Journal of Alzheimer's Disease - Volume 9, issue s3

Authors: Schellenberg, Gerard D.

Article Type: Research Article

Abstract: The genetics community working on Alzheimer's disease and related dementias has made remarkable progress in the past 20 years. The cumulative efforts by multiple groups have lead to the identification of three autosomal dominant genes for early onset AD. These are the amyloid-β protein precursor gene (APP), and the genes encoding presenilin1 and 2. The knowledge derived from this work has firmly established Aβ as a critical disease molecule and lead to candidate drugs currently in treatment trials. Work on a related disease, frontotemporal dementia with parkinsonism – chromosome 17 type has also added to our understanding of pathogenesis by …revealing that tau, the protein component of neurofibrillary tangles, is also a critical molecule in neurodegeneration. Lessons learned that still influence work on human genetics include the need to recognize and deal with genetic heterogeneity, a feature common to many genetic disorders. Genetic heterogeneity, if recognized, can be source of information. Another critical lesson is that clinical, molecular, and statistical scientists need to work closely on disease projects to succeed in solving the complex problems of common genetic disorders. Show more

Keywords: Alzheimer disease, AβPP, genetics, mutation, tau

DOI: 10.3233/JAD-2006-9S341

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 367-372, 2006

Authors: Spillantini, Maria Grazia | Murrell, Jill R. | Goedert, Michel | Farlow, Martin | Klug, Aaron | Ghetti, Bernardino

Article Type: Research Article

Abstract: Work in 1980s and early 1990s established that the microtubule-associated protein tau is the major component of the paired helical filament of Alzheimer's disease. Similar filamentous deposits are also present in a number of other diseases, including progressive supranuclear palsy, corticobasal degeneration and Pick's disease. In 1998, the relevance of tau dysfunction for the neurodegenerative process became clear, when mutations in the tau gene were found to cause the inherited “frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)”. The paper highlighted here [Spillantini M.G., Murrell J.R., Goedert M., Farlow M., Klug A. and Ghetti B. (1998) Mutation in the …tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737–7741] reported a mutation at position + 3 in the intron following alternatively spliced exon 10 of the tau gene in a family with abundant filamentous deposits made exclusively of four-repeat tau. Levels of soluble four-repeat tau were increased in individuals with this mutation. It was proposed that the + 3 mutation destabilises a stem-loop structure located at the end of exon 10 and the beginning of the intron, thus resulting in an abnormal ratio of three-repeat to four-repeat tau isoforms. Show more

Keywords: Mutation, tau, tauopathy

DOI: 10.3233/JAD-2006-9S342

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 373-380, 2006

Authors: Rogaeva, Ekaterina | Kawarai, Toshitaka | George-Hyslop, Peter St

Article Type: Research Article

Abstract: About 1% of Alzheimer's Disease (AD) cases have an early-onset autosomal dominant familial form of the disease, genetic analyses of which have found three causal genes: amyloid β-protein precursor (AβPP), presenilin 1 (PS1) and presenilin 2 (PS2). The APOE gene is the only robustly replicated risk factor for the common form of AD with onset after 65 years of age. In at least half of the AD cases, there is no known cause of the disease. Here we provide an overview on known AD-linked genes and discuss the strategies of searching for novel AD genetic risk factors.

Keywords: Alzheimer's disease, presenilin, gene, AβPP, APOE

DOI: 10.3233/JAD-2006-9S343

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 381-387, 2006

Authors: Van Broeckhoven, Christine | Kumar-Singh, Samir

Article Type: Research Article

Abstract: Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer's disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AβPP that have led to our better understanding of the pathogenesis of AD. Specifically, we will …discuss how pathologies linked to the Dutch (E693Q) and Flemish AβPP (A692G) mutations have helped in understanding the role of CAA in dementia and in the development of dense-core plaques. In addition, this review will also point directions that warrant additional studies. Show more

Keywords: Dementia, Alzheimer's disease, Cerebral Amyloid Angiopathy (CAA), cerebral hemorrhages, AβPP mutations, Flemish APP692 disease, HCHWAD

DOI: 10.3233/JAD-2006-9S344

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 389-398, 2006

Authors: Skoch, Jesse | Hyman, Bradley T. | Bacskai, Brian J.

Article Type: Research Article

Abstract: Multiphoton microscopy is an optical imaging technique that allows high resolution detection of fluorescence in thick, scattering tissues. The technique has been used for trans-cranial imaging of the brains of living transgenic mouse models of Alzheimer's disease. Direct detection of senile plaques in these mice has allowed the characterization of the natural history of individual senile plaques, the evaluation of plaque clearance during immunotherapy, and the characterization of the kinetics and biodistribution of the PET ligand, PIB. With the expanding repertoire of structural and functional fluorescent probes, and the preclinical characterization of new contrast agents for complementary imaging modalities like …MRI, PET, SPECT, and NIRS, multiphoton microscopy will continue to be a powerful tool in understanding and combating Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S345

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 401-407, 2006

Authors: Khachaturian, Zaven S.

