Alzheimer Disease: US Pacific Zone

McConnell LM, Koenig BA, Greely HT, Raffin TA. · Stanford Program in Genomics, Ethics, and Society, Stanford University Medical Center, Palo Alto, CA 94304, USA. · Genet Test. · Pubmed #10464572 No free full text.

Abstract: Several genes associated with Alzheimer disease (AD) have been localized and cloned; two genetic tests are already commercially available, and new tests are being developed. Genetic testing for AD--either for disease prediction or for diagnosis--raises critical ethical concerns. The multidisciplinary Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society (PGES) presents comprehensive recommendations on genetic testing for AD. The Group concludes that under current conditions, genetic testing for AD prediction or diagnosis is only rarely appropriate. Criteria for judging the readiness of a test for introduction into routine clinical practice typically rely heavily on evaluation of technical efficacy. PGES recommends a broader and more comprehensive approach, considering: 1) the unique social and historical meanings of AD; 2) the availability of procedures to promote good surrogate decision making for incompetent patients and to safeguard confidentiality; 3) access to sophisticated genetic counselors able to communicate complex risk information and effectively convey the social costs and psychological burdens of testing, such as unintentional disclosure of predictive genetic information to family members; 4) protection from inappropriate advertising and marketing of genetic tests; and 5) recognition of the need for public education about the meaning and usefulness of predictive and diagnostic tests for AD. In this special issue of Genetic Testing, the PGES recommendations are published along with comprehensive background papers authored by Working Group members.

Kukull WA. · National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, WA, USA. · Alzheimers Dement. · Pubmed #19328444 No free full text.

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Aisen PS. · Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA. · Alzheimers Dement. · Pubmed #19328440 No free full text.

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Cummings JL. · Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328437 No free full text.

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Schneider LS, Lahiri DK. · Departments of Psychiatry, Neurology, and Gerontology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. · Curr Alzheimer Res. · Pubmed #19199878 No free full text.

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Sparks L. · Sun Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ 85351, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #19091701 No free full text.

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Connor DJ, Sabbagh MN, Cummings JL. · Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #19012863 No free full text.

Abstract: BACKGROUND: The Neuropsychiatric Inventory (NPI) is commonly used in dementia trials to quantify and qualitate changes in psychiatric symptoms. METHODS: A questionnaire was administered to clinical trial raters to assess whether they were being trained to administer and score the NPI differently between clinical trial protocols. RESULTS: Responses to the survey indicated that there are differences between clinical trials protocols in how the instrument is administered and scored. DISCUSSION: Clarification of administration and scoring rules are provided, including the behavioral sampling period, whether premorbid characteristics are considered, and what behaviors are considered in rating frequency, severity, and caregiver distress.

Griffin-Pierce T, Silverberg N, Connor D, Jim M, Peters J, Kaszniak A, Sabbagh MN. · Department of Anthropology, University of Arizona, Tucson, AZ, USA. · Alzheimers Dement. · Pubmed #18631981 No free full text.

Abstract: Little is known about Alzheimer's disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Schenk D. · Chief Scientific Officer, Elan Corporation, 800 Gateway Blvd., South San Francisco, CA 9480, USA. · Curr Alzheimer Res. · Pubmed #16842091 No free full text.

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Barceloux DG. · Emergency Department, Pomona Valley Hospital Medical Center, Pomona, California, USA. · Dis Mon. · Pubmed #19446678 No free full text.

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Quinn JF, Crane S, Harris C, Wadsworth TL. · Oregon Health and Science University, Portland VA Medical Center, Department of Neurology, Portland, OR 97239, USA. · Expert Rev Neurother. · Pubmed #19402774 No free full text.

Abstract: A considerable amount of literature has accrued examining the role of copper in the pathogenesis of Alzheimer's disease. Remarkably, there is in vitro and animal data to support both copper toxicity and copper deficiency as relevant mechanisms in Alzheimer's disease. These data have prompted preliminary clinical trials of both copper complexing therapy and copper supplementation therapy, which have yielded mixed results. The preclinical and clinical studies are discussed here in an effort to determine how to move forward with rational clinical trials focused on copper modulation.

Henderson VW. · Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, Stanford, California 94305-5405, USA. · Semin Reprod Med. · Pubmed #19401959 No free full text.

