There’s no getting away from it: Baby boomers—members of the generation born from 1946 through 1964—are not young anymore. Many have reached (or will soon reach) retirement age, and even the youngest will celebrate their 50th birthdays this year. With this graying of the United States comes an ever-more-pressing need for an improved understanding of Alzheimer disease and other dementias that plague the elderly, as well as for an enhanced tool set for diagnosing and treating these conditions.
Norman L. Foster, MD, is a professor of neurology at the University of Utah School of Medicine in Salt Lake City. Foster, who also serves as director of the university’s Center for Alzheimer’s Care, Imaging & Research and as senior investigator at the Brain Institute at the University of Utah, concedes that progress is being made on the Alzheimer-disease/dementia diagnosis and research fronts. He notes, “The prevalence of these conditions and the cost of care warrant so much more,” however.
Statistics paint a grim picture of the incidence and effects of Alzheimer disease and other dementias alike. According to the Alzheimer’s Association1, an estimated 5.2 million US patients currently have Alzheimer disease. This population includes approximately 200,000 individuals under age 65 who have been diagnosed with younger-onset Alzheimer disease.
The report also indicates that the US Alzheimer-disease/dementia population will see explosive growth, in the near future, as baby boomers continue to age. Barring effective means of preventing or arresting these conditions, the number of people 65 or more years old who have Alzheimer disease might more than triple, reaching 16 million; of these patients, 7 million will be 85 or older. Alzheimer disease is the number-six cause of death in the United States and the fifth most frequent cause of death for those 65 and older, killing more than prostate cancer and breast cancer combined.
While incidence rates for death from other major diseases (including cancer) decreased between 2000 and 2010 (the last year for which figures are available), the rate of death caused by Alzheimer disease trended upward by 68% Equally staggering are the potential costs of addressing Alzheimer disease/dementia, which have been projected to rise sharply as the number of US residents 65 or older doubles (to 72 million) over the next 20 years.
Deeming Alzheimer disease “the most expensive condition in the nation,” the Alzheimer’s Association report pegs the current cost of Alzheimer-disease/dementia care at $214 billion per year, including $113 billion borne by Medicare, $37 billion by Medicaid, $36 billion by patients/families, and $28 billion by insurers and uncompensated providers. By many estimates, Foster observes, US Alzheimer-disease/dementia care will, in 2050, carry a price tag of $1.2 trillion per year (in today’s dollars).
Foster notes that more of the financial burden connected with Alzheimer disease/dementia is also falling onto the shoulders of patients and their families, in part because of a growing preference among all parties for home-care programs or assisted-living facilities over nursing homes. “Home care often means lost wages for the adult caregiver,” he says, “and while assisted-living facilities are cheaper than nursing homes, not all states will pay for patients to move to one.”
Foster says that Utah ranks among exceptions to the rule; it picks up the assisted-living tab for about 60% to 70% of Alzheimer-disease/dementia patients who would otherwise be required to reside in nursing homes in order to receive state-funded care. Michigan offers a similar program under which individuals with Alzheimer disease or other dementias can, in certain instances, bypass nursing-home care and be waived into assisted-living facilities instead, with their expenses covered by Medicaid. The catch, Foster says, is that the state limits the number of available Medicaid waivers to about 2,500 per year; those usually have been spoken for, each year, by the end of February.
Recent research has brought to light entirely new perspectives on Alzheimer disease and other forms of dementia. Clifford Jack, MD, PhD, is a professor of radiology and noted Alzheimer-disease researcher at the Mayo Clinic (Rochester, Minnesota). He says that research increasingly validates the theory that biomarkers become abnormal before clinical symptoms of Alzheimer disease/dementia develop.
“This has been a revelation for the field—for two reasons,” he explains. “First, it means we can predict who is on the path to disease using biomarker methods. Just as important, it pushes us away from enrolling symptomatic people in clinical trials of various therapies; nearly all trials that have targeted this population have failed. It sends us in the direction of identifying and enrolling patients in trials on the basis of biomarker abnormalities.”
Jack adds that 30 years ago, clinicians automatically attributed patients’ progressive memory loss to Alzheimer disease. “As we see it now,“ he says, “other pathologies produce these symptoms, too—so what may look like Alzheimer isn’t.” At the same time, in 30% of autopsies of elderly patients who met, in life, the clinical criteria for a diagnosis of Alzheimer disease, pathology results are normal.
In 2010, Jack and several of his colleagues proposed a hypothetical model of the sequence of change in Alzheimer-disease biomarkers, relating them to each other and to the emergence and progression of outward dementia symptoms. In that model, beta-amyloid markers were said to become abnormal first, with biomarkers of neurodegeneration and clinical symptoms following (in that order).
A revised model2 was unveiled last year. In this model, amyloid beta 42 appears in cerebrospinal fluid before images of amyloid buildup are obtained through amyloid PET studies. Changes in tau protein measured in the cerebrospinal fluid occur next, while brain volume, measured using FDG–PET and MRI, is the last biomarker to become abnormal, tracking most closely with progressive cognitive impairment.
