Burden Of Alzheimer's Disease Research Articles

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified. During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.

The Impact of Dementia Severity on Caregiver Burden in Frontotemporal Dementia and Alzheimer Disease

Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD- behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)-or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

Estrogens and Alzheimer disease risk

Alzheimer disease (AD) is largely a disorder of old age, yet factors that influence risk may operate years before the disease is clinically manifest. There is increasing consensus that interventions to reduce the burden of AD will be more successful if implemented during middle age rather than later

Astrocytic Adenosine A2A Receptors Control the Amyloid-β Peptide-Induced Decrease of Glutamate Uptake

Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ(1-42)). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Aβ to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A(2A) receptors (A(2A)R) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A(2A)R also modulate astrocytic glutamate uptake, we now tested if A(2A)R blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, Aβ(1-42). (1 μM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A(2A)R agonist, CGS 26180 (30 nM), and prevented by the A(2A)R antagonist, SCH 58261 (100 nM). Aβ1-42 also decreased D-aspartate uptake by 28 ± 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A(2A)R. In accordance with the long term control of glutamate transporter expression by A(2A)R, Aβ(1-42). enhanced the expression and density of astrocytic A(2A)R and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A(2A)R knockout mice. This impact of Aβ(1-42). on glutamate transporters and uptake, dependent on A(2A)R function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ(1-42). . These results provide the first demonstration for a direct key role of astrocytic A(2A)R in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.

Economic Evaluation of Treatment Options in Patients with Alzheimerʼs Disease

Alzheimer's disease (AD) is common among the elderly; it is responsible for 60-80% of all dementia cases. AD is characterized by cognitive decline, behavioural and psychological symptoms, and reductions in functioning and independence. Because of its progressive neurodegenerative nature and unknown aetiology, the burden of AD becomes increasingly significant in an aging population. Estimates indicate that 35.6 million people worldwide suffered from AD in 2010. By 2030 and 2050, this figure is predicted to increase to 65.7 million and 115.4 million, respectively. Costs will also rise along with the increase in the number of people diagnosed with AD. In 2010, the worldwide costs associated with dementia were estimated to be $US604 billion. The objective of this study was to conduct a systematic review of current publications dealing with the pharmacoeconomic factors associated with AD medications and to describe the decision-analytic models used to evaluate long-term outcomes. A systematic literature search was performed to identify articles published between 1 January 2007 and 15 July 2010. The search was also based on a previous systematic review, which included literature up to 2007. Articles were included if they were complete and original economic evaluations of AD and if they were comparative in nature. A quality assessment of the included publications was conducted and relevant information was extracted into tables. Seven out of 2067 identified articles were included in this systematic review. Four articles evaluated treatment with donepezil, one with galantamine and two with memantine. The studies were conducted in America, Europe and Asia. Five different groups of medications were compared. The incremental cost-effectiveness ratios (ICERs) for the group of patients treated with donepezil versus no drug treatment ranged from a dominant value to 281, 416.13 euros per quality-adjusted life-year (QALY). Patients treated with donepezil versus placebo showed ICERs with a range from a dominant value (not specified) up to 20, 866.77 euros per QALY. Treatment with memantine in addition to donepezil versus treatment with donepezil alone showed an ICER range from a dominant value to 6818.33 euros per QALY. In comparison with the memantine treatment as an add-on therapy, the ICER of memantine monotherapy versus standard care (without cholinesterase inhibitors [CEIs]) ranged from a dominant value to 63, 087.20 euros per QALY. Finally, the economic evaluation of galantamine in comparison with usual care without any AD drugs showed ICERs ranging from 1894.70 euros to 6953 euros per QALY. The seven identified publications included in this review indicate that treatment with CEIs or memantine seems to be reasonable in terms of clinical effects and costs for patients with AD. Depending on different hypotheses, assumptions and variables (e.g. time horizon, discount rates, initial number of patients in different states, etc.) in the sensitivity analyses, treatment with these drugs seems to be primarily a cost-effective strategy or even a cost-saving strategy. Nevertheless, the results generally are associated with a degree of uncertainty. The comparability of the results from the different economic evaluations is limited because of the different assumptions made.

An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology

PurposeThe study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.MethodsA multicentre autopsy...

An overview of biomarkers in Alzheimer′s disease

Alzheimer’s disease (AD) is the commonest progressive, dementing neurodegenerative disease in elderly, which affects innumerable people each year, and these numbers are likely to further increase as the population ages. In addition to the financial burden of AD on health care system, the disease has powerful emotional impact on caregivers and families of those afflicted. In this advancing era of AD research, with the availability of new treatment strategies having disease-modifying effects, there is growing need for the early diagnosis in AD, often hampered by paucity of biomarkers of AD. Various candidate biomarkers for AD have been developed that can detect patients with AD at an early stage. In the recent years, the search for an ideal biomarker has undergone a rapid evolution. Novel technologies in proteomics, genomics, and imaging techniques further expand the role of a biomarker not only in early diagnosis, but also in monitoring the response to various treatments. However, the availability of sensitive and specific biomarkers requires the method to be standardized so as to be able to compare the results across studies. Inspite of tremendous advances in this field the quest for an “ideal biomarker” still continues. In this review, we will discuss the various candidate markers in five spheres namely biochemical, neuroanatomical, metabolic, genetic and neuropsychological, and their current status and limitations in AD diagnosis.

