2007 Progress Report on Alzheimer's Disease: Discovery and Hope -- 2 Progress Continues

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PROGRESS IN AD RESEARCH CONTINUES

In 2007, scientists supported by NIH have made advances in a number of areas important to AD:

* Basic research on AD
* Normal cognitive aging
* The interface between healthy cognitive aging and AD
* Genetic causes and risk factors for AD
* Nongenetic risk and protective factors for AD
* Diagnosis
* Translational research
* AD clinical trials
* Caregiver support

These areas of investigation focus on the central issues of AD—what occurs during the very first steps of the disease process, what we can do to promote healthy cognitive aging and prevent AD, and what we can do once the disease has taken hold. The following sections describe new knowledge in these areas that may hold the key to future prevention, treatment, and caregiving strategies.


IMPROVING OUR BASIC UNDERSTANDING OF AD

From the beginning, studies at the cellular and molecular levels have focused on understanding the wide range of processes that interfere with, or enhance, the function and survival of neurons and their connections. The aim is to identify targets that can be translated and developed into AD therapies. Such therapies may avoid or reduce the cell dysfunction and cell death that occur as the disease progresses and also may keep memory intact.

Interest in mechanisms at the basic level is ongoing, and the potential roles of different forms of beta-amyloid and abnormal tau in neuronal toxicity continue to be a source of intense investigation.


Beta-amyloid

Scientists now know a fair amount about the metabolism of amyloid precursor protein (APP), a large protein associated with the cell membrane that is the starting point for the beta-amyloid that forms plaques. Scientists also know the basic steps of beta-amyloid and plaque formation. They know that three different enzymes—alpha-secretase, beta-secretase, and gamma-secretase—are involved in cleaving APP into discrete fragments, the functions of which are still not completely understood. Depending on which enzymes are involved and where the cleaving occurs, APP processing can follow one of two pathways—a pathway that is helpful to neurons or one that is harmful because it leads to the formation of beta-amyloid and plaques.

Studies in this area have evolved to the point that investigators have begun initial testing in humans of potential therapies aimed at halting the synthesis of beta-amyloid, reducing its levels, or degrading early aggregates before harmful complexes have formed. At the same time, basic science investigators are still probing the mysteries of plaque formation and seeking to understand the potentially toxic effects that beta-amyloid exerts on neurons.

* Because gamma-secretase is involved in the production of harmful beta-amyloid, scientists have hypothesized that it could be a useful therapeutic target. However, gamma-secretase also is involved in the helpful APP processing pathway and in the cleavage of other developmentally important proteins, so actions to strongly inhibit its activity could have negative side effects. Johns Hopkins University School of Medicine researchers supported by the National Institute of Neurological Disorders and Stroke (NINDS) and NIA demonstrated that genetically reducing gamma-secretase activity by as little as about 30 percent in mice is enough to reduce beta-amyloid formation but leave sufficiently high gamma-secretase levels for the enzyme’s other essential reactions (Li et al., 2007). These findings may have identified a possible anti-amyloid therapeutic strategy—gamma-secretase inhibitors—as well as a way to preclude potentially harmful effects from the inhibitors.

A key focus of beta-amyloid research has always been to understand how this protein peptide actually damages neurons. Recent research suggests that early, small, and soluble aggregates of amyloid, called beta-amyloid-derived diffusible ligands (ADDLs), or oligomers, may be the main culprits in harming neurons. Much evidence also suggests that synapses, the tiny gaps between neurons that are essential for neuronal communication, are oligomers’ prime targets. Several recent studies have examined the pathways that lead from beta-amyloid to eventual synaptic dysfunction or neuron death and studied how beta-amyloid oligomers target specific synaptic connections between neurons, causing them to deteriorate.

* A research group at Northwestern University examined the ability of ADDLs to affect the composition, structure, and abundance of synapses (Lacor et al., 2007). In this test tube study of neurons situated in the hippocampus, the researchers found that ADDLs bound to synapses of a specific subset of hippocampal neurons, promoting a detrimental change in the composition, structure, and abundance of those synapses. Continued exposure to ADDLs also damaged the neurons’ dendritic spines (the structures that receive messages from other neurons), affecting their ability to function properly.
* A study in mice by scientists at the Salk Institute for Biological Studies in La Jolla, California, provides evidence that the APP cleavage at a site known as D664 may be necessary for the synaptic dysfunction characteristic of AD to occur (Saganich et al., 2006). The research team, supported by NINDS and NIA, found that synaptic loss and behavioral abnormalities were completely prevented by a mutation at D664, even in mice that had high levels of beta-amyloid and many plaques. Uncovering the mechanism by which the D664 cleavage contributes to dysfunction may ultimately help researchers understand synaptic loss in AD and develop treatment strategies.

Another continuing line of research focuses on the possibility of harnessing an immunization response in people with AD that involves antibodies to beta-amyloid. Immunizing people against disease has been a cornerstone of medical practice for decades, and investigators have pursued the idea that it might be possible to immunize people against AD by injecting them with a beta-amyloid-related immunogen (a substance designed to elicit an immune response). This kind of injection would cause a person’s immune system to make antibodies that, in turn, would lower the levels of brain amyloid.

This technique, called active immunization, has been tested in AD transgenic mice that were actively immunized with a beta-amyloid immunogen. (Transgenic animals are those that have been specially bred to develop AD-like features, such as beta-amyloid plaques.) The mice had fewer plaques and improved performance on memory tests. This finding led to a clinical trial in humans to test the safety and effectiveness of active immunization with the beta-amyloid immunogen. However, about 6 percent of participants in the trial developed brain inflammation in response to the treatment, so the trial was stopped. Despite this setback, interest in developing an AD vaccine remains high.

Research into new ways of shaping the antibody response continues in the laboratory, and more refined antibody approaches are being tested in clinical trials.

* Using several strains of mice, including transgenic and normal mice, Harvard Medical School investigators tested four different partial fragments of beta-amyloid as potential immunogens (Maier et al., 2006). The researchers found that the immunogens evoked the desired immune response in both sets of mice, reducing plaque levels in their brains without an accompanying inflammatory reaction. The transgenic mice also showed slight improvements in memory tests.