In addition, the new model demonstrates more overlap between changes in biomarkers, which are now described in relation to time (rather than severity of symptoms, as in the initial version). Cognitive outcome is expressed as a range of possible values, reflecting the fact that individual patients exhibit unique responses to Alzheimer-disease pathology. “The original model did not account for the abnormalities in tau protein in the brain that are a nearly universal feature of aging,” Jack observes. “Conversely, the new one distinguishes between biomarkers of Alzheimer-disease pathology and biomarkers of normal aging.”
A Protracted Process
Two recent studies—the conclusions of which were validated, in part, via imaging—lend credence to the overall contention that biomarkers appear well before clinical symptoms of Alzheimer disease. In one study3, conducted at the University of Melbourne in Australia, 151 healthy controls, 36 subjects with mild cognitive impairment, and 19 participants with Alzheimer disease were evaluated at the outset and every 18 months for an average of 4.1 years.
Using data from neuropsychological exams and from MRI and PET studies, researchers projected that, on average, more than 10 years elapse from the time that an individual is free of beta-amyloid until he or she exhibits an amyloid level that is considered abnormal. From this juncture, they concluded, it takes an average of 19 years for amyloid levels to reach those usually found in Alzheimer disease, at which point beta-amyloid deposition starts to slow, trending toward a plateau. Changes in the hippocampus were found to appear about five years before the onset of full-blown dementia; memory changes, about three years before.
The researchers also found that amyloid-deposition rates among participants closely resembled projected deposition rates among patients with dominantly inherited Alzheimer disease. This, they indicated, suggests that similar basic mechanisms are at work, irrespective of dissimilar pathogenic pathways, and that beta-amyloid deposition in Alzheimer disease is a protracted process, likely to extend for more than two decades.
For the second study4, conducted at VU University Medical Center Amsterdam, researchers investigated 284 subjects with abnormal beta-amyloid, using amyloid levels in cerebrospinal fluid as a diagnostic marker and following subjects for four years. The study included 44 subjects with asymptomatic Alzheimer disease, 148 with Alzheimer-related mild cognitive impairment, and 92 with Alzheimer dementia, along with a control group of cognitively normal subjects with normal amyloid levels. Participants were assessed, at regular intervals, for amyloid biomarkers, neuronal dysfunction, and brain atrophy, using tests of their cerebrospinal fluid and amyloid imaging; for cognition, they were assessed using standard clinical scales and tests.
At the start of the initiative, participants with asymptomatic Alzheimer disease exhibited impaired executive function and abnormal levels of beta-amyloid and tau. During the follow-up period, ventricular volume increased and functional impairments in daily life decreased, but FDG–PET imaging, other measures of brain atrophy, and other cognitive measures showed no changes.
With the exception of whole-brain volume, participants with Alzheimer-related mild cognitive impairment showed alterations in all markers at the start of the study. They subsequently showed changes in tau (determined via cerebrospinal-fluid testing), as well as in FDG–PET, atrophy-marker, and cognition-testing results.
Participants with dementia also showed alterations in all biomarkers and cognitive markers at the start of the study. During the following four years, they exhibited changes in FDG–PET, atrophy-marker, and cognition-testing results. The researchers found that the rate of change in beta-amyloid and tau, in these subjects, decreased between the preclinical stage and the dementia stage. Their rates of change in FDG–PET, atrophy-marker, and cognition-testing results, however, increased as their Alzheimer disease progressed.
The Next Frontier
It’s not surprising, given these discoveries, that many believe that the greatest promise in Alzheimer-disease/dementia diagnostics (and possible treatment) lies in taking full advantage of imaging (and other methods) to identify and track biomarkers and changes in the brain prior to the appearance of symptoms. “The key,” Jack observes, “will be to obtain readouts on patients when little or no damage to the brain has occurred. Imaging does enable (and will enable) us to look at pathologies in vivo, determining with exactness the burden of amyloid plaque and the amount of atrophy in the brain, as well as where in the brain they are. We will be able to tell who is in what stage of disease, to classify patients better and to predict long- and short-term outcomes alike.”
Despite a few drawbacks, certain types of imaging are said to have particular value here. Carolyn Cidis Meltzer, MD, FACR, is William P. Timmie professor and chair of radiology and imaging sciences and associate dean for research at the Emory University School of Medicine. She cites FDG–PET as an example, noting that while it is extremely valuable in distinguishing between Alzheimer disease and frontotemporal dementia, there have been questions about its sensitivity, early in the diagnostic process. FDG–PET also correlates well with clinical symptoms, Jack says.
Amyloid PET is used to detect plaque in the brain. “On the other hand, because plaque occurs only in Alzheimer disease, amyloid PET doesn’t work for looking at the various dementias,” Meltzer states. “Although it has been approved by the FDA, it is expensive. Insurers do not want to cover it, which would be a drawback for monitoring treatment.”