Abstract: Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

Ghochikyan A. · The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, CA 92647, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355933 No free full text.

Abstract: Amyloid-beta (Abeta) immunotherapy has received considerable attention as a promising approach for reducing the level of Abeta in the CNS of Alzheimer's disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Abeta(42) developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients that received the vaccine. Generated antibodies reduced beta-amyloid deposits in the parenchyma of patients' brains, but no reduction in soluble Abeta or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Abeta is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Abeta, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Abeta immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Abeta antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.

Town T. · Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355932 links to  free full text

Abstract: In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Abeta vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Abeta(1-42) plus adjuvant (so-called "active" Abeta immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Abeta and histological evidence of clearance of the hallmark AD pathology, beta-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Abeta immunotherapy approach. This review focuses on alternative approaches to active Abeta vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.

Vasilevko V, Head E. · Institute for Brain Aging & Dementia, University of California, Irvine, CA 92697-4540, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355931 No free full text.

Abstract: Alzheimer disease (AD) is the most common form of dementia in the elderly and the number of individuals developing the disease is rapidly rising. Interventions focused on reducing beta-amyloid (Abeta), a component of senile plaques within the AD brain offer a promising approach to prevent or slow disease progression. In this review, we describe the immune system and cognitive and neurobiological features of a natural model of human brain aging, the beagle. The immune system of dogs shares many features of the human immune system, including developmental and aging characteristics. Further, dogs naturally accumulate human sequence Abeta as they age, which coincides with declines in learning and memory. A longitudinal study (approximately 2 years) of the response of aged beagles to vaccination with fibrillar Abeta1-42 indicated that despite significant clearance of Abeta, there were limited benefits in cognitive function. However, there was evidence for maintenance of executive function over time. These results are strikingly similar to reports of human clinical immunotherapy trials. We propose that the canine model complements existing animal models and will be helpful in developing new vaccine approaches to slowing or preventing Abeta pathology that can be translated to human clinical trials.

Kokjohn TA, Roher AE. · Sun Health Research Institute, Sun City, Arizona 85351, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355930 No free full text.

Abstract: Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-beta (Abeta) 40/42 increased in the gray matter compared to sporadic Alzheimer's disease (AD) patients and total brain Abeta levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular amyloid and hyper-phosphorylated tau deposits appeared refractory to this therapy. In addition, vaccination resulted in the consequential and drastic expansion of the white matter (WM) amyloid pool to levels without precedent in sporadic AD patients. Although vaccination disrupted amyloid plaques, this therapy did not enhance long-term cognitive function or necessarily halt neurodegeneration. The intricate involvement of vascular pathology in AD evolution and the firm recalcitrance of vessel-associated amyloid to antibody-mediated disruption suggest that immunization therapies might be more effective if administered on a prophylactic basis before vascular impairment and well ahead of any clinically evident cognitive decline. Amyloid-beta is viewed as pathological based on the postmortem correlation of senile plaques with an AD diagnosis. It remains uncertain which of the various forms of this peptide is the most toxic and whether Abeta or senile plaques themselves serve any desirable or protective functions. The long-term cognitive effects of chronic immunotherapy producing a steadily accumulating and effectively permanent pool of disrupted Abeta peptides within the human brain are unknown. In addition, the side effects of such therapy provided on a chronic basis could extend far beyond the brain. Eagerly seeking new therapies, critical knowledge gaps should prompt us to take a more wholistic perspective viewing Abeta and the amyloid cascade as aspects of complex and many-faceted physiological processes that sometimes end in AD dementia.

Caccamo A, Fisher A, LaFerla FM. · Department of Neurobiology, University of California, Irvine, Irvine, CA 92697, USA. · Curr Alzheimer Res. · Pubmed #19355845 No free full text.

Abstract: Cholinergic deficit is a cardinal feature of Alzheimer's disease, and cholinesterase inhibitors represent one of the most prominent means of mitigating this dysfunction. Cholinesterase inhibitors provide mild symptomatic relief, although they lose their efficacy over time most likely because they are not disease-modifying agents. An alternative strategy for restoring cholinergic function and attenuating the cognitive decline involves acting on the receptors on which acetylcholine acts. Stimulation of muscarinic acetylcholine receptors and in particular the M1 subtype has been shown to have a beneficial effect in restoring cognition in patients with Alzheimer's disease and in attenuating Abeta and tau pathology in different animal models. In this review, we discuss the role of M1 agonists as a potential disease-modifying therapy for Alzheimer's disease.