In a second approach to protecting against AD, called passive immunization, antibodies are produced or manufactured outside the body. For example, humanized antibodies to beta-amyloid have been made in cell cultures using recombinant DNA techniques. The antibodies can then be isolated and administered to subjects. Scientists presume that passive immunotherapy produces less of an inflammatory response than active immunotherapy, and a number of investigators are pursuing this approach.

* Cerebral amyloid angiopathy (CAA) is the accumulation of beta-amyloid in the walls of arteries in the brain. Because CAA is commonly found in AD, many scientists are interested in how beta-amyloid deposits in blood vessels and neurons may generate human disease and whether they can be treated by immunotherapy. Researchers at Massachusetts General Hospital, supported by NIA and the National Institute of Biomedical Imaging and Bioengineering, used microscopy at different time intervals to monitor CAA in a mouse model of AD to evaluate the effects of anti-beta-amyloid passive immunotherapy (Prada et al., 2007). The investigators saw clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, but the effect was short-lived. Chronic administration of antibody over 2 weeks led to better clearance without evidence of hemorrhage or other destructive changes. This imaging study directly demonstrated that CAA in a transgenic mouse model can be cleared with an enhanced immunotherapy regimen.

Additional insights about beta-amyloid have come from studies of neuronal networks. These studies show how beta-amyloid may damage normal electrical activity of hippocampal neurons, thereby diminishing the cells’ ability to communicate with each other.

* A research group at the Gladstone Institute of Neurological Research in San Francisco discovered that, compared with normal mice, transgenic mice show anatomical and biochemical alterations in certain brain regions as well as abnormal excitatory electrical activity (Palop et al., 2007). The study focused on the hippocampus (a region of the brain that is key to learning and memory). These findings are important because they suggest another damaging effect of beta-amyloid—namely, that beta-amyloid presumably triggers abnormal electrical activity throughout the brain. This abnormal activity in turn triggers compensatory inhibitory activity, perhaps contributing to AD-related network dysfunction.

Other aspects of beta-amyloid also are yielding their secrets to AD researchers.

* Scientists at the Buck Institute for Age Research in Novato, California, bred transgenic mice to develop features of AD and to overproduce neuroglobin, a protein expressed predominantly in neurons that is closely related to hemoglobin, the oxygen-carrying protein in the blood. Neuroglobin is abundant in the brains of vertebrates. The function of this globin family protein is largely unknown, but the expression of neuroglobin can be induced when oxygen levels in the brain are lowered, as in a stroke. The transgenic mice performed significantly better on memory tasks and had fewer beta-amyloid plaques than did transgenic mice that only developed AD features (Khan et al., 2007). The researchers, supported by NINDS, speculate that increasing neuroglobin levels may merit additional research as a therapeutic target, not only for cerebrovascular disease but also for beta-amyloid toxicity.


Tau

Tau is a leading player in AD pathology and is generating new excitement as an area of study. The focus on tau was spurred by the finding that a mutant form of this protein is responsible for frontotemporal dementia and parkinsonism linked to chromosome 17, another neurodegenerative disorder that shares some features with AD. That finding indicated that abnormalities in tau can cause dementia.

Recent research has provided other new insights. For example, some studies have suggested that tau’s influence on cell death may have more to do with its interference in the normal cell cycle process than with its involvement in the formation of neurofibrillary tangles. Other studies suggest that, like beta-amyloid, early soluble forms of abnormal tau (not the final neurofibrillary tangle) may be the trigger for cell death.

Transgenic mouse models have played a big role in pushing forward tau research because they can be studied methodically for clues to human diseases. For example, the “triple transgenic” mouse forms plaques and tangles similar to those in human AD over time in brain regions. Another new transgenic mouse model, which contains only human tau, forms clumps of damaging tau filaments in a region-specific fashion similar to that seen in humans with AD.

* A research group from the Gladstone Institute of Neurological Research supported by NIA and NINDS explored the possibility that a treatment aimed at tau could block the cognitive impairments that result from beta-amyloid accumulation (Roberson et al., 2007). In this study with AD transgenic mice that normally are cognitively impaired, the scientists eliminated the animals’ tau gene. The resulting lower levels of tau produced by the mice prevented behavioral problems that usually occur when too much beta-amyloid is produced, even though beta-amyloid levels remained high. This surprising result suggested that reducing tau levels may present another target for future AD treatments.


AD and Other Neurodegenerative Diseases

Studies of brain abnormalities resulting from common mechanisms in a number of neurodegenerative diseases are providing important insights into AD. Diseases such as AD, Lewy body disease, Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Parkinson’s disease, and Creutzfeldt-Jacob disease have similar clinical symptoms, including memory loss, movement problems, and sleep-wake disorders.

People with any of these disorders also exhibit the same pathological hallmark—misfolded and mutant proteins in the brain. Under normal conditions, most misfolded proteins are either repaired or degraded, but when too many of these proteins are produced over a long period of time, the body’s repair and clearance process may be overwhelmed. The toxic misfolded proteins accumulate and lead to the age-related neurodegenerative disorder.

In 2007, several studies provided valuable insights into how this process may occur and why some neurodegenerative diseases have overlapping features.

* Scientists at the University of Pennsylvania School of Medicine identified, for the first time, a protein called TDP-43 as a component of the protein aggregates that form in ALS and in some forms of frontotemporal dementia (Neumann et al., 2006). Finding the same molecular signature in the two diseases suggests that they may represent different facets of the same neurodegenerative disorder. It may be that a number of neurodegenerative diseases that affect different groups of neurons have similar disease processes. If that is true, then developing therapies for these disorders and other similar diseases may be simplified.

* Another research team, working at Northwestern University, explored how the expression of a single protein that is prone to abnormal aggregation can lead to the disruption of many cellular pathways. These researchers also examined whether one general mechanism might explain the many common features of protein misfolding diseases (Gidalevitz et al., 2006). The investigators used the worm C. elegans as a model to test whether expression of a pathogenic protein known as a “polyQ protein” (similar to the abnormal huntingtin protein that causes Huntington’s disease) could affect the folding or degradation of other proteins.

Worms with the polyQ protein were crossed with worms that expressed other mutant proteins in either muscle or brain cells. The researchers found that the offspring of those worms showed chronic expression of the aggregation-prone polyQ protein, which caused the other proteins to become toxic under conditions where they were normally innocuous. Moreover, the toxic action was reciprocal in that the other mutant proteins, which had no adverse effect under normal physiological conditions, could enhance the aggregation of polyQ proteins. These clues about the interactions between abnormal proteins and their effects on neurons may provide a valuable boost to efforts to target potential treatments for various age-related neurodegenerative diseases.