FACTORS ASSOCIATED WITH RESISTANCE TO DEMENTIA DESPITE HIGH ALZHEIMER DISEASE PATHOLOGY

Background: Autopsy series have shown that some elderly people remain with normal cognitive function during life despite having high burdens of pathologic lesions associated with Alzheimer disease (AD) at death. Understanding why these individuals show no cognitive decline, despite high AD pathologic burdens, may be key to discovery of neuroprotective mechanisms. Methods: A total of 36 subjects who on autopsy had Braak stage V or VI and moderate or frequent neuritic plaque scores based on Consortium to Establish a Registry for Alzheimer9s Disease (CERAD) standards were included. Twelve had normal cognitive function and 24 a diagnosis of AD before death. Demographic characteristics, clinical and pathologic data, as well as antemortem brain volumes were compared between the groups. Results: In multiple regression analysis, antemortem hippocampal and total brain volumes were significantly larger in the group with normal cognitive function after adjusting for gender, age at MRI, time from MRI to death, Braak stage, CERAD neuritic plaque score, and overall presence of vascular disease. Conclusion: Larger brain and hippocampal volumes were associated with preserved cognitive function during life despite a high burden of Alzheimer disease (AD) pathologic lesions at death. A better understanding of processes that lead to preservation of brain volume may provide important clues for the discovery of mechanisms that protect the elderly from AD. AD = Alzheimer disease; CDR = Clinical Dementia Rating Scale; CERAD = Consortium to Establish a Registry for Alzheimer9s Disease; CIRS = Cumulative Illness Rating Scale; ICV = intracranial volume; LB = Lewy bodies; MMSE = Mini-Mental State Examination; NCSE = Neurobehavioral Cognitive Status Examination; NFT = neurofibrillary tangle; NIA = National Institute on Aging; NP = neuritic plaques; OHSU = Oregon Health & Science University; Ref = reference; SES = socioeconomic status; UPDRS = Unified Parkinson9s Disease Rating Scale.

New drug discovery for Alzheimer′s disease: Challenges and hopes

Byline: T. Sathyanarayana Rao, K. Rao Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. It is a common dementia related to aging and a fatal neurodegenerative disease, which is on rise in both the developed and the developing countries. The disease has a complex pathology and etiology. There are no biomarkers for early detection of the disease. There are no successful drugs either to cure or to manage the disease. It has affected 4.5 million people in the United States alone in 2000 and is expected to reach about 15 million by the year 2050 in spite of all the medical advancement. Patients develop progressive cognitive decline with psychiatric and behavioral problems that impair daily living activities and also passively affect quality of life of the patient and the family. The burden of AD has an extraordinary social and economic impact on the families and on the world itself. This makes the development of potential therapies a high priority area in biomedical research. The main challenge is to choose the right biochemical target for drug discovery because of complex neuropathology of the AD brain. The large extracellular beta-amyloid (A[sz] ) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective.[sup] [1] However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD.[sup] [2] Most of the evidence indicates that precursor protein (APP) processing has a central role in the AD process. The A[sz] in the form of plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase enzymatic pathway) is utilized for processing. A total of six mutations have been described in the APP gene, which leads to AD by influencing APP metabolism.[sup] [3] One of the leading theories is that A[sz] in plaques leads to AD because A[sz] is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque A[sz] oligomers. Now, AD has been understood as a more general problem with protein processing, from accumulation of intraneuronal A[sz] or extracellular, preplaque A[sz] leading to neuronal cell death. However, recently functional imaging studies implied that functional decline in humans can occur separately from both neuronal loss and neurofibrillary tangles. A[sz] , a 39-43 aminoacid peptide derived from APP is the major component of senile plaques observed in AD. Evidences implicate a central role for A[sz] in the pathophysiology of AD. Av40 is the dominant species in human cerebrospinal fluid, accounting for approximately 90% of total A under normal conditions. There is a disease-specific increase in A[sz] 40 brain tissue levels compared with the A[sz] 42 change observed both in the aged and in the AD brain. It is now speculated that A[sz] pathological significance is also known to be associated with a-synuclein aggregation, a protein implicated in Parkinson's disease. A[sz] is a self-aggregating protein and the conformational transition from unfolded state to a beta sheet-rich conformation leads to deposition of protein aggregates. Although A[sz] deposits are primarily extracellular, studies have demonstrated an intraneuronal accumulation of A[sz] in AD-vulnerable regions. It is said that the amyloid is deposited first in the neuron and later in the extracellular space. Thus, neurodegeneration (ND) includes complex pathology and etiology. No animal model completely reflects human ND seen in the brain. The major challenges are how to choose the best neuronutraceuticals for clinical trials, what kind of preclinical study design is required and whether we can formulate a synthetic or modification of the natural compound best suited for the brain. …

