The Critical Role of Biomarkers for Drug Development Targeting the Biology of Aging.

Alzheimer's disease is a devastating neurodegenerative disorder that poses a significant societal burden. Approval of anti-amyloid antibody therapies is a significant milestone for treatment that was enabled by the inclusion of biomarkers. The use of biomarkers in clinical trials for Alzheimer's disease has enabled selective participant recruitment, improved treatment monitoring, and supported more rigorous trial designs. This review discusses emerging biomarkers associated with the biology of aging and their application in Alzheimer's disease clinical trials. Aging is the primary risk factor for sporadic Alzheimer's disease and is associated with biological processes implicated in disease development and progression. Novel therapies targeting these underlying biological aging processes are currently undergoing clinical development. Biomarkers that capture the biology of aging are integral to accelerating the development of these therapies. Current progress in biomarker development demonstrates efforts to capture the full spectrum of aging biology. Further work is needed to expand the range of biomarkers that enable comprehensive assessment of brain pathology and aid in prognosis, diagnosis, and measuring treatment response. Establishing a comprehensive arsenal of biomarkers will support strategic decision making and increase the likelihood of positive clinical trials and drug registration for the next generation of Alzheimer's disease drugs targeting the biology of aging.

Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia.

Alzheimer's disease is a progressive neurodegenerative disease for which there is no cure and only a few treatments providing little relief. Increased oxidative stress that is associated with aging is strongly implicated in the pathogenesis and progression of Alzheimer's disease. Studies have shown that levels of the endogenous antioxidant glutathione decline at an early stage of Alzheimer's disease with decreased levels correlating with worse cognitive functions. N-acetylcysteine, a drug also widely available as a dietary supplement, is a precursor of L-cysteine, which in turn is a component of glutathione. Because cysteine availability is a limiting factor for glutathione synthesis, treatment with N-acetylcysteine may increase glutathione levels and thereby counter oxidative stress, promote redox -regulated cell signaling, and improve immune responses. In this review, we evaluate the existing literature and the potential of N-acetylcysteine in promoting cognitive health and alleviating cognitive decline associated with dementia. Discussion will also include possible mechanisms of action of N-acetylcysteine, its effects on aging biology, and safety of long-term use. Based on the available literature, a nutraceutical formulation containing N-acetylcysteine among other compounds has shown some pro-cognitive benefits in Alzheimer's patients and older adults, but the evidence for N-acetylcysteine alone is less robust. Although N-acetylcysteine crosses the blood-brain-barrier, low bioavailability is an obstacle. One promising avenue of research may be to explore derivatives of N-acetylcysteine such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to N-acetylcysteine.

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease.

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ε4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.

Public attitudes about genetic testing for Alzheimer's disease.

In a general population survey (N = 314), 79 percent of respondents stated that they would take a hypothetical genetic test to predict whether they will eventually develop Alzheimer's disease. The proportion fell to 45 percent for a "partially predictive" test (which had a one in ten chance of being incorrect). Inclination to obtain testing was similar across age groups. Respondents were willing to pay $324 for the completely predictive test. Respondents stated that if they tested positive, they would sign advance directives (84 percent), get their finances in order (74 percent), and purchase long-term care insurance (69 percent). Only a third of respondents expressed concern about confidentiality. The results suggest that people value genetic testingfor personal and financial reasons, but they also underscore the need to counsel potential recipients carefully about the accuracy and implications of test information.

Prevalence, costs, and treatment of Alzheimer's disease and related dementia: a managed care perspective.