* Researchers at the University of Texas Southwestern Medical Center used transgenic mice to explore relationships between AD and Parkinson’s disease. This study, supported by the National Institute of Mental Health (NIMH), showed that in the spinal cords of mice made to overexpress human normal and mutant alpha-synuclein (a protein implicated in Parkinson’s disease) a change occurred in the ubiquitin/proteasome system. This is a cellular system that degrades misfolded proteins (Gallardo et al., 2008). Curiously, the mice also exhibited a fourfold increase in levels of the ApoE protein (ApoE is a genetic risk factor implicated in AD). This overexpression produced marked increases in aggregates of alpha-synuclein and insoluble beta-amyloid. Deleting the APOE gene, which makes ApoE, had a number of positive effects in the transgenic mice—alpha-synuclein-induced neurodegeneration was delayed, survival increased, accumulation of alpha-synuclein aggregates decreased, and accumulation of beta-amyloid was suppressed. These findings suggest that ApoE is involved in the response to alpha-synuclein toxicity, and that AD and Parkinson’s disease may share a molecular link through the ubiquitin/proteasome system. This insight may have important implications for preventing and treating these devastating diseases.


AD and Aging

Another set of insights about AD derives from an apparent risk factor common to a number of neurodegenerative diseases: aging itself. Age-related changes, such as inflammation, changes in expression of certain proteins, and the generation of free radicals, may precede, follow, or exacerbate the neuronal damage that occurs in AD. In addition, age-related changes in one or more of the hundreds of varieties of proteins could result in inefficient functioning of certain synapses, predisposing neurons to failed communication and death. Scientists are investigating all of these possibilities.

* In a study using the C. elegans worm, scientists at the Salk Institute for Biological Studies introduced a gene that increased the lifespan of the worms and a gene that made beta-amyloid (Cohen et al., 2006). The investigators found that the worms containing the increased-lifespan gene also suppressed the aggregation-related toxicity of beta-amyloid. These findings suggest that aging itself plays a role in the rate at which beta-amyloid aggregates, and investigators identified two genes essential for this process.
* An intramural research group at NIA identified disease-specific changes in gene expression in different regions of brain tissue from people with AD, people with other types of dementia, and cognitively healthy people (Weeraratna et al., 2007). The analysis revealed that genes that differed in expression the most between the groups were related to nervous system development and function and neurological disease, followed by genes involved in inflammation and immunological signaling. A specific group of genes associated with beta-amyloid accumulation and clearance was found to be significantly altered in the AD group. The most significantly down-regulated gene in this dataset was one containing the genetic information necessary to make an enzyme implicated in beta-amyloid clearance. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and enzymes associated with amyloid clearance in AD patients.
* Scientists at the University of North Dakota School of Medicine and Health Sciences supported by the National Center for Research Resources (NCRR) have been investigating cytokines, substances produced by immune system cells. These substances are secreted by cells during the body’s response to inflammation. The investigators found that a cytokine called tumor necrosis factor alpha, which is present in the brain during an inflammatory response, can begin a process in nerve cells that ultimately leads to cell death (Jara et al., 2007). This finding may help explain one mechanism leading to cell death in AD and related diseases.
* Free radicals—oxygen or nitrogen molecules that combine easily with other molecules—are important in the aging process and may be important in AD as well. Free radicals can help cells in some ways, but overproduction of these highly reactive molecules can damage neurons in a process called oxidative stress. A substance called 4-hydroxy nonenal (4-HNE), formed as a result of oxidative stress, is increased in AD. 4-HNE also is found in AD plaques. Scripps Research Institute scientists, supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), found that 4-HNE modifies beta-amyloid fragments, triggering the formation of toxic beta-amyloid oligomers (Siegel et al., 2007). These findings provide impetus for additional research on whether, or to what extent, oxidative stress is a risk factor or a consequence of AD.


New Insights into New Neurons

Until recently, scientists believed that neurons in mammals were formed only during the fetal period and for a short time after birth. The belief was that once a mammal had reached a certain level of maturity early in life, neurons could only be lost. The notion that new neurons could develop later in life was radical. Finding that this was true, in fact, the case was revolutionary.

This shift in thinking over the past few years was based on studies showing that neurogenesis (the formation of new neurons) takes place in the adult brain, at least in a limited number of brain regions, such as the hippocampus. Neurogenesis declines during aging but can be stimulated by environmental influences, including physical activity and learning tasks.

This evidence raises a big question: Do these new neurons actually help brain regions function or are they merely a reservoir to replace dying neurons? Several recent studies, conducted by scientists from Johns Hopkins University, the Chicago Medical School of the Rosalind Franklin University of Medicine and Science, and the University of Arizona, have helped answer this question.

In studies with mice and rats, investigators showed that new neurons produced in the adult hippocampus are better able to adapt (an attribute called “plasticity”) and to mature (Ge et al., 2007). In fact, they found that because of their enhanced “excitability,” new neurons may help process information and form memories in the hippocampus (Ramirez-Amaya et al., 2006). The researchers also found that certain types of stress disrupted neurogenesis by decreasing the survival of the new neurons (Thomas et al., 2007).
These and other similar findings may help researchers develop future interventions that maintain or enhance the formation of new neurons, thereby helping to slow age-related cognitive decline.



LEARNING ABOUT COGNITIVE AGING

Improvements in public health, medical care, nutrition, and living standards mean that we are now living longer than ever. Many older adults enjoy active, productive lives, but they also face the risk of cognitive and memory problems.

This challenge has provided a major impetus for research into healthy cognitive aging. Scientists want to know how and why some people remain cognitively healthy all their lives while others do not. Answers to these questions also can help researchers understand what goes wrong in AD and other neurodegenerative diseases and can point the way to interventions that might maintain successful brain and cognitive aging.

* Working memory is an important kind of short-term memory that maintains information in a temporary “buffer” that can be continually updated as needed. This type of memory is important for cognitive and emotional function, allowing us to inhibit inappropriate actions and plan future actions. Working memory appears to depend on recurring activity in networks involving neurons in the front part of the brain (the prefrontal cortex). This activity allows neurons to continue firing during periods of delay when the stimulus or event to be remembered is not present in the environment, thus maintaining a representation of the information over time, even in the face of distracting stimuli or information. With increasing age, working-memory deficits become a consistent feature of declines in cognitive performance.

