Alzheimer's Diseasea Research Articles

Peptide-Bound Glycative, AGE and Oxidative Modifications as Biomarkers for the Diagnosis of Alzheimer's Disease-A Feasibility Study.

Background: The diagnosis of Alzheimer's disease (AD) relies on core cerebrospinal fluid (CSF) biomarkers, amyloid beta (Aβ) and tau. As the brain is then already damaged, researchers still strive to discover earlier biomarkers of disease onset and the progression of AD. Glycation, advanced glycation end products (AGEs) and oxidative modifications on proteins in CSF mirror the underlying biological mechanisms that contribute to early AD pathology. However, analyzing free AGEs in the body fluids of AD patients has led to controversial results. Thus, this pilot study aimed to test the feasibility of detecting, identifying and quantifying differentially glycated, AGE or oxidatively modified peptides in CSF proteins of AD patients (n = 5) compared to a control group (n = 5). Methods: To this end, we utilized a data-dependent (DDA) nano liquid chromatography (LC) linear ion trap-Orbitrap tandem mass spectrometry (MS/MS) ) approach and database search that included over 30 glycative and oxidative modifications in four search nodes to analyze endogenous modifications on individual peptides. Furthermore, we quantified candidate peptide abundance using LC Quan. Results: We identified 299 sites of early and advanced glycation and 53 sites of oxidatively modified tryptophan. From those, we identified 17 promising candidates as putative biomarkers (receiver operating curve-area under the curve (ROC-AUC) > 0.8), albeit without statistical significance. Conclusions: The potential candidates with higher discrimination power showed correlations with established diagnostic markers, thus hinting toward the potential of those peptides as biomarkers.

Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aβ42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Effects of low-intensity ultrasound opening the blood-brain barrier on Alzheimer's disease-a mini review.

Due to the complex pathological mechanisms of Alzheimer's disease (AD), its treatment remains a challenge. One of the major difficulties in treating AD is the difficulty for drugs to cross the blood-brain barrier (BBB). Low-intensity ultrasound (LIUS) is a novel type of ultrasound with neuromodulation function. It has been widely reported that LIUS combined with intravenous injection of microbubbles (MB) can effectively, safely, and reversibly open the BBB to achieve non-invasive targeted drug delivery. However, many studies have reported that LIUS combined with MB-mediated BBB opening (LIUS + MB-BBBO) can improve pathological deposition and cognitive impairment in AD patients and mice without delivering additional drugs. This article reviews the relevant research studies on LIUS + MB-BBBO in the treatment of AD, analyzes its potential mechanisms, and summarizes relevant ultrasound parameters.

Iron chelators as a therapeutic option for Alzheimer's disease-A mini-review.

Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.

Tracing the Path between Mushrooms and Alzheimer's Disease-A Literature Review.

Alzheimer's disease (AD) is well-known among neurodegenerative diseases for the decline of cognitive functions, making overall daily tasks difficult or impossible. The disease prevails as the most common form of dementia and remains without a well-defined etiology. Being considered a disease of multifactorial origin, current targeted treatments have only managed to reduce or control symptoms, and to date, only two drugs are close to being able to halt its progression. For decades, natural compounds produced by living organisms have been at the forefront of research for new therapies. Mushrooms, which are well-known for their nutritional and medicinal properties, have also been studied for their potential use in the treatment of AD. Natural products derived from mushrooms have shown to be beneficial in several AD-related mechanisms, including the inhibition of acetylcholinesterase (AChE) and β-secretase (BACE 1); the prevention of amyloid beta (Aβ) aggregation and neurotoxicity; and the prevention of Tau expression and aggregation, as well as antioxidant and anti-inflammatory potential. Several studies in the literature relate mushrooms to neurodegenerative diseases. However, to the best of our knowledge, there is no publication that summarizes only AD data. In this context, this review aims to link the therapeutic potential of mushrooms to AD by compiling the anti-AD potential of different mushroom extracts or isolated compounds, targeting known AD-related mechanisms.

