Alzheimer’s disease (AD) is a progressive, currently irreversible brain disorder. People with AD gradually suffer memory loss and a decline in thinking abilities, as well as major personality changes. These losses in cognitive function are accompanied by pathologic changes in the brain, including the buildup of insoluble protein deposits called amyloid plaques and the development of neurofibrillary tangles, which are abnormal collections of twisted protein threads found inside nerve cells. Such changes result in death of brain cells and breakdown of the connections between them. AD advances gradually but inexorably, from early, mild forgetfulness to a severe loss of mental function called dementia. Eventually, people with AD become dependent on others for every aspect of their care. The risk of developing AD increases exponentially with age, but it is not a part of normal aging.
AD is the most common cause of dementia among people age 65 and older and is a major public health issue for the United States because of its enormous impact on individuals, families, the health care system, and society as a whole. Scientists now estimate that as many as 4.5 million people currently suffer with the disease, and this number is expected to increase to 13.2 million persons by 2050, an almost 3-fold increase.5
This update on advances in AD and related neuroscience includes findings from across the spectrum of research, from the development of a new mouse model that will provide important insights into the etiology of the disease to clinical trials of interventions to prevent or arrest the course of the disease. We also discuss important findings in other neurological diseases, including Parkinson’s disease and amyotrophic lateral sclerosis.
The Genetics of Neurological Disease
A genetic locus for age-at-onset of Alzheimer disease and Parkinson Disease. Last year, investigators identified a region on chromosome 10 that contained a locus associated with age at onset (AAO) in both AD and Parkinson’s disease (PD). Recently, these investigators used a novel scientific approach called “genomic convergence,” which combines complementary lines of genetic evidence, and identified a gene, GSTO1, that appears to modify AAO in AD and PD. GSTO1 may be involved with inflammatory processes – of particular interest due to the possible role of inflammation in these two diseases. While further studies are needed to confirm that this is an AAO gene for AD and PD, further study of this gene and the pathway it affects may open new avenues of research for delaying onset of disease in patients at risk for these disorders.
Synuclein gene triplication as a cause of Parkinson’s Disease (PD). Previous work has shown that mutations in the gene that produces a protein called synuclein are one cause of PD, and that synuclein is a major component of Lewy bodies, the pathological hallmark of PD. However, the precise relationship between synuclein, Lewy body formation, and PD was not clear. Recently, NIH investigators screened members of a large family with the inherited form of the disease and found that affected members have three copies of the region on which a single synuclein gene is normally found. The additional copies of the synuclein gene result in overproduction of the protein, which is then deposited in the brain in the form of Lewy bodies. These findings provide strong support for the hypothesis that synuclein is at the center of the etiology and pathogenesis of Parkinson’s disease and that simple overproduction of the protein can cause its deposition in the brain. This finding will have a profound impact on our understanding of the disease mechanisms and may eventually influence treatment strategies.
Early Diagnosis of AD
Early diagnosis of AD benefits affected individuals and their families, clinicians, and researchers. For patients and their families, a definitive early diagnosis provides the opportunity to plan and to pursue options for treatment and care while the patient can still take an active role in decision-making. For clinicians, accurate early diagnosis facilitates the selection of appropriate treatments, particularly as new interventions are developed to stop or slow progression of symptoms. And for researchers, earlier and more accurate diagnosis may facilitate clinical studies of new therapies and preventive measures by allowing early intervention, before cognitive loss becomes significant.
Research suggests that the earliest AD pathology begins to develop in the brain long before clinical symptoms yield a diagnosis, and scientists are now searching for reliable, valid, and easily attainable biological markers that can identify cases very early in the course of disease. Eventually, very early diagnosis of AD may be possible through combinations of strategies to image the brain, along with genetic, biological, clinical, and neuropsychological assessments.