Investigators at the Yale University School of Medicine conducted an extensive series of experiments in rats and nonhuman primates and found that stimulating neuronal receptors in the prefrontal cortex improved working memory (Wang et al., 2007). They also found that weakened connections within neuronal networks in this brain region may underlie some of the cognitive deficits seen in older adults.

* A research team at the University of Kentucky and Memory Pharmaceuticals Corporation in Montvale, New Jersey, took another approach to studying cognitive aging (Rowe WB et al., 2007). This study in rats combined analyses of changes in expression of many genes with behavioral testing to determine gene changes that are selectively associated with age-related cognitive dysfunction in the hippocampus. Results showed clear differences in expression of genes that occurred in the brain between the cognitively impaired and cognitively healthy rats, suggesting a model for age-related cognitive impairment. In this model, if decreases in expression of genes important for the use of glucose and in energy production by cells that support neuronal function were coupled with deficiencies in neuronal energy production, neurons would be unable to trigger activity that enables plasticity and memory formation in response to learning tasks. In this model, these deficiencies also might generate signals that activate harmful pathways, further disrupting cognitive processes.

* The multi-site Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) clinical trial, funded by NIA and the National Institute of Nursing Research (NINR), is designed to test the effects of brief cognitive training in older adults. In one component, researchers at the Indiana University School of Medicine examined the effects of cognitive training on participants who exhibited declines in cognitive function (Unverzagt et al., 2007). Participants received training in memory, reasoning, or speed of processing of visual information.

Compared with a control group that received no training, the participants who received the memory training and had normal memory at the start of the study showed significant improvement in memorization skills. Among participants with pre-existing declines in memory function, however, those in the memory training group showed no benefit. Those who received the reasoning or the speed-of-processing training showed improvement comparable to participants with normal memory.

These findings suggest that older adults with pre-existing mild memory impairment may not benefit from memory training as much as those with normal memory function, but they benefit just as much from certain forms of cognitive training that do not rely on memorization. This training may be able to improve the ability of older adults to maintain skills that allow them to carry out daily tasks and lead a higher quality of life.



NORMAL COGNITIVE AGING, COGNITIVE DECLINE, AND AD: WHAT'S THE DIFFERENCE?

As knowledge grows about normal cognitive aging, AD, and the stages in between, it is increasingly evident that there is no clear line between a completely healthy brain and a diseased brain. Evidence shows that most people develop some plaques and tangles in their brains as they get older, but not everyone develops cognitive problems, amnestic MCI, or AD. At what point does an age-related process become a disease-causing process? Several recent studies have explored this question.

Recent Advances

* Evidence from the Religious Orders Study and the Memory and Aging Project—two community-based epidemiologic studies conducted by Rush University Medical Center scientists—indicated that about one-third of individuals between the ages of 82 to 85 who did not have clinical dementia or aMCI when they died still met the neuropathologic criteria for intermediate or high likelihood of AD (Bennett et al., 2006a). In earlier tests of memory and other cognitive functions, those who met the AD neuropathologic criteria scored a little lower on tests of episodic memory (the ability to place information in long-term storage for later retrieval) than other study participants but showed no differences on other cognitive domains.
* The development of Pittsburgh Compound-B (PiB) has allowed scientists to take huge steps forward in their understanding of normal and abnormal age-related changes in the brains (Klunk et al., 2004). PiB is a radiolabeled compound that binds to beta-amyloid plaques in the brain and can be imaged in living people using positron emission tomography (PET) scans. Two recent studies conducted by researchers at Washington University School of Medicine and the Centre for PET in Victoria, Australia, showed that approximately 20 percent of 66- to 86-year-olds with normal cognition showed positive PiB binding, indicating an abundance of beta-amyloid in the brain (Mintun et al., 2006; Rowe CC et al., 2007).

These and other findings show that studies to explore further the interface between a pathological process (formation of beta-amyloid plaques) and the aging process are both feasible and necessary. Future studies will clarify the relationship between AD brain pathology and the eventual diagnosis of aMCI and AD, as well as when the diagnosis can be made with certainty.



ACCELERATING THE SEARCH FOR GENETIC CAUSES AND RISK FACTORS

Until recently, only four of the approximately 30,000 genes in the human genome were conclusively shown to affect the development of AD. Mutations in three genes—the APP gene found on chromosome 21, the presenilin 1 gene on chromosome 14, and the presenilin 2 gene on chromosome 1—are linked to the rare early-onset form of familial AD. The APP gene is responsible for making APP, the precursor to beta-amyloid. The presenilin genes contain the information necessary to make the proteins that are part of one of the enzymes that help to cleave APP to form beta-amyloid. Mutations in each of these genes promote the breakdown of APP in a way that leads to increased production of harmful beta-amyloid.

The fourth gene, APOE, found on chromosome 19, contains the information necessary to make a protein called apolipoprotein E (ApoE). ApoE carries lipids in the bloodstream and is important in clearing lipids from the blood. APOE has three common forms, or alleles—ε2, ε3, and ε4. The ε2 form may provide some protection against AD, and ε3 is thought to play a neutral role. The ε4 form is a known risk-factor gene for the common late-onset form of AD, and many studies are underway to clarify its impact.

* Boston University School of Medicine scientists supported by the National Heart, Lung, and Blood Institute (NHLBI) and NIA examined whether APOE ε4 affects the relationship between brain volume and cognitive performance in 1,477 participants in the Framingham Study population (Palumbo et al., 2007). Those with an APOE ε4 allele and smaller brain volume did less well on tests of visual memory, new learning, and executive function than those without APOE ε4, who also had smaller brain volumes. It may be that having APOE ε4 not only increases the risk of AD, but also leads to poorer outcomes in those who do not yet have symptoms of the disease.

* People who have two copies of the APOE ε4 allele may be at high risk of developing AD at an earlier age of onset and for experiencing far more rapid declines in memory performance, compared with people without this allele and people with only one copy. Such memory declines, even within a normal range of performance, could be early markers of disease, detectable before the individual experiences clear symptoms of the disorder. Investigators supported by NIMH and NIA examined how performance on neuropsychological tests by a sample of healthy adults in their 50s and 60s related to their APOE ε4 status (Caselli et al., 2007). The investigators, with the Mayo Clinic in Scottsdale, Arizona, and the University of Arizona, found that even before a diagnosis of aMCI, individuals with two copies of APOE ε4 showed higher rates of cognitive decline than those at lower genetic risk for AD.