Jack adds tau PET to the imaging list as well. “There really is no more helpful way to identify tau deposits in the brain,” he says.
As for the future of treatment, optimism currently centers on amyloid-clearing drugs that might prevent (or at least delay) Alzheimer disease in cognitively normal individuals found to be at risk for Alzheimer disease. Trials designed to investigate the validity of the amyloid hypothesis have been completed, are now enrolling patients, or have recently gotten underway. The hypothesis suggests that amyloid accumulation in the brain constitutes a major catalyst in the progression of Alzheimer disease, and that antiamyloid treatments might someday slow or stop its progression before it damages the brain.
“These trials are fundamentally different from previous ones, in which participants had already been diagnosed with Alzheimer dementia and showed no significant improvement in cognition and daily function with therapeutic drugs,” Jack explains. “The entire research paradigm has shifted from reversing the damage to attacking and blocking the causes of the disease at the earliest possible point.” The roster of trials includes four of particular interest.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Trial: Funded primarily by the National Institute on Aging (NIA), this trial is being conducted through its Alzheimer’s Disease Cooperative Study, a consortium of research sites in the United States and Canada. Led by Reisa A. Sperling, MD, MMSc, professor of neurology at Harvard Medical School and director of the institution’s Center For Alzheimer’s Research and Treatment, the trial will involve 1,000 cognitively normal subjects, 65 to 85 years old, in whom abnormal amyloid levels have been detected via amyloid PET studies.
Subjects will receive a three-year course of the monoclonal antibody solanezumab or a placebo; 500 individuals who do not exhibit biomarkers for Alzheimer disease also will participate in the study. Solanezumab binds to soluble monomeric forms of beta-amyloid after they are produced and clears them from the brain before they clump together to form beta-amyloid plaques. In the A4 study, researchers will examine whether (and how) solanezumab affects normal subjects’ rate of cognitive decline, using cognitive/memory tests and various imaging studies to track brain structure and function.
The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Trial: The first of a planned series of trials, this five-year, double-blinded study represents a collaborative effort of the National Institutes of Health; Banner’s Alzheimer’s Institute (Phoenix, Arizona); and the University of Antioquia in Colombia, with support from the NIA and a pharmaceutical company. In the initial phase, the experimental antiamyloid crenezumab is being administered to approximately 300 members of a large extended family from Colombia who share the risk for a rare genetic mutation that typically triggers Alzheimer-disease symptoms at around age 45.
A smaller group of US subjects who also have a rare genetic predisposition to early-onset Alzheimer disease is participating in the trial as well. Researchers will investigate whether crenezumab can reduce the likelihood of developing Alzheimer-disease symptoms and can preserve subjects’ memory and cognitive abilities.
They will also explore the potential of the drug to slow the progression of Alzheimer-disease biomarkers (and whether biomarkers could be used to test new therapies more rapidly). Amyloid PET and various forms of MRI, along with cerebrospinal-fluid tests and cognitive measurements, will be used to monitor reductions in amyloid and other protein accumulation in subjects’ brains, as well as to assess the maintenance of brain size, brain function, and mental performance.
The Dominantly Inherited Alzheimer Network (DIAN) Trial: Funded by a multiyear NIA grant, DIAN is an international research partnership of scientists from 13 institutions in the United States, Canada, the UK, Germany, and Australia. Now enrolling subjects at the Washington University School of Medicine, the initial DIAN study is a phase II trial to investigate the effects of three antiamyloid drugs on 160 individuals who carry a gene for early-onset Alzheimer disease and either are symptom free or have only mild symptoms of the disease. Efficacy (as assessed through amyloid imaging), safety, and tolerability will be assessed to decide which of the three antiamyloid drugs will be studied in a follow-up phase III trial.
The API Apolipoprotein E (ApoE) Trial: This will be a multicenter, randomized, controlled clinical trial of a beta-amyloid–modifying agent in 650 cognitively unimpaired 60– to 75–year-old patients who have inherited two ApoE epsilon-4 alleles. Amyloid and other yet-to-be-determined forms of imaging, cognitive measurements, and cerebrospinal-fluid testing for preclinical Alzheimer disease will be used to evaluate the agent’s efficacy.
Still, there are kinks to be worked out; Meltzer says, “What may be a good biomarker may not be useful for monitoring a response to therapy. Of course, imaging is very expensive; examining every older person via PET or MRI to look for biomarkers before the onset of symptoms is not a very practical solution—but significant progress is being made in the field; we cannot discount that.”
- Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Accessed April 6, 2014.
- Jack CR, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-216.
- Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-367.
- Bertens D, Scheltens P, Visser PJ. Temporal evolution of biomarkers and cognitive markers from preclinical to clinical Alzheimer’s disease: An Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study. Alzheimers Dement. 2013;9(4)(suppl):P523.