety of ways: They activate scavenger cells of the immune system, called microglia, which can misguidedly attack healthy neurons while clearing up detritus in the brain; they cause oxidative damage to nearby cells with the help of metals embedded in the plaques (see "The Two Faces of Oxygen"); they possibly stimulate apoptosis, or programmed cell death (see "More Than a Sum of Our Cells"); and they probably physically block neuron-to-neuron connections. amyloid can also gum up capillaries and arterioles, fine blood vessels that are often deformed in Alzheimer's. Some investigators believe that amyloid, perhaps in some prefibrillar form, does its damage inside the cell. In any case, the genetic data strengthen the case that amyloid drives AD; PS1 and PS2 (genes that are required to produce active -secretase) and APP all are linked to familial forms of the disease.
Tau, meanwhile, works a different side of the street. The protein normally builds and stabilizes microtubules, tiny tracks along which supplies are carted throughout the cell. When tau goes bad--in most cases no one knows how or why--it twists up in pairs. These protein couples tangle together within the neuron, where they eventually distort the cell physically and hobble its internal machinery (see "The Halting Way of Tau"). Tau tangles are seen in several unrelated neurodegenerative diseases. One was considered a type of AD until it was found to be a pure tau pathology, without any trace of AD's other defining feature, amyloid plaques. That disease is now called frontotemporal dementia; it's caused by a mutation of the tau gene (21-23) (see Honig, Bell, and Chin Case Study).
amyloid and tau pathologies seem to operate fairly independently at early stages of the disease, says Donald Price. Plaques first accumulate throughout the cortex, the outer portion of the brain responsible for most high-level cognition. Tangles, meanwhile, concentrate in the hippocampus, a subcortical area crucial for memory. Then, "at some stage, the two pathologies become interactive, facilitating each other," says Donald Price, although no one's quite sure why or how. (For a possible interaction, see "Take Two.") Any hypothesis about how AD works, he says, will have to explain both plaques and tangles; most researchers agree, allowing the aptists and Tauists to reach a truce.
Tanzi says the aptists-versus-Tauists debate has subsided in part because recent research suggests that neither plaques nor tangles initiate the sequence of neuropathological train wrecks, such as cell death and disrupted neurotransmitter systems, that characterize Alzheimer's. Instead, plaques and tangles might be "tombstones" that mark sites of earlier carnage, he says. Before these tombstones are erected, free-floating fibrils of amyloid--not yet clumped together in plaques--appear to damage neurons. Compared to the -amyloid fibrils, amyloid plaques are relatively benign, says Tanzi.
Melbourne's Masters points out that there's still a "big gap" between the field's recognition that -amyloid overproduction is one of the earliest malfunctions in AD and an understanding of how amyloid might drive later symptoms, including -amyloid plaque deposition and tangle formation. "One of the major challenges" facing the field of AD research, says Masters, is to "prove or disprove the amyloid hypothesis"--the theory that amyloid sets off and maintains the cascade of AD neuropathology--"by actively intervening" in -amyloid production. If drugs that prevent buildup of the peptide stop the progression of AD--including the formation of tau tangles--"everyone will be satisfied" that amyloid is key to AD, he says.
For now, "there are still skeptics [of the amyloid hypothesis], and rightly so," says Masters. "In my book, it has still not been thoroughly tested." Others are convinced. "I will say it boldly: I think this disease is caused by excess amyloid in the brain," says Dennis Selkoe of Harvard Medical School (see Hardy and Selkoe Science Article) (24). He points to 10 key findings that support his causal arrow, such as the preponderance of AD in people with Down syndrome, who are known to have excess amyloid from birth. What's more, no other culprit, such as a toxin or virus, has emerged. And recent animal studies have backed up the hypothesis. Transgenic mice reported in 2001 develop both -amyloid plaques and neurofibrillary tangles, so researchers are now able to explore the relation between the two. The presence of amyloid accelerates the accumulation of tauopathies, suggesting that amyloid can spur formation of both types of damage (25, 26).
Plaques and tangles are AD's most definitive marks, but the disease causes plenty of other neuropathology as well. In later stages of AD, communication between surviving neurons sputters and sparks; they share fewer synapses, the points of near-contact where neurons exchange chemical signals.