These findings support the notion of a presymptomatic state of disease, the identification of which might aid in early detection and diagnosis of AD among people at increased genetic risk. Further prospective studies are needed to examine how rates of cognitive decline relate to rates of AD disease progression and conversion to a final diagnosis of AD. Results from these studies may suggest new targets for possible interventions to delay onset or progression of AD.

* Though scientists know that APOE ε4 is a risk factor for cognitive decline that eventually leads to AD, they have yet to understand the steps in that process. Many think that it involves an interaction between genetic and environmental factors. One study, supported by NIMH and conducted by a research team at the University of California San Diego examined the role of one such environmental factor, prolonged psychological stress (Peavy et al., 2007). Stress generally involves elevations in the hormone cortisol, which have been linked to hippocampal atrophy and to memory and learning impairments. This study assessed APOE status, stress levels, salivary cortisol, and memory performance of 91 older adults without dementia.

The researchers found that having either one or two APOE ε4 alleles and high stress were associated with reduced memory performance. In addition, the investigators found significant interactions between stress and APOE ε4; participants with high levels of stress and the APOE ε4 allele consistently manifested worse memory and higher cortisol concentrations than other participants. These findings point the way to future studies that could follow individuals over time to determine whether stress levels and APOE status in combination could be used to predict future development of cognitive decline leading to clinically diagnosable dementia.

Most experts believe that in addition to APOE ε4, at least half a dozen more genes may influence the development of late-onset AD in some way. Geneticists around the world are searching for these genes.

* In 2007, a worldwide collaboration of scientists supported by NIA, the National Human Genome Research Institute, NCRR, the Canadian Institutes of Health Research, and private foundations in the United States, Canada, and Japan unveiled their discovery of a new AD risk-factor gene called SORL1 (Rogaeva et al., 2007). This gene is involved in recycling APP from the surface of cells, and its association with AD was identified and confirmed in three separate studies (Lee JH et al., 2008; Lee JH et al., 2007; Meng et al., 2007). The researchers found that when SORL1 is expressed at low levels or in a variant form, harmful beta-amyloid levels increase, perhaps by moving APP away from its normal pathways and toward cellular compartments that generate beta-amyloid.

Studies are ongoing to clarify SORL1’s role in the AD process. For example, NHLBI-supported scientists at Boston University School of Medicine conducted a genome-wide association study on Framingham Study participants using cognitive data collected in an NIA-funded add-on study (Seshadri et al., 2007). A genome-wide association study tests for linkage between genes and a particular disease across all the genes in a specific population of individuals. The researchers found that the SORL1 gene was associated with measures of abstract reasoning and that another gene, CDH4, was related to total cerebral brain volume. This association of an AD risk-factor gene with cognitive function suggests there may be a common pathway in the brain aging process and in AD.

NIA’s Alzheimer’s Disease Genetics Initiative (ADGI) provides critical support to all of this work. Launched in 2003, this study aims to identify at least 1,000 families with members who have late-onset AD and members who do not have the disease. Investigators are collecting blood samples and other clinical data from participating volunteers. These biological specimens allow investigators to create and maintain “immortalized” cell lines—cells that are continuously regenerated in the laboratory. The cell lines will be used in DNA analyses to further understand SORL1 and to identify additional AD risk-factor genes, a critical task even if individual risk-factor genes may have relatively small effects on AD development. More than 4,000 new cell lines are now available for researchers to study risk-factor genes for late-onset AD.

A second investigator-led initiative, the Alzheimer’s Disease Genetics Consortium, was launched in 2007 to accelerate the application of genetics technologies to late-onset AD through collaborations among leading researchers in AD genetics. The ultimate goal of this effort is to obtain genetic material from 10,000 people with AD and 10,000 cognitively healthy people and then to scan the entire genome for the remaining AD risk-factor genes, as well as genes for age-related cognitive decline. Some of the genetic material will be drawn from existing samples of blood and tissue that are mostly held at Alzheimer’s Disease Centers. Other genetic material will be collected from new participants.

With such efforts, the search for the genetic underpinnings of late-onset AD is intensifying, allowing investigators to identify who is at high risk of developing AD, understand the mechanisms at work, and focus on new pathways amenable to prevention or treatment.


Other Genetics Initiatives Are Key to Successful AD Research

Rapid advances in AD genetics research are fostered though several other essential initiatives funded by NIA and NIH.

National Cell Repository for Alzheimer’s Disease (NCRAD)
www.ncrad.org
This research resource, located at Indiana University, is the central repository for the AD Genetics Initiative and provides the cell lines and DNA needed for genetic analyses.

Genetics of Alzheimer’s Disease Data Storage Site
www.niageneticsdata.org
Scientists who use NCRAD samples and other NIA-funded AD geneticists are required by NIA to submit their published data to this site, which was established in 2006 at Washington University in St. Louis. The data then undergo additional analysis by AD genetics experts.

Database of Genotype and Phenotype (dbGaP)
www.ncbi.nlm.nih.gov/entrez/query/Gap/gap_tmpl/about.html
This NIH collaboration was developed to archive and distribute the results of large-scale genome-wide association studies, gene sequencing studies, and analyses of the association between genotype and genetic traits. Datasets from multiple studies done using different types of analysis can then be merged. This process allows data from thousands of study participants to be analyzed together, with increased probability of gene discovery.

National Institute of Mental Health (NIMH) Genetics Dataset
www.nimh.nih.gov
NIMH has established a national resource of demographic, clinical, and genetic data from 1,411 individuals from families with AD. Housed at Washington University, the NIMH AD Genetics Dataset offers researchers clinical and genetics data from both NIMH and NIA.



ATTENTION TO NONGENETIC RISK AND PROTECTIVE FACTORS PAYS OFF

Epidemiologic studies, animal studies, and clinical trials are all important in identifying potential factors that may contribute to or protect people from AD risk—separately or interactively with genetics. In the past several years, two areas of focus have emerged: lifestyle factors and the management of health conditions. Scientists also have continued their research interest in looking at estrogen and AD.