Brain chips dip into genes affecting aging and cognitive decline. Identifying changes in gene activity in the brain throughout life may suggest genes that are protective of brain health, as well as those that contribute to age-related brain disorders when altered; this knowledge could point to novel sites for therapeutic interventions. In a recent study, young, middle-aged, and aged rats were trained on two memory tasks. Investigators then used a powerful microarray chip technique to identify genes in the hippocampus – a brain area important for learning – whose expression changed with aging, as well as those that were involved in age-related changes in the performance of the rats on the memory tests. From this analysis, they identified 146 aging- and cognitive-related genes (ACRGs) and assigned them to categories of specific cell processes or functions. Based on the pattern of changes in the ACRGs, they posited a model of brain aging in which loss of neuronal processes and increase of myelin turnover fuel brain inflammation, eventually leading to impaired neuronal function and cognition. Most of the gene expression changes were seen in mid-life, before cognition was impaired, suggesting that such changes in early adulthood might initiate cellular or biological changes that could lead to functional changes later in life.
Visual memory predicts AD more than ten years before diagnosis. Investigators recently found that individuals who scored six or more errors on the Benton Visual Retention Test, which measures perception of spatial relations and memory for newly learned material, up to fifteen years prior to the study had approximately twice the risk of developing AD as did those with zero to five errors. The interval between the test results and the development of the disease is significantly longer than that seen in previous studies of the relationship between cognitive test performance and AD. This finding suggests that with AD, manifestation of the disease process may begin much earlier than was believed previously, and that AD may be best represented as a chronic disease that is initiated early and promoted by many factors throughout life.
Comparison of memory fMRI response among normal, MCI, and Alzheimer’s patients. Investigators using functional magnetic resonance imaging (fMRI) recently demonstrated that patients both with AD and with mild cognitive impairment (MCI), a population at high risk for developing AD, showed less activation in the medial temporal lobes during a memory task than elderly individuals with no cognitive impairment. The medial temporal lobes include the hippocampus and other brain structures important to the formation of memories. These results suggest that decreased activation in the medial temporal lobes during a memory encoding task as measured using fMRI may be a specific and early marker of neurodegeneration in AD, and that fMRI is sufficiently sensitive to detect changes during the early (MCI) phase of the disease.
Environmental Factors and AD
There is a great deal of interest in finding risk and preventative factors for age-related cognitive decline and AD. Of particular interest are those factors that are modifiable, because interventions that decrease the effect of a risk factor or facilitate a preventative factor could potentially delay the onset of the disease or prevent it altogether.
Dietary enrichment reduces cognitive dysfunction in dogs. Investigators recently studied the effects of an enriched diet on age-related cognitive decline in dogs, a model that mimics the behavioral and brain pathological declines of older humans more closely than rodent models. Young and old dogs were given a series of baseline cognitive tests. Half of each age group then remained on a standard dog chow diet, while the other half of each age group was placed on a diet enriched with antioxidants and mitochondrial co-factors, which improve nerve cell energy and efficiency and decrease production of molecules that contribute to oxidative damage in the brain. Animals remained on their respective diets for six months and then were assessed again for cognitive performance on a variety of tasks. When tested, old dogs on the control diet learned more slowly than the young dogs and made significantly more errors; however, when compared to the old animals on the control diet, old animals on the enriched diet showed significantly better learning, although not to the level of the younger animals. The enriched diet had minimal effect on the behavioral performance of young dogs. The success of this simple, cost-effective intervention has significant implications for dietary interventions that might lessen or even prevent some of the cognitive decline seen with age and with disease, and a pilot trial in humans is currently underway.
Animal Models of Neurodegenerative Disease
Animal models that mimic human disease are central to research for many reasons. Animals and humans share many genetic and physiologic features, so experimental results obtained in animals can frequently (although not always) be extrapolated to humans. It is much easier to create specific genetic mutations and observe their effects in animals than to search for them in humans, and because the lifespan of most animals is relatively short, it is easier to observe the effects of those mutations over several generations.