If we step back from the microscope for a moment, we can see that the brain as a whole looks shrunken after years of AD (Fig. 4). The gross atrophy cuts a distinctive swath across the cortex, which Tanzi likens to a tornado that topples some houses and skips over others. The disease chews up some parts of the cortex--the frontal, parietal, and temporal lobes, which are grossly associated with higher cognition, spatial abilities, and memory, respectively--while leaving the occipital cortex, which processes vision, largely unscathed. Below the surface of the brain, the olfactory bulb, amygdala, and hippocampus suffer the greatest neural losses. These neural clusters are responsible (again, grossly and respectively) for smell, emotion, and memory.
Alzheimer's corrupts the brain's neurochemistry as well. Another subcortical structure, the nucleus basalis, shrinks dramatically in Alzheimer's. It produces acetylcholine, one of the main ingredients in the neurotransmitter soup that swirls around, conveying messages in the brain. Acetylcholine regulates sleep and facilitates higher cognitive functions as well. Drugs that inhibit the breakdown of this neurotransmitter improve thinking skills in people with mild or moderate Alzheimer's.
Prevention Back to TopSometimes the abundance of diseases that plague one's later years proves fortuitous--for scientific observations, at least. Researchers noticed in the 1990s that people who suffer from rheumatoid arthritis don't develop AD as often as do their peers. After some head scratching, this observation led to several studies showing that certain types of painkillers--nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen but not acetaminophen--delay the onset of AD (27). One of the strongest of such studies analyzed 8 years' worth of pharmacy records for 7000 people in Rotterdam, the Netherlands, and found that people who took NSAIDs for at least 2 years had 20% the AD risk of controls (28). A randomized, placebo-controlled clinical trial sponsored by the National Institute on Aging is now recruiting subjects to participate in a more rigorous--double-blind, placebo-controlled--test of whether taking NSAIDs can prevent or delay the onset of AD.
Although the NSAID studies were inspired more by unexpected observations than by theory, the results fit with basic research showing that amyloid inflames surrounding microglia. These immune system cells release inflammatory cytokines, nitric oxide, and other neurotoxins that can destroy nearby neurons; alternatively, the microglia might turn phagocytic and chew up neurons directly, says Barbara Tate of Pfizer in Groton, Connecticut. Tanzi points out that when microglia attack senile plaques, they might free amyloid to roam around the space between cells. Whatever the mechanism, cooling off inflammation might restrain some of AD's early progression.
Alzheimer's researchers are currently debating whether NSAIDs impede AD by another mechanism that isn't related to inflammation. Some NSAIDs limit production of a particularly toxic type of amyloid. The peptide comes in several flavors, the most common one of which has 40 amino acids. The one with 42 amino acids, however, appears even more prone to provoking AD. Several mutations responsible for familial AD increase the ratio of -amyloid 42 to -amyloid 40, for instance. In contrast, NSAIDs such as ibuprofen somehow reduce this ratio, at least in very high doses in cultured neurons (29) (see "More Than a Painkiller").
Another relation epidemiologists are still trying to get their heads around is whether brain injuries predispose people to AD. A few population-based studies, including some analyzing the records of World War II veterans, turned up an increased risk of AD in those who'd suffered a nonpenetrating head wound compared to those with other hospital-treated injuries (30-32). And animal studies have shown that head trauma elicits the molecular monsters responsible for AD: amyloid and tau both accumulate near damaged spots in badly shaken pig brains (33). But as epidemiologist Walter Kukull of UW Seattle points out, "it's really a muddy issue." Many of the studies are retrospective and thus might suffer from recall bias and other confounding factors. But one of the biggest obstacles to discerning whether there's a link might lie in the slippery diagnosis of AD. For instance, dementia pugilistica, the permanent state of punch-drunkenness that clouds the minds of some former boxers, resembles AD clinically but has a different neuroanatomical basis.
Other risk factors, alas, are much more widely accepted. As if there weren't enough nagging reasons to eat healthfully, epidemiological studies show that high cholesterol levels predispose people to AD (34). Reducing cholesterol with drugs in the statin family appears to alleviate this risk dramatically (35, 36) (see "Greasing Aging's Downward Slide"). Cholesterol congregates in so-called lipid rafts that float around in the cellular membrane. APP, -secretase, and -secretase are attracted to these rafts, and as Brian Austen of St. George's Hospital Medical School in Tooting, U.K., says, they're "marooned together" where they can interact and brew up amyloid. APP appears to exist in two separate pools; those proteins floating on the lipid rafts are clipped by -secretase and can spawn amyloid; APP floating free of the rafts is more likely to be cut by -secretase and yield harmless proteins (37). At the Stockholm meeting in 2002, Konrad Beyreuther of Heidelberg University in Germany reported preliminary results from a small clinical trial of statins in people with mild AD and normal cholesterol concentrations. Patients taking the drug appeared to decline more slowly than those taking a placebo, he reported.