Lifestyle Factors and AD

Several elements of a healthy lifestyle, including a nutritious diet, regular physical activity, not smoking, and strong social networks, can help people stay healthy as they grow older. An important reason for this benefit is that lifestyle choices strongly affect the risk of several chronic diseases, including heart disease, diabetes, and stroke, that commonly affect people as they age. Evidence is emerging that AD may share some of these risk factors. Findings from epidemiologic research, basic studies in animals, and limited clinical trials suggest that an array of lifestyle factors may influence the risk of developing age-related cognitive decline, aMCI, or even AD.

* As part of a large longitudinal study of older women, researchers at the San Francisco Coordinating Center and California Pacific Medical Center Research Institute examined the relationship between quality of sleep and cognitive function (Blackwell et al., 2006). The investigators found that disruptions to sleep, rather than the total amount of sleep, were consistently related to reductions in cognitive function. Another study of cognitively healthy women living in the community found a similar association between cognitive decline and sleep quality but not total sleep time (Yaffe et al., 2007).
* It is well recognized that the damage of AD often adds to and interacts with other changes in the brain to cause cognitive impairment. Two studies from the Memory and Aging Project provide supporting evidence for this observation. In one analysis of more than 600 cognitively healthy people, investigators found that chronic psychological distress was associated with a nearly threefold increased risk of AD; change in a global measure of cognition; and change in episodic memory, the clinical hallmark of AD (Wilson et al., 2006). In a separate study, researchers found that social engagement might also modify the severity of dementia (Bennett et al., 2006b). Although individuals with larger social networks did not have fewer plaques or tangles than more isolated individuals in the study, AD pathology had a smaller effect on the cognition of the more socially connected individuals. This correlation was similar to the protective effect provided by years of formal education.
* Investigators with the Group Health Cooperative in Seattle, Washington, have been following 1,740 older adults in the Adult Changes in Thought Study (Larson et al., 2006). Every 2 years, participants undergo physical and cognitive tests, answer questions about their lifestyles, and are assessed for dementia. After 6 years, the investigators found that the risk of AD in people who exercised three or more times per week, at least 15 minutes per day, was 31 percent lower than in those who exercised fewer than three times per week. This result suggests that regular exercise is associated with a delay in the onset of AD.

Epidemiologic studies correlate lifestyle factors with altered cognitive function. Epidemiology cannot, however, establish a cause-and-effect relationship. To directly examine cause and effect, NIA is sponsoring several clinical trials to test the questions raised by observational and animal studies and to specifically look at the effects of one lifestyle factor—physical activity and exercise—on cognitive function in older adults.

* Researchers from the University of Illinois at Urbana-Champaign conducted functional magnetic resonance imaging (MRI) tests on older adults before and after a 6-month program of brisk walking (Erickson et al., 2007). Results showed that neuronal activity in the frontal cortex increased with increases in participants’ cardiovascular fitness. A similar trial conducted by University of Illinois investigators showed that brain volume increased as a result of a walking program (Colcombe et al., 2006). These findings suggest a strong biological basis for the role of aerobic fitness in helping to maintain the health and cognitive functioning of adults as they age, at least in the short term.
* A small-scale clinical trial is looking at the effects of 1 year of aerobic fitness training on cognition and brain activity and structure in older adults. Other small trials are examining the role of aerobic exercise on electrocortical and behavioral measures in older adults and assessing the effects of a short aerobic conditioning program on cognitive function in older adults with aMCI.
* A 3-year trial of a group exercise and health education intervention in people with aMCI is examining a variety of issues, such as whether the exercise intervention will slow the progression from aMCI to dementia. More recently, researchers at Wake Forest University started a pilot study to assess whether an intervention involving physical activity and cognitive training reduces significant cognitive decline in memory-impaired older individuals. The Seniors Health and Activity Research Program-Pilot (SHARP-P) will compare the outcomes of physical activity, cognitive training, and combined physical activity and cognitive training with those of health education.

Additional clinical trials are critical to discern whether physical activity and exercise can, in fact, prevent or delay long-term cognitive decline or AD and, if so, to determine the type and amount of physical activity necessary.


Advising the Public Before All the Scientific Results Come In

Although the evidence to date suggests that physical activity and other lifestyle choices, such as mentally stimulating activity, a healthy diet, and social engagement, have positive effects on brain function and may reduce risks of cognitive decline and AD, results from definitive clinical trials will not be available for several years.

Even so, experts can recommend that older adults (and other age groups) participate in these activities. These low-risk, low-cost interventions have many proven benefits for overall healthy aging. For example, regular physical activity and a healthy diet help reduce the risk of age-related diseases and conditions, such as heart disease and type 2 diabetes. Social activities with friends and family and the pursuit of mentally stimulating activities help people feel engaged.


Health Conditions and AD

A growing body of evidence suggests that the metabolic changes that occur in a variety of age-related chronic diseases, such as heart disease, stroke, high blood pressure, and type 2 diabetes, may contribute to the development of AD, affect the severity of AD, or cause vascular dementia (a loss of thinking and reasoning abilities caused by stroke or other forms of brain injury related to damage to the brain’s blood vessels). However, these relationships are complex. Several studies in the past year have attempted to untangle them.

* Investigators with the Memory and Aging Project examined the brain tissue of deceased participants who had donated their brains to the study (Schneider et al., 2007). Results showed that about one-third of the participants had evidence of strokes, which increased the odds of having AD-related reductions in memory function.

* At least four long-term studies have linked diabetes with a decline in cognitive function. In one of these studies, a Columbia University research team examined whether diabetes is related to an increased risk of aMCI (Luchsinger et al., 2007). Working with a large multiethnic population with a high prevalence of diabetes, the researchers found that diabetes was associated with a significantly increased risk of aMCI as well as other types of MCI.

* Evidence increasingly suggests that overweight and obesity may increase AD risk. Two studies explored this issue by examining the relationship of obesity or overweight at midlife and cognitive performance or AD in later life. In the first study, conducted at the Kaiser Permanente Division of Research in Oakland, California, and supported by NIDDK, investigators found that participants who were obese (a body mass index of 30 or more) during midlife had a threefold increase in AD risk (Whitmer et al., 2007). Those who were overweight (a body mass index of 25 to 29) had a twofold increase in AD risk.