A new mouse model sheds light on AD pathology. Researchers recently developed the first mouse model that displays the primary neuropathological features of AD – the development of amyloid plaques and neurofibrillary tangles (NFTs) – as well as synaptic loss in the central nervous system, which in humans correlates best with the cognitive declines observed in AD. Of particular interest to scientists is the novel method – microinjection of mutant amyloid precursor protein (APP) and tau transgenes into single-cell mouse mutant embryos – used to develop this “triple transgenic” model. Studies in the new model suggest that synaptic dysfunction actually occurs before extracellular amyloid deposition and NFT development, and coincides with the accumulation of intraneuronal amyloid. This model may enable a more complete understanding of AD etiology, as well as improved evaluation of new diagnostic techniques and treatments.
There are currently no effective, generally useful treatments for AD – i.e., a treatment that works on large numbers of patients, that maintains its effectiveness for a long period, that works in both early and late stages of the disease, that improves functioning of patients in activities of daily living as well as performance on sensitive neuropsychological measurements, and that has no serious side effects. In addition, none of the treatments presently approved for AD alter the progressive underlying pathology of the disease. One way to treat the disease successfully may be to interfere with early pathological changes in the brain, including the development of amyloid deposits and the formation of neurofibrillary tangles. A number of promising approaches are currently being developed and tested in model systems; if these approaches prove safe and effective in animals, studies in humans could follow.
New gene therapy approach for treatment of neurodegenerative disorders. In two recent studies, investigators used genetically modified viruses to attack features of AD and amyotrophic lateral sclerosis (ALS), a disease in which motor neurons in the spinal cord degenerate, leading to muscle paralysis and death. In one study, a virus carrying the human neprilysin gene, which makes an enzyme that degrades beta amyloid, was injected into brain areas containing amyloid plaques in mice that were genetically modified to develop AD pathology. The production of neprilysin appeared to increase degradation or reduce the growth of existing plaques; in fact, the plaque load was reduced to less than half that found in untreated areas. In the second study, researchers modified a virus to produce one of two growth factors, insulin growth factor 1 (IGF-1) or glial cell line-derived neurotrophic factor (GDNF). These vectors were then injected into muscles of ALS transgenic mice either before or at the time of disease onset. The virus was taken up by nerves in the muscle and transported to the spinal cord, where the growth factor was produced. The researchers found that delivery of IGF-1 delayed the onset and rate of progression of the disease when given before onset of symptoms, and extended lifespan and delayed motor functional decline when given at disease onset. GDNF was less effective in these experiments. These two studies suggest that boosting normal protective processes in the nervous system might help prevent or treat degeneration associated with AD or ALS. Both studies offer new hope for the treatment of these disorders.
NSAIDS reduce amyloid ß-peptide formation in culture and in animal models. Evidence from epidemiological and clinical studies shows a correlation between a decreased risk of developing AD and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), suggesting that inflammatory processes may be involved in AD pathophysiology. Investigators recently studied the effects of twenty clinically used NSAIDs on Aß1-42, a particularly toxic form of amyloid, on cells in culture and in animal models of AD. Eight of the compounds significantly lowered Aß1-42 levels both in vitro and in the mice. These drugs worked through a mechanism independent of cyclooxygenase inhibition, the primary anti-inflammatory action of most NSAIDs; in fact, the researchers suggest that these eight NSAIDs might delay accumulation of toxic amyloid by inhibition of ?-secretase, a key enzyme in the development of Aß1-42. The researchers also found that newer specific cyclooxygenase-2 inhibitors, in wide use and with fewer side effects, do not lower Aß1-42 levels in vitro or in vivo. These studies identify a novel neuroprotective mechanism of some NSAIDs and suggest that it may be useful to screen new agents for their actions on a key biochemical process in AD neuropathology, although whether or not the amyloid-lowering drugs or others will be effective in clinical trials is yet to be determined.