Other epidemiological studies have uncovered promising hints that estrogen replacement therapy might protect women from Alzheimer's. One followed almost 2000 women in Cache County, Utah--the United States' longest-lived county. Those who had been on hormone replacement therapy (in this study, most women were treated with estrogen only) in the past were less likely to develop AD than were those who had never been on HRT (38). Current use didn't seem to help, leading researchers to conclude that there might be a "critical time" during which estrogen can forestall AD (39). But the purported benefits of HRT didn't hold up in a massive, case-controlled, randomized study. The Women's Health Initiative (WHI) showed that estrogen plus progestin increased rather than decreased the risk that postmenopausal women would develop dementia or mild cognitive impairment (see "Weathering the HRT Storm") (40). Another arm of the WHI trial examined whether estrogen (without progestin) alleviates the clinical symptoms of women already suffering from mild or moderate AD; it turned up no evidence of such a benefit (41). However, an earlier postmortem neuroanatomical study from the WHI showed that at a cellular level, at least, estrogen did seem to exert a positive effect. Women with early signs of AD who had taken estrogen lost fewer neurons in vulnerable brain regions than did women who had taken placebos (42).
Other ongoing clinical prevention trials will assess the protective effects, if any, of antioxidants such as vitamin E and ginkgo biloba. One trial of vitamin E in people with established AD showed that the treatment delayed their entry into nursing homes, a major milestone in the progression of the disease (43).
The AD-prevention hypothesis dearest to the hearts of many researchers goes by several different names: the cognitive reserve hypothesis, the cortical reserve hypothesis, and the "use it or lose it" hypothesis. According to the theory, stimulating the brain, say, by regularly reading research or introductory review articles, decreases the risk of developing Alzheimer's. Although the mechanism for such a protective factor is a bit murky--scientists talk about building extra neural connections that somehow compensate for early AD neuropathology--a few studies have backed up initial observations that people with more years of education are less likely to develop Alzheimer's. For instance, those with AD were less likely to have engaged in intellectual activities in early and middle adulthood than their nondemented peers (44).
Some of the most intriguing evidence for the cognitive reserve hypothesis comes from a longitudinal study of nuns in convents (see "Sister Knows Best"). These women are an epidemiologist's dream: They live in similar rooms, eat the same kinds of foods, and have similar chores and hobbies, thus reducing the number of confounding variables that normally plague population studies. Researchers analyzed writing samples gathered when the young women entered their convents. Low grammatical and cognitive complexity correlated with likelihood of AD (45); in contrast, one particularly sharp woman lived to age 101 with all her wits, even though her brain was studded with plaques and tangles at autopsy (46), providing more anecdotal evidence for the cognitive reserve hypothesis.
Treatment Back to TopAlzheimer's disease used to be one of the grimmer areas of research, but these days, AD researchers are remarkably optimistic. New transgenic and knockout mouse lines offer "ways to get into the nervous system of living animals," says Donald Price. The potential for helping millions of people live fuller, longer lives contributes to the new sense of urgency and enthusiasm. But there's also the specter of an aging population; a person's risk of AD doubles every decade. As Stephen McConnell of the Alzheimer's Association in Chicago, Illinois, points out, "unless we arrest AD, we will bankrupt the health care system."
The treatment of choice for AD in the United States has been drugs that inhibit the enzyme acetylcholinesterase and thus boost the brain's supply of acetylcholine, the neurotransmitter that dwindles in AD due to a shrinking nucleus basalis. In Germany, however, AD patients take memantine, a drug that dampens the activity of a glutamate receptor. In AD, as in other diseases, hyperactive glutamate can kill neurons. Memantine improves the quality of life in patients with later stages of AD, and the U.S. Food and Drug Administration (FDA) approved its use in October 2003 (47). However, at best, both drug treatments slightly slow the death march of degeneration.
In addition to NSAIDs, statins, and antioxidants already mentioned--which are generating excitement largely or originally because of their capacity to prevent the disease--several new major treatment strategies are undergoing intensive scrutiny. Although no one can predict whether or how well they'll work, the hope is that they'll be more effective than acetylcholinesterase inhibitors or memantine. Their approaches and underlying logic differ, but their goal is the same: to prevent the accumulation and clear existing deposits of amyloid. One treatment aims to block the secretase enzymes that clip amyloid from APP. Another chelates, or binds, the heavy metals zinc and copper from amyloid plaques, where the metals spur oxidative damage. The third, a vaccination, attempts to rope the immune system into the battle against Alzheimer's. The first vaccination clinical trial was halted due to serious side effects, but many researchers believe that the strategy is sound and can be modified for safety.