BACKGROUND: The number of patients with Alzheimer's disease (AD) and related dementia treated in managed care organizations (MCOs) is increasing, and this trend is expected to continue. Therefore, it is critical that MCOs develop disease management strategies for this population. OBJECTIVE: To review the literature on the prevalence, costs, and treatment of AD and related dementia. STUDY DESIGN: Review of published articles from MEDLINE and peer-reviewed journals. RESULTS: Prevalence of AD and related dementia is approximately 5.7% among those aged 65 and older. Prevalence data from claims-based studies of AD in managed care are lower, ranging from 0.55% to 0.83%. Costs for formal care average $27,672 per patient annually, with long-term care being the most costly component. Annual costs for informal care are estimated to be $10,400 to $34,517 per patient. Additional costs associated with AD include lost wages and productivity of patients and caregivers and costs associated with increased morbidity of caregivers. Donepezil treatment is well tolerated and has been extensively tested and evaluated in clinical settings. Early diagnosis and treatment of AD with donepezil has been shown to slow cognitive decline in AD. Although study findings regarding the cost offsets of donepezil-treated patients to date are mixed, there is a growing body of evidence to support the inclusion of this and other therapies into an MCO's AD treatment armamentarium. CONCLUSIONS: It is unlikely that MCOs will escape the increased prevalence and costs associated with AD. Opportunities exist through patient management programs targeted toward early diagnosis, effective use of medications, control of comorbidities, and patient and family support to partially offset these costs while providing quality patient care.

Impact of donepezil on caregiving burden for patients with Alzheimer's disease.

Comprehensive Alzheimer's disease (AD) treatment should address caregiver well-being. We predicted that caregiver burden would be lower among caregivers of AD patients who received donepezil relative to caregivers of patients not treated with donepezil. A self-administered, nationwide survey of AD caregivers was used to match caregivers of patients treated with donepezil (n = 274) to caregivers of patients not treated with donepezil (n = 274). The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Respondents were three-quarters female, with an average age of 60 years. Results demonstrated that donepezil caregivers reported significantly lower scores on difficulty of caregiving. This difference remained when statistical controls for multiple patient and caregiver variables were imposed. However, selection factors must be recognized as a possible explanation for differences. The groups reported no difference on the time-demand subscale. In conclusion, better management of AD symptoms through donepezil treatment may reduce the burden of caregiving, providing physicians with a pharmacologic approach to improving quality of life for AD patients and their families.

Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1.

Interactions of heparin with intact human thrombospondin-1 (TSP1) and with two heparin-binding fragments of TSP1 were characterized using chemically modified heparins, a vascular heparan sulfate proteoglycan, and a series of heparin oligosaccharides prepared by partial deaminative cleavage. The avidity of TSP1 binding increased with oligosaccharide size, with plateaus at 4 to 6 and at 8 to 10 monosaccharide units. The dependence on oligosaccharide size for binding to the recombinant amino-terminal heparin-binding domain of TSP1 was the same as that of the intact TSP1 molecule but differed from that of a synthetic heparin-binding peptide from the type 1 repeats, suggesting that the interaction between intact TSP1 and heparin is primarily mediated by the amino-terminal domain. Based on activities of chemically modified heparins, binding to TSP1 depended primarily on 2-N- and 6-O-sulfation of glucosamine and to a lesser degree on 2,3-O-sulfation and the carboxyl residues of the uronic acids. In contrast, all of these modifications were required for binding of heparin to the type 1 repeat peptides. Affinity purification of heparin octasaccharides on immobilized TSP1 type 1 repeat peptides revealed a preference for oligosaccharides containing the disaccharide sequence IdoA(2-OSO(3))alpha1-4-GlcNS(6-OSO(3)). Binding of these oligosaccharides to the peptide required the Trp residues. These data demonstrate that the heparin-binding specificities of intact TSP1 and peptides from the type 1 repeats overlap with that of basic fibroblast growth factor (FGF2) and are consistent with the ability of these TSP1-derived molecules to inhibit FGF2-stimulated angiogenesis.

The pharmacoeconomics of Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of disability in people older than 75 years of age, has direct and indirect medical costs estimated at $100 billion per year. Yet underdiagnosis, coding, and reimbursement barriers result in most patients with AD receiving inadequate care. The vast majority of managed care organizations (MCOs) still lack formal disease management programs for AD. In several documented studies, the total costs for managing patients with AD increased significantly over age- and comorbidity-matched controls without AD. Importantly, these extra costs include not only nursing home care but also medical claims for inpatient stays, emergency department visits, and outpatient care. The extra costs are especially high in those patients with comorbidities such as diabetes or heart failure. Emerging pharmacoeconomic data indicate potential savings in medical care costs associated with early treatment of AD and the potential cost effectiveness of cholinesterase inhibitors such as donepezil. These studies document that Medicare MCOs are in need of directed efforts to improve medical management for members with AD.