Today, the few FDA-approved drug treatments for AD maintain cognitive function in AD patients in only a subset of patients and for only a limited time. However, an estimated 30 compounds are presently or will soon be tested in human AD clinical trials. These studies are sponsored by a number of sources, including the NIA, other NIH institutes, and the private sector, primarily pharmaceutical companies. Compounds now under scrutiny focus on three major areas of treatment: Short-term maintenance of cognitive function; slowing the progress of the disease, delaying AD’s onset, or preventing the disease altogether; and managing behavioral problems associated with AD.
Interest is currently focusing on compounds that directly target disease-related pathologies. An important research focus is in prevention trials, and a number are underway to test the effectiveness of therapies in people without symptoms or who have only slight memory problems. The first NIH AD prevention trial is currently under way at more than 70 sites across the U.S. This trial compares the effects of vitamin E and donepezil (brand name Aricept) in preventing AD in people diagnosed with mild cognitive impairment. Further examination of estrogen and studies of various classes of anti-inflammatory drugs and antioxidants are also ongoing, and as scientists test these currently available medications, the next generation of drugs is being developed, targeting specific abnormal cellular pathways, including plaque and tangle formation and death of brain cells. Prevention trials are among the most costly of research projects, but, if successful, the payoff in terms of reduced disease and disability will be significant.
Caregiving of AD Patients
Most of the approximately 4 million Americans with AD today are cared for outside the institutional setting by an adult child or in-law, a spouse, another relative, or a friend. Caregivers frequently experience significant emotional stress, physical strain, and financial burdens, yet they often do not receive adequate support. Several recent studies have explored the problems faced by caregivers of AD patients, as well as possible interventions to reduce their burdens.
End-of-life care stresses caregivers of dementia patients. Although family caregiving has been extensively studied, there has been less research on the impact of end-of-life care on caregivers who are family members of persons with dementia or to the caregivers' responses to the death of the patient. As part of the NIA’s Resources for Enhancing Alzheimer’s Caregiver Health (REACH) study, a multisite randomized clinical intervention of 1222 caregiver and recipient dyads, investigators assessed the type and intensity of care provided by 217 family caregivers to persons with dementia during the year before the patient's death, as well as the caregivers' responses to the death. Additionally, this group was compared to the 180 caregivers who institutionalized their family member. The researchers found that the in-home caregivers reported tremendous levels of stress in the year leading up to the care recipient’s death, and that levels of caregiver depression “spiked” immediately following the care recipient death. However, the caregivers in this study demonstrated tremendous resilience: Within fifteen weeks of the recipient’s death, depression returned to pre-death levels, and within one year, depression was significantly lower than pre-care recipient death levels. Importantly, caregiver depression for those placing their loved ones in an institution were slightly higher both pre- and post-death than for those caring for the patient at home.
Selected Future Research Directions in AD and the Neuroscience of Aging
Advances in neuroimaging have the potential to transform the way we predict, diagnose, monitor, and even treat mild cognitive impairment and AD. The NIA is currently developing an Alzheimer’s Disease Neuroimaging Initiative, a longitudinal, prospective, natural history study of normal aging, mild cognitive impairment, and early AD to evaluate neuroimaging techniques (e.g. MRI, PET) and other potential biomarkers of the disease. Biomarkers may decrease the time and cost of clinical trials, which increases the safety and efficiency of drug development. An important aspect of this initiative is that the clinical, imaging, and biological data and samples will be made available promptly to all qualified scientific investigators in academic as well as industrial research communities. The initiative is planned as a partnership among the NIA/NIH and several other private and government organizations.
The NIA is accelerating the pace of Alzheimer’s disease genetics research with its AD Genetics Initiative, a major new program to speed the process of creating a large repository of DNA and cell lines from families with multiple AD cases. The goal of this initiative is to develop the resources necessary for identifying the remaining late-onset AD (LOAD) risk factor genes, associated environmental factors, and the interactions of genes and the environment. The AD Genetics Initiative will intensify sample collection and encourage data sharing by providing access to the repository to qualified investigators.