In the second study, Boston University School of Medicine researchers used data from 1,814 Framingham Study participants to examine whether obesity at midlife affected the impact of hypertension (a key risk factor for heart disease) on cognitive abilities (Wolf et al., 2007). The study, supported by NIA, NHLBI, and NINDS, found that participants with a high measure of abdominal obesity and hypertension did worse on tests of executive function and visuomotor skills than did those who weighed less and had normal blood pressure. Furthermore, hypertensive participants who were most obese did less well on the tests compared with those who were not as obese. This finding suggests that obesity may have exacerbated the impact of hypertension on the brain. The researchers concluded that controlling abdominal obesity and blood pressure in midlife may help reduce the risk of cognitive problems and dementia in later life.

As noted earlier, epidemiologic studies cannot determine cause-and-effect relationships even though they provide valuable information about associations between chronic diseases and aMCI or AD. As a result, NIA is supporting several clinical trials to see whether managing these conditions might reduce the risk of cognitive decline and dementia.

Clinical trials have examined whether two treatments—simvastatin (a cholesterol-lowering drug) and vitamin supplements that reduce homocysteine (an amino acid linked to heart disease and AD)—could slow the rate of cognitive decline in older adults with AD. These trials were recently completed, and the data are being analyzed.

Other clinical trials are underway to examine whether diabetes-related interventions can prevent or delay the progression of cognitive decline or AD:

* ACCORD-MIND (ACCORD-Memory in Diabetes). This NIA-funded trial is nested within NHLBI’s Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which is evaluating whether intensive glucose, blood pressure, and lipid management can reduce cardiovascular disease in people with type 2 diabetes. ACCORD-MIND will test whether these interventions also can reduce the rates of cognitive decline and structural brain change in 2,800 of the ACCORD study participants over a 4-year period. Participants will undergo periodic cognitive testing and MRI scans to assess change over time (Williamson et al., 2007).
* RECALL. In this 18-month multi-center trial, researchers from the University of Washington will test the effects of the drug rosiglitazone on attention and memory skills in older adults with aMCI. Rosiglitazone has anti-inflammatory properties and improves the body’s ability to use insulin. This trial will examine the medication’s effects on brain structures that support memory and other cognitive abilities, as well as on biological markers associated with inflammation, insulin resistance, and cardiovascular disease. As with most clinical trials, participants will be divided into two groups—one will receive rosiglitazone, the other a placebo (an inactive substance). Participants also will have MRIs before and at the end of treatment to determine whether rosiglitazone slows the rate of atrophy in brain structures that support memory. The RECALL trial will provide valuable data about the effects of improved insulin sensitivity, reduced insulin levels in the body, and reduced inflammation on cognitive function and biological markers in aMCI.
* SNIFF 120. This 4-month clinical trial will examine the effects of a nasal-spray form of insulin on cognitive function, ability to carry out daily activities, glucose metabolism in the brain, and levels of beta-amyloid in people with aMCI or AD. AD is associated with reduced levels of insulin in cerebrospinal fluid, and treatment with insulin has been shown to improve memory performance. Insulin injections can be problematic because they can result in hypoglycemia (low blood sugar). A nasal spray delivers insulin directly to the brain. Preliminary data on this way to administer insulin show that people with AD improved their verbal memory and did not develop hypoglycemia. This clinical trial will provide useful data on the safety, feasibility, and potential efficacy of this innovative treatment approach, which investigators may use to plan future large-scale clinical trials.
* Metformin. This NIA-funded clinical trial’s primary aim is to determine whether metformin, a drug used safely and effectively to treat diabetes, reduces the risk of cognitive decline. Very high blood insulin levels have surfaced as a potential risk factor for AD. Half of the population 60 years and older may have such high insulin levels, and the prevalence is increasing with the epidemic of overweight and obesity. The research team at Columbia University hypothesized that metformin could prevent cognitive decline by reducing insulin levels in overweight and obese people who do not have diabetes but who do have aMCI. In this new, 12-month pilot trial, 60 people with aMCI will receive either metformin (1,000 mg twice a day) or a placebo. The investigators also want to determine whether metformin prevents the decrease in brain metabolism that is characteristic of the transition from aMCI to AD.
* POEM (Pioglitazone or Exercise). Metabolic syndrome is an increasingly prevalent medical condition that raises a person’s risk of developing diabetes and heart disease. Its cardinal features are insulin resistance (a condition in which muscle, fat, and liver cells are not able to use insulin properly), physical inactivity, and abdominal obesity. Recently, several large studies have linked metabolic syndrome to the development of cognitive impairment. In a new NIA-funded pilot trial, investigators at the University of Colorado, Denver, will examine whether treatments for metabolic syndrome in older people with aMCI can improve, stabilize, or lessen the decline in cognitive function compared with a no-treatment group. Investigators plan to test the diabetes drug pioglitazone and endurance exercise training, both of which have been shown to ameliorate many components of metabolic syndrome, including insulin resistance, and to have positive effects on cognition. This pilot trial also will evaluate how the interventions affect cognition and inflammatory biomarkers.


Estrogen and AD

Production of estrogen, a hormone made by a woman’s ovaries, declines dramatically after the childbearing years. During the past 25 years, laboratory and animal research and human observational studies have suggested that estrogen may protect the brain. Experts have wondered whether using estrogen could reduce the risk of AD or slow its progression.

Clinical trials have shown that estrogen does not slow the progression of already-diagnosed AD and does not effectively treat or prevent the disease if treatment begins in later life. However, questions remain as to whether some forms of estrogen might help if started somewhat earlier than the older ages already tested. These questions are now being investigated.

* NINDS-supported investigators at the Mayo Clinic College of Medicine have found that women who had one or both ovaries removed before menopause had an increased risk of cognitive impairment or dementia compared with a control population (Rocca et al., 2007). They also found that ovary removal at a young age (younger than age 45) further increased the risk of dementia. This risk was significantly diminished when women were treated with estrogen until the age of natural menopause. These findings underscore the relationship between estrogen and cognition and open additional avenues of investigation into estrogen’s full therapeutic effects.


Framingham Study Data Provide Insights into the Lifetime Risk of Stroke and Dementia

The Framingham Heart Study, begun in 1948, is a long-term investigation of physical and environmental factors that influence the development of cardiovascular disease in healthy individuals. The study, funded by NHLBI, is still following the remaining members of the original study group, as well as the remaining members of a group of 5,000 people who were recruited in 1971 into the Framingham Offspring Study. Investigators are now working with the third generation of volunteers in this landmark epidemiologic study.