When it comes to cutting APP, "there's a good way to process it and a bad way to process it," says George Martin of UW Seattle. The enzyme in the white hat, -secretase, clips APP straight through the heart of the -amyloid amino acid sequence. The bad guys--and the ones implicated in AD---secretase and -secretase, cut APP at either end of what floats free as amyloid.
-secretase and -secretase are "intriguing" therapeutic targets, says Donald Price. A gene called BACE1 encodes -secretase (48). As predicted, mice that lack BACE1--which don't appear to suffer from the gene's absence--can't cleave APP in the -secretase spot. BACE1 knockout mice also don't accumulate amyloid deposits, even when they carry a gene that churns out buckets of APP.
Meanwhile, two genes--Presenilin 1 (PS1) and Presenilin 2 (PS2)--build some component of -secretase (49). The genes' products are necessary cofactors for -secretase's activity; blocking them prevents -secretase from liberating amyloid from APP (50). Researchers have identified other proteins that abet -secretase, but the identity of the enzyme itself remains a mystery (see Wolfe Perspective). Several proteins in addition to the presenilins contribute to the enzyme's active site, including nicastrin, aph-1, and pen-2 (51), but it's not yet clear whether they'd be good targets for preventing APP cleavage. Stifling either - or -secretase would prevent -amyloid production, but -secretase appears to be a more attractive target. It cuts APP at a site outside the cell membrane, whereas -secretase somehow clips APP in a segment embedded in the cell membrane, a site that's hard to target with drugs. -secretase has another disadvantage, Donald Price points out: Blocking it could interfere with the Notch pathway, because a -secretase-like cut releases the active portion of the Notch protein, which is necessary for cell maturation. Although the brain doesn't produce many new cells, a drug that shuts down Notch systemically would derail the production of the immune system's lymphocytes, for example.
Researchers from several drug companies are searching for secretase inhibitors, many by using high-throughput screening that can scan millions of compounds for anti-- or anti--secretase superpowers. Companies have been secretive about their results so far, but rumor has it that about 100 compounds have tested positive in transgenic mice, says William Thies of the Alzheimer's Association. As yet no one in the business is willing to confirm various whispers about which compounds are in or headed to clinical trials.
Other researchers have engaged a different foe than amyloid proper: the metals that spur amyloid to aggregate. Ashley Bush (see "Mindful of Metal") of Harvard Medical School discovered years ago while working with Tanzi that zinc causes loose strands of amyloid peptide to clump together in the test tube. Chelating zinc reverses the process. And in brain slices from people who died with AD, zinc chelators dissolve amyloid plaques (52).
"Nobody understands what free zinc is doing in the brain," says Melbourne's Masters, a collaborator on the project. Even in healthy people, it congregates in the parts of the brain most prone to AD damage, and it appears to interact with the neurotransmitter glutamate. The zinc somehow prompts amyloid to aggregate, and then it sucks copper into the clumps as well. Together, the metals generate hydroxyl radicals that probably cause oxidative damage to nearby tissue. Mopping up these heavy metals, the researchers reasoned, would squelch some neurotoxicity and either prevent plaques or, in the best case, dissolve plaques that have already taken hold.
Bush announced at the Society for Neuroscience meeting in November 2000 that high-throughput screening had identified several candidate compounds that chelate copper and zinc. Conveniently, one chelator, called clioquinol, had already been approved by FDA for use as an antibiotic (although it was later recalled due to adverse reactions in some people in Japan). The drug prevented plaque formation when given at a young age to animals engineered to mass-produce -amyloid deposits (53). The drug is being tested in humans with AD now. At the 2002 Stockholm meeting, Masters announced preliminary results from a small phase II clinical trial. Patients with moderate AD who took the drug declined less rapidly than controls did, although the difference wasn't significant. The team is continuing the work with a larger clinical trial.
A third promising approach to clearing -amyloid deposits from the brain treats them like a germ. It fared well in animal and early human tests but failed in a larger human trial. Dale Schenk of Elan Pharmaceuticals in South San Francisco, California, pioneered the method, which involves vaccinating animals with amyloid to induce an immune response. In mice, at least, the vaccination triggers antibodies to amyloid, some of which make it past the blood-brain barrier. As in the chelation studies, vaccinating young mice prevents buildup of amyloid plaques, and vaccinating older animals clears plaques that have already formed; neither group showed obvious side effects (54). What's more, the vaccine prevents the memory deficits normally seen in mice engineered to develop Alzheimer-like plaques (55, 56).