Managed care decisions in Alzheimer's disease.

Alzheimer's disease (AD) and dementia are responsible for high levels of excess per-member costs within managed care organizations (MCOs). To deal with anticipated increases in the prevalence of this disease within their populations, MCOs should take steps to integrate and target proven pharmacologic and non-pharmacologic AD treatments. Key areas of AD care improvement include protocol-driven diagnosis, referral, and treatment; education of primary care physicians and caregivers; development of an integrated case management approach; and use of validated measures to assess outcomes. Published evidence-based guidelines are available to assist MCOs in developing clinical protocols for diagnosis and treatment with effective agents such as cholinesterase inhibitors. Because of the opportunity to prevent costly hospitalizations and other complications as a result of medical and behavioral comorbidities, and because of the need for tightly integrated care, a disease management approach for AD may be justified.

Polypharmacy management in Medicare managed care: changes in prescribing by primary care physicians resulting from a program promoting medication reviews.

OBJECTIVE: To examine the effects of medication reviews by primary care physicians on prescriptions written for elderly members of a Medicare managed care organization who were at risk for polypharmacy. STUDY DESIGN: Prospective study with follow-up survey. PATIENTS AND METHODS: We conducted a study in 1995 to demonstrate the prevalence of polypharmacy (defined as receiving 5 or more prescription medications during the 3-month study period) among elderly members of our managed care organization. Two years later, elderly members identified as being at risk for polypharmacy were sent a letter encouraging them to schedule a medication review with their primary care physician. Each primary care physician was provided with clinical practice guidelines on polypharmacy and patient-specific medication management reports. Patients and physicians were subsequently mailed a survey to assess the impact of the medication review program on prescribing practices. RESULTS: Of 37,372 elderly members screened, 5737 (15%) were at risk for polypharmacy. Of these, 2615 (46%) responded to the follow-up survey. Of the survey respondents, 1087 (42%) had gone to their primary care physician for a medication review. During the review, 96% of patients discussed their prescription medications and 72% discussed nonprescription medications they were taking. Twenty percent reported that their physician discontinued medications, 29% reported that the physician changed the dose of a medication, and 17% informed their physician about a new prescription or nonprescription medication they were taking. Of the 275 primary care physicians surveyed, 56 (20%) returned the questionnaire. Of these, 61% reported that the medication review program was "very" or "somewhat useful." Thirty-five percent reported discontinuing unnecessary medications, and 23% reported decreasing the frequency of dosing. Overall, 45% of physicians reported making at least one change in their prescribing to a member at risk for polypharmacy. CONCLUSIONS: Our program promoting medication reviews between primary care physicians and their elderly patients resulted in significant changes in prescribing by physicians. This type of program is likely to decrease the risk of polypharmacy among older members of a Medicare managed care organization.

How the principles of geriatric assessment are shaping managed care.

In traditional geriatric medicine, comprehensive assessment is considered crucial to the care of frail older patients. The principles of geriatric assessment--identifying high-risk patients and targeting them for preventive interventions--are also practiced by managed care organizations (MCOs). Self-reported health surveys and administrative data are two methods used by MCOs to identify members at high risk for adverse health outcomes and functional decline who may benefit from geriatric case management. For a successful partnership with primary care physicians, it is very important that geriatric care managers should be knowledgeable in the principles of geriatric medicine.

Heparin promotes beta-secretase cleavage of the Alzheimer's amyloid precursor protein.

In Alzheimer's disease, abnormal processing of the amyloid precursor protein (APP) is thought to play an important role in amyloid deposition. We investigated the effect of heparin, a highly sulfated glycosaminoglycan related to heparan sulfate, on the secretion of the beta-secretase cleavage product of APP (sAPP beta) in a human neuroblastoma cell line. Heparin induced an increase in the secretion of total APP, and an even greater relative increase in the secretion of sAPP beta. The effect on sAPP beta was specific to heparin. These data support the hypothesis that highly sulfated heparan sulfate proteoglycans may promote amyloidogenic pathways of APP metabolism.