Article Type: Research Article

Abstract: A retrospective view of the critical events and advances in the development of criteria, instruments and algorithms in the diagnosis of Alzheimer's disease. The review is from the vantage point of the National Institute on Aging and its role in the development of the national infrastructure, in the US, for clinical research on dementia. The paper discusses future research needs and challenges for developing new diagnostic armamentarium for early and accurate detection of neurodegenerative processes of dementia in the early prodromal stages or during early mild cognitive impairments.

Keywords: Diagnosis, dementia, Alzheimer's disease, mild cognitive impairments, MCI, diagnostic criteria, biomarkers, diagnostic instruments, neuroimaging, National Institute on Aging, NIA, NIH

DOI: 10.3233/JAD-2006-9S346

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 409-415, 2006

Authors: McKeith, Ian G.

Article Type: Research Article

Abstract: Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980's. Subsequent recognition that 10–15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer's …disease and Parkinson's disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtu-ally unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life. Show more

Keywords: Dementia with Lewy bodies, diagnosis

DOI: 10.3233/JAD-2006-9S347

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 417-423, 2006

Authors: Morgan, Dave

Article Type: Research Article

Abstract: A primary goal of research on Alzheimer's disease is to develop disease modifying therapeutics. The amyloid cascade hypothesis has focused the initial efforts on methods to reduce amyloid. One surprising approach that has shown considerable success in mouse models and has hinted at benefits in human trials is anti-Aβ immunotherapy. Schenk first showed the amyloid reducing potential of active immunization in 1999. This prompted our group and that of St. George-Hyslop to investigate whether active immunization would similarly retard the memory deficits that develop in amyloid depositing transgenic mice. Contrary to our initial predictions of premature memory dysfunction due to …inflammation, vaccination protected amyloid depositing mice from developing memory deficits. Subsequent studies found that passive immunization could reverse memory deficits, even when administered for short periods. These encouraging findings led to a trial of an Aβ vaccination in Alzheimer patients. The trial was cut short due to meningoencephalitic symptoms in 6% of patients, yet, in a subset of patients, those developing brain reactive antibodies benefited from slower rates of cognitive decline. These observations have accelerated the development of passive immunization protocols and safer vaccines. At this time, anti-amyloid immunotherapy stands poised to be the first test of the amyloid hypothesis in the treatment of Alzheimer disease. Show more

Keywords: Alzheimer disease, amyloid-β, therapeutics, transgenic, vaccine

DOI: 10.3233/JAD-2006-9S348

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 425-432, 2006

Authors: Solomon, Beka

Article Type: Research Article

Abstract: Site-directed antibodies which modulate conformation of amyloid-β peptide (Aβ) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3–6 of the N-terminal region of Aβ, found to be a key position in modulation of Aβ conformation, prevent formation of fibrillar Aβ and dissolve already formed amyloid plaques. The performance of anti-Aβ antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Aβ. Moreover, these antibodies protected the mice from learning and age-related memory …deficits. Development of such antibodies via active and/or passive immunization against Aβ peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Aβ 1-42 in hu-mans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Aβ plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics. Show more

Keywords: Amyloid-β, site-directed antibodies, therapeutic chaperones, single-chain antibodies, EFRH sequence, immunomodulation

DOI: 10.3233/JAD-2006-9S349

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 433-438, 2006

Authors: Summers, William K.

Article Type: Research Article

Abstract: The story of the development of tacrine began from its synthesis as an intravenous antiseptic in 1940 by Adrian Albert in Australia. In the 1970's William Summers began using tacrine in treating drug overdose coma and delirium. He felt it might have application in Alzheimer's based on work done in England by Peter Davies. In 1981, Summers et al. gave intravenous tacrine to Alzheimer's patients showed measurable improvement. Between 1981 and 1986, Summers worked with Art Kling and his group at UCLA to demonstrate usefulness of oral tacrine in treatment of Alzheimer's patients. The average length of tacrine use in …14 completing patients was 12.6 months and improvement was robust. This sparked controversy in the field. In 1993, after larger studies replicated the positive effect of tacrine, it was approved by the US Food and Drug Administration for treatment of Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S350

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 439-445, 2006

Authors: Whitehouse, Peter J.

Article Type: Research Article

Abstract: Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson's disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. …In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD. Show more

Keywords: Cholinergic basal forebrain, Alzheimer disease, neuropathology, drug development, quality of life, bioethics, cognitive science

DOI: 10.3233/JAD-2006-9S351

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 447-453, 2006