Health service utilization among Alzheimer's disease patients: Evidence from managed care

Background The objective of this study was to assess the disease burden of Alzheimer's disease (AD) in a commercial managed care setting by comparing direct health care costs and adverse event outcomes between patients with AD and without AD. Methods The study design used eligibility, medical, and pharmacy claims data from a large, national, geographically diverse, fee-for-service U.S. managed health plan. Commercially insured patients aged 65 years and older with a pharmacy benefit with evidence of AD (n = 4,450) and a control group without AD (n = 13,650) were matched by age, gender, plan location, and length of enrollment. Adverse event outcomes, comorbid conditions, and annualized health care costs were compared. Incremental costs were calculated by using a two-part model to estimate the burden of illness; incremental cost confidence intervals were estimated by bootstrap analysis. Results Patients with AD had generally higher health care costs and higher risk of acute adverse outcomes than the control cohort. Annual adjusted total health care costs per patient were approximately $1,418 greater for the AD cohort. Patients with AD had an unadjusted fracture risk of 14.6% versus 6.2% in the matched cohort and accidental injury/falls risk of 27.4% versus 11.4%. Conclusions Few studies have examined the disease burden of AD in commercial managed care settings. Similar to results of comparative studies with Medicare data, the disease burden is greater for patients with AD compared with a matched control cohort, with a different mix and a greater number of comorbid health care conditions partially accounting for this difference. As membership in commercial and Medicare managed care plans increases, plans will need to develop effective mechanisms to manage the health care of high-risk, high-cost patients with AD.

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

The needs of the caregiver in the long-term treatment of Alzheimer disease.

The long-term well-being of caregivers should be included as part of the treatment of patients with Alzheimer disease (AD). Throughout the process of caring for patients with AD, caregivers frequently experience social, emotional, physical, and financial losses, which become more significant as the disease progresses. Minimizing these losses is a goal in the overall management of AD. Successful treatment of the patient has been shown to positively impact quality of life for the caregiver. Randomized, controlled studies of acetylcholinesterase inhibitors (AChEIs) have demonstrated the effectiveness of these agents in stabilizing cognitive function and delaying behavioral symptoms. Moreover, a decrease in the incidence of nursing home placement has been associated with this therapy. The growing burden of AD on families and society as a whole warrants the investigation of ways to minimize the impact of AD. AChEIs play an important role in this effort. Further studies are needed to more closely examine the impact of specific AChEIs on caregiver burden.

Managing Alzheimer's disease

These are exciting times for research into Alzheimer's disease (AD). Significant investments in research, coupled with an infrastructure of AD research centers, have led to unprecedented advances in our understanding of the disease. From advances in pathobiological understanding, pharmacologic treatments have emerged that involve two major strategies: relieving the symptoms of AD, using cholinergic system enhancers or metabolic enhancers, and slowing the progression of AD with medications directed at retarding or halting the neurodegenerative sequence. The development of strategies to identify presymptomatic AD, and the associated use of medications that slow the progression of disease, would prevent the emergence of many cases of symptomatic AD. Given the advanced age of the population most susceptible to AD, delayed emergence coupled with slowed progression of symptoms would diminish the burden of AD and potentially eliminate it. The topics for this Neurology supplement on AD …

Twin studies of Alzheimer's disease: An approach to etiology and prevention

Epidemiologic studies of environmental factors associated with risk of Alzheimer's disease (AD) have produced inconsistent and disappointing results. By contrast, family/genetic studies and case control investigations suggest that genetic causes of AD are important. The investigation of such genetic causes remains an important aim in all forms of AD including typical, late-onset disease where linkage work is impractical. But the public health burden of AD creates an especially urgent need to identify environment risk factors, if these exist, since they will more likely be susceptible to intervention. Such environmental factors may interact with genetic susceptibility to accelerate or retard disease expression, and environmental interventions that delay onset may constitute an important strategy for prevention. All these issues may be addressed by twin studies of AD, but the few such studies to date have been limited by small samples and other methodologic difficulties. This paper reviews the rationale for twin studies of AD, and describes briefly the work in this area to date. It also discusses a number of suggestions for methodologic improvements. We conclude that the time is ripe for twin studies of AD, and that such work holds considerable potential for the investigation of etiology and, possibly, for the identification of strategies for prevention.