Schneider LS. · Department of Psychiatry and Behavioral Sciences and Department of Neurology, Keck School of Medicine, and Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328454 No free full text.

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Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. · Mary S. Easton Center for Alzheimer's Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328453 No free full text.

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Bookheimer S, Burggren A. · Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California-Los Angeles, CA 90095, USA. · Annu Rev Clin Psychol. · Pubmed #19327032 No free full text.

Abstract: Many years before receiving a clinical diagnosis of Alzheimer's disease (AD), patients experience evidence of cognitive decline. Recent studies using a variety of brain imaging technologies have detected subtle changes in brain structure and function in normal adults with a genetic risk for AD; these brain changes have similar pathological features as AD, and some appear to be predictive of future cognitive decline. This review examines the most recent data on brain changes in genetic risk for AD and discusses the benefits and potential risks of detecting individuals at risk.

Craft S. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, 98108, USA. · Arch Neurol. · Pubmed #19273747 No free full text.

Abstract: In recent years a rapidly increasing number of studies has focused on the relationship between dementia and metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. Etiological heterogeneity and comorbidity pose challenges for determining relationships among metabolic disorders. The independent and interactive effects of brain vascular injury and classic pathological agents such as beta-amyloid have also proved difficult to distinguish in human patients, blurring the lines between Alzheimer disease and vascular dementia. This review highlights recent work aimed at identifying convergent mechanisms such as insulin resistance that may underlie comorbid metabolic disorders and thereby increase dementia risk. Identification of such convergent factors will not only provide important insight into the causes and interdependencies of late-life dementias but will also inspire novel strategies for treating and preventing these disorders.

Rafii MS, Aisen PS. · Department of Neurosciences, University of California-San Diego, Gilman Drive M/C 0949, La Jolla, CA 92093, USA. · BMC Med. · Pubmed #19228370 links to  free full text

Abstract: Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *'disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.

Palop JJ, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94158, USA. · Arch Neurol. · Pubmed #19204149 No free full text.

Abstract: Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.

Seeley WW. · Department of Neurology, University of California, San Francisco, and UCSF Memory and Aging Center, San Francisco, CA 94143-1207, USA. · Front Neurol Neurosci. · Pubmed #19182474 No free full text.

Abstract: Frontotemporal dementia represents an important cause of dementia that requires differentiation from Alzheimer's disease. As molecular therapies for both diseases begin to emerge, neuroimaging biomarkers will be needed that can improve diagnostic accuracy and enable treatment monitoring.At present, structural magnetic resonance imaging provides a useful adjunct to clinical assessment,helping to distinguish frontotemporal dementia from Alzheimer's disease and from nonneurodegenerative disease. Future imaging research will seek to more directly assay disease by assessing network level pathophysiology and accumulation of misfolded proteins in cerebral tissues.

Wright JW, Harding JW. · Department of Psychology, Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA. · J Renin Angiotensin Aldosterone Syst. · Pubmed #19126664 No free full text.

Abstract: Over recent years antihypertensive drugs, particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have been reported to have beneficial effects upon cognitive impairment. Such findings suggest that pharmacological manipulation of angiotensin ligands may be of clinical importance in slowing or halting the cognitive deterioration seen in vascular dementia and Alzheimer's disease. The mechanism(s) underlying these improvements in cognitive function remains unclear; however, important leads are emerging. The angiotensin AT4 receptor subtype, discovered by our laboratory in 1992, influences several important behaviours and physiologies, including learning and memory, and may play a role in this cognitive improvement. This review initially describes the therapeutic drugs approved by the Federal Drug Administration and new approaches presently being developed to treat Alzheimer's disease-induced cognitive impairment. Next, the biologically-active angiotensin ligands and their respective receptor subtypes are discussed, followed by the roles of angiotensin II, angiotensin IV, ACE inhibitors and ARBs in cognitive function. We conclude with a working hypothesis concerning the importance of the AT4 receptor subtype as a new potential drug target for the treatment of Alzheimer's disease-associated memory loss.