One of the distinguishing elements of the study has been “add-on” components funded by other NIH institutes, including NIA and NIMH. These add-on components have provided a cost-effective opportunity for scientists to examine additional issues using existing study populations.

The Framingham Study’s rich harvest of data has allowed researchers to explore many dimensions of the relationship between cardiovascular risk factors, cognitive health, and AD. The fact that it has been going on for so many years also gives scientists a unique opportunity to study certain aspects of an issue. For example, in describing the burden of any disease, scientists often refer to incidence, or the number of people who may develop the disease in a given time period, usually a year. However, some investigators have argued that “lifetime risk,” or the risk of developing a disease across the remaining estimated lifespan, may provide a more accurate measure of the possible burden to a population than incidence. They note that lifetime risk reflects risk across a longer period of time rather than does risk over a single year.

Framingham investigators at the Boston University School of Medicine conducted a lifetime risk analysis using many years of follow-up data from the original group of Framingham participants. This analysis, which was supported by NHLBI, NIA, and NINDS, focused on the lifetime risk of stroke and AD, two conditions of enormous public health concern.

Using 51 years of follow-up data, the analysis showed that the lifetime risk of stroke was 1 in 5 for a middle-aged woman and 1 in 6 for a middle-aged man. For AD, using 29 years of follow-up data, lifetime risk was 1 in 5 for a middle-aged woman but only 1 in 10 for a middle-aged man. The authors concluded that measures of age- and sex-specific lifetime risk indicate that a middle-aged person has a 1 in 3 chance of having a stroke or becoming demented. These rates have serious implications for the provision and cost of future health care services.



EXPLORING ALL POSSIBILITIES TO IMPROVE AD DIAGNOSIS

AD pathology begins to develop long before clinical symptoms are readily apparent. However, AD diagnosis currently depends on assessing a range of cognitive and behavioral changes over time. Finding a way to detect the disease at the earliest point possible will allow clinicians to treat it as early as possible. One active area of AD research focuses on the development of sensitive screening instruments and neuropsychological tests to diagnose cognitive decline, aMCI, and AD as early as possible.

Ambitious efforts also are underway to find new ways to measure changes in the structure and function of the brain and in other biomarkers, such as substances in cerebrospinal fluid (CSF), and blood. These biomarkers may hint at pathological changes that occur before clinical signs of aMCI or AD are evident or when they emerge. Improvements in brain imaging and new findings about CSF biomarkers are already yielding results. For example, the development of PiB has enabled scientists to visualize beta-amyloid plaques in the living brain. Advances like this may lead to very early diagnosis of AD and will help researchers and clinicians develop new treatments and monitor their effectiveness.

* Clinicians need practical tools to help them differentiate memory and thinking changes that come with normal aging from those of very mild dementia. Existing cognitive tests may not be sensitive enough to detect problems in highly educated individuals or may falsely identify people with poor lifelong cognitive functioning as demented. Other tests are not practical for general clinical use.

Investigators at the Washington University School of Medicine developed a new tool, the AD8, which takes advantage of the knowledge that family and close friends have of a person with memory or cognitive problems. The AD8 asks about changes in the way a person remembers or acts in various circumstances, such as forgetting appointments or having difficulty handling financial affairs. Since the AD8 was published in 2005, two studies (Galvin et al., 2006; Galvin et al., 2007) have demonstrated its reliability, validity, and flexibility. The tool can be used in face-to-face encounters or over the phone, and it can even be completed by a person with memory problems. These studies suggest that a tool like the AD8 could improve dementia diagnoses in primary care, where dementia often goes undetected. This tool also may be valuable in screening for clinical trials, community surveys, and epidemiologic studies.

* Because AD is a progressive disease, investigators want to be able to predict the progression from normal cognition to aMCI to AD. Two studies used neuropsychological tests to explore this area. The first study, by scientists at Harvard Medical School, indicated that the risk of progressing from normal cognition to aMCI was greater in individuals with relatively low scores on tests of episodic memory, and that the risk of progressing from aMCI to AD was increased in people with relatively low scores on tests of both episodic memory and executive function (Blacker et al., 2007). In the second study, conducted within the Alzheimer’s Disease Cooperative Study (ADCS), investigators found that the best predictor of progression from aMCI to AD over the 36-month trial period was a combination of four easily administered cognitive measures (Fleisher et al., 2007). The results of these studies not only may help in diagnosing aMCI and AD, but also will be important in evaluating the efficacy of interventions to modify the progression of the disease.

* Investigators at the Washington University School of Medicine assessed the ability of biomarkers found in CSF to identify people who were likely to get AD (as defined by clinical criteria or the presence of beta-amyloid as shown with PiB on PET scans) within a group of nondemented older people (Fagan et al., 2007). Previous work has shown that levels of beta-amyloid in CSF typically decrease in AD, but that levels of tau in CSF increase. This study had three main findings. First, people with very mild symptoms of AD showed the same CSF biomarker profile as those in more advanced stages of the disease, suggesting that it may be possible to diagnose AD accurately at an early stage. Second, combining CSF amyloid measures with amyloid imaging in the PET scans revealed that low CSF amyloid levels can predict whether individuals have amyloid deposits in the brain, regardless of the presence of dementia. Information about CSF amyloid levels may therefore be a useful preclinical biomarker of AD. Third, the investigators found the same relative ratio of beta-amyloid and tau as earlier studies have done, suggesting that this ratio may have promise as a biomarker to predict future dementia in cognitively normal older adults.

* In recent years, scientists have become increasingly interested in the role of inflammation in AD. A research team at Beth Israel Deaconess Medical Center, Harvard Medical School, and Boston University conducted a study, supported by NIA, NHLBI, and NINDS, to assess whether the presence of markers of inflammation was linked to increased risk of AD (Tan et al., 2007). From 1990 to 1994, the researchers measured several inflammatory markers, including CRP, IL-6, IL-1, TNF-α, and IL-1-RA, in 691 original participants in the Framingham Study. The participants were then followed for 7 years to see whether they developed AD. Participants who produced the most of two markers, IL-1 or TNF-α, showed a greater risk of developing AD than those who produced the least. The researchers concluded that high levels of some inflammatory substances may be an early risk marker of AD, and that inflammation may play a role in AD development.

* Although people w