Photobiomodulation in Alzheimer's Disease-A Complementary Method to State-of-the-Art Pharmaceutical Formulations and Nanomedicine?

Alzheimer's disease (AD), as a neurodegenerative disorder, usually develops slowly but gradually worsens. It accounts for approximately 70% of dementia cases worldwide, and is recognized by WHO as a public health priority. Being a multifactorial disease, the origins of AD are not satisfactorily understood. Despite huge medical expenditures and attempts to discover new pharmaceuticals or nanomedicines in recent years, there is no cure for AD and not many successful treatments are available. The current review supports introspection on the latest scientific results from the specialized literature regarding the molecular and cellular mechanisms of brain photobiomodulation, as a complementary method with implications in AD. State-of-the-art pharmaceutical formulations, development of new nanoscale materials, bionanoformulations in current applications and perspectives in AD are highlighted. Another goal of this review was to discover and to speed transition to completely new paradigms for the multi-target management of AD, to facilitate brain remodeling through new therapeutic models and high-tech medical applications with light or lasers in the integrative nanomedicine of the future. In conclusion, new insights from this interdisciplinary approach, including the latest results from photobiomodulation (PBM) applied in human clinical trials, combined with the latest nanoscale drug delivery systems to easily overcome protective brain barriers, could open new avenues to rejuvenate our central nervous system, the most fascinating and complex organ. Picosecond transcranial laser stimulation could be successfully used to cross the blood-brain barrier together with the latest nanotechnologies, nanomedicines and drug delivery systems in AD therapy. Original, smart and targeted multifunctional solutions and new nanodrugs may soon be developed to treat AD.

Dose-dependent phosphorylation of endogenous Tau by intermittent hypoxia in rat brain.

Intermittent hypoxia, or intermittent low oxygen interspersed with normal oxygen levels, has differential effects that depend on the "dose" of hypoxic episodes (duration, severity, number per day, and number of days). Whereas "low dose" daily acute intermittent hypoxia (dAIH) elicits neuroprotection and neuroplasticity, "high dose" chronic intermittent hypoxia (CIH) similar to that experienced during sleep apnea elicits neuropathology. Sleep apnea is comorbid in >50% of patients with Alzheimer's disease-a progressive, neurodegenerative disease associated with brain amyloid and chronic Tau dysregulation (pathology). Although patients with sleep apnea present with higher Tau levels, it is unknown if sleep apnea through attendant CIH contributes to onset of Tau pathology. We hypothesized CIH characteristic of moderate sleep apnea would increase dysregulation of phosphorylated Tau (phospho-Tau) species in Sprague-Dawley rat hippocampus and prefrontal cortex. Conversely, we hypothesized that dAIH, a promising neurotherapeutic, has minimal impact on Tau phosphorylation. We report a dose-dependent intermittent hypoxia effect, with region-specific increases in 1) phospho-Tau species associated with human Tauopathies in the soluble form and 2) accumulated phospho-Tau in the insoluble fraction. The latter observation was particularly evident with higher CIH intensities. This important and novel finding is consistent with the idea that sleep apnea and attendant CIH have the potential to accelerate the progression of Alzheimer's disease and/or other Tauopathies.NEW & NOTEWORTHY Sleep apnea is highly prevalent in people with Alzheimer's disease, suggesting the potential to accelerate disease onset and/or progression. These studies demonstrate that intermittent hypoxia (IH) induces dose-dependent, region-specific Tau phosphorylation, and are the first to indicate that higher IH "doses" elicit both endogenous, (rat) Tau hyperphosphorylation and accumulation in the hippocampus. These findings are essential for development and implementation of new treatment strategies that minimize sleep apnea and its adverse impact on neurodegenerative diseases.