Dismayingly, however, several patients in a phase II trial of the vaccine developed a potentially deadly central nervous system inflammation. Elan cancelled the trial in January 2002, and Peter Seubert of the company says that researchers are still determining exactly what went wrong. They and others knew that stirring up the immune system could backfire by prompting an autoimmune response or rampaging inflammation, but animal studies and a phase I safety trial induced no such side effects.
Not everyone is writing off the approach, however (57). An autopsy study of a patient who had received the vaccine (but didn't have an adverse reaction) showed that his plaque burden was substantially less than that in otherwise similar patients who hadn't been vaccinated (58). Seubert reported plans to develop vaccines that contain a fragment of amyloid rather than the entire peptide. In mice, at least, some stretches spur antibodies but don't draw the attention of the T cells that are probably responsible for the inflammation. As Thies points out, "if you look at the history of vaccines, the ultimate therapeutic target is virtually never the first one tested."
While some researchers fine-tune secretase inhibitors, await clinical trial results for chelators, or attempt to revive immune-system strategies, others are searching for new techniques. For instance, a sluggish protein-degradation system could allow bad amyloid to accumulate in the brain; stimulating enzymes that break down amyloid might fight AD (59).
Despite the auspicious early results from treatments that block or clear amyloid, Masters points out that researchers are still debating whether the other AD villain, tau, would make a good target for future therapies. For instance, tangled tau is phosphorylated, and some have suggested that preventing or reversing this phosphorylation might clear tangles. However, researchers are still trying to determine whether phosphorylation triggers the tangles (see "Tau Tangler").
Whereas most researchers are focused on neuropathological mechanisms in AD, says UW's Martin, many tend to overlook the number one risk factor for AD: aging. If half of all people develop the neuropathological features and clinical symptoms of AD after a certain age, he says, it makes more sense to think of AD not as a disease but as a "common senescent phenotype." In order to figure out AD, he says, researchers will have to understand the fundamental mechanisms of aging.
October 29, 2003
Laura Helmuth is a news editor at Science. She uses her brain as much as possible.
Abbreviations: amyloid. Also called A. This short amyloid protein is clipped out of -amyloid precursor protein. It can be either 40 or 42 amino acids long. A 40 appears to be relatively harmless; A 42 more readily clumps into free-floating fibrils and then senile plaques. ApoE. Apolipoprotein E gene. It comes in three major flavors: ApoE2 and ApoE3 are either harmless or protective against AD; ApoE4 increases a person's risk of Alzheimer's disease, particularly if present in two copies. It's not yet clear how other, less common types of ApoE relate to Alzheimer's. APP. -amyloid precursor protein. When cut by -secretase, it yields harmless peptides. When cut by - or -secretase, it gives rise to amyloid. Mutations in its gene--designated APP--are responsible for some cases of early-onset, familial Alzheimer's. BACE1. -secretase, one of the enzymes necessary for clipping amyloid from -amyloid precursor protein. The gene that encodes it is called BACE1. DAT. Dementia of the Alzheimer's type. This abbreviation is frequently seen in research publications. It acknowledges that Alzheimer's disease is an umbrella term for what may prove to be many symptomatically similar yet etiologically distinct diseases. IDE. This gene located on chromosome 10 produces insulin-degrading enzyme, or insulysin. It could be the next AD risk gene identified. Presenilin 1. Presenilin 1 (PS1) and Presenilin 2 (PS2) are similar genes on different chromosomes. Their protein products facilitate -secretase's action. Mutations in the PS1 and PS2 genes are responsible for some forms of early-onset, familial Alzheimer's. Presenilin 2. Presenilin 1 (PS1) and Presenilin 2 (PS2) are similar genes on different chromosomes. Their protein products facilitate -secretase's action. Mutations in the PS1 and PS2 genes are responsible for some forms of early-onset, familial Alzheimer's. -secretase. One of the enzymes necessary for clipping amyloid from -amyloid precursor protein. -secretase. One of the enzymes necessary for clipping amyloid from the -amyloid precursor protein. SNPs. Single-nucleotide polymorphisms. These are common, single-base-pair variations in DNA. Tau. This protein normally stabilizes microtubules in the cell. In Alzheimer's and some other neurodegenerative diseases, it bunches up to form neurofibrillary tangles.
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