P 28 Add-on Effects of Transcranial Pulse Stimulation (TPS) in State-of-the-art Treated Neurodegeneration

Question Clinical effects of current therapies for neurodegeneration are limited. Very recently, a novel therapeutic approach has been developed as non-invasive add-on therapy: Transcranial Pulse Stimulation TPS (Beisteiner et al. 2019, Beisteiner & Lozano 2020, Popescu et al. 2021). This presentation intends to give an overview about clinical add-on effects in patients with neurodegenerative disease. Methods TPS applies repeated ultrashort pressure pulses in the ultrasound frequency range. TPS is the first brain stimulation technique which allows precise targeting of deep and superficial areas of grossly changed pathological brains. Clinical effects in patient cohorts with Alzheimer’s Disease, Depression and Parkinson’s disease will be presented. Statistical analyses are based on the CERAD score for documentation of cognitive improvements, BDI-II for documentation of mood improvement and UPDRS for documentation of motor improvements. In all studies, only state-of-the-art treated patients are included. Results In the AD study with 35 patients a significant improvement of CERAD scores was found, lasting 3 months. Improvements correlated with improved functional connectivity values within the Default Mode Network (fMRI data). In the Depression study (18 AD patients with Depression as comorbidity), we found significant improvement in BDI-II after TPS therapy. Functional connectivity (fMRI data) showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex). In the running PD study, preliminary analysis of observational data show significant improvements in UDRS scores in patients with optimized medications. Final PD analyses will be presented. Conclusion First evidence indicates, that Transcranial Pulse Stimulation TPS may show beneficial add-on effects in state-of-the-art treated neurodegeneration. References Popescu T, Pernet C, Beisteiner R. Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: A follow-up study. Alzheimers Dement (N Y). 2021 Feb 25;7(1):e12121. doi: 10.1002/trc2.12121. PMID: 33681449; PMCID: PMC7906128. Beisteiner R, Lozano AM. Transcranial Ultrasound Innovations Ready for Broad Clinical Application. Advanced Science 2020 Oct 27;7(23):2002026. doi: 10.1002/advs.202002026. PMID: 33304757; PMCID: PMC7709976 Beisteiner R, Matt E, Fan C, Baldysiak H, Schönfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrner J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse-Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. Advanced Science 2019 Dec 23;7(3):1902583. doi: 10.1002/advs.201902583. PMID: 32042569; PMCID: PMC7001626.

Expression of Regional Amyloid Deposition in Centiloid Scale and Used for Quantitative Analysis in Alzheimer's Disease-A Multi-Site Study

Expression of Regional Amyloid Deposition in Centiloid Scale and Used for Quantitative Analysis in Alzheimer's Disease-A Multi-Site Study

Environmental Substances Associated with Alzheimer's Disease-A Scoping Review.

Alzheimer’s disease (AD) is the most common form of dementia, prevalent in approximately 50–70% of the dementia cases. AD affects memory, and it is a progressive disease interfering with cognitive abilities, behaviour and functioning of the person affected. In 2015, there were 47 million people affected by dementia worldwide, and the figure was estimated to increase to 75 million in 2030 and to 132 million by 2050. In the framework of European Human Biomonitoring Initiative (HBM4EU), 18 substances or substance groups were prioritized for investigation. For each of the priority substances, a scoping document was prepared. Based on these scoping documents and complementary review of the recent literature, a scoping review of HBM4EU-priority substances which might be associated with AD was conducted. A possible association between risk of AD and pesticides was detected. For mercury (Hg), association is possible but inconsistent. Regarding cadmium (Cd) and arsenic (As), the results are inconsistent but inclined towards possible associations between the substances and the risk of disease. The evidence regarding lead (Pb) was weaker than for the other substances; however, possible associations exist. Although there is evidence of adverse neurological effects of environmental substances, more research is needed. Environmental chemical exposure and the related hazards are essential concerns for public health, and they could be preventable.

Characterization of Guazuma Ulmifolia for the Bioprotection of Neurodegenerative Diseases: Alzheimer's Disease, Stroke and Parkinson's Disease-A Review

Guazuma ulmifolia is an arboreal species found in Central and South American countries, its parts are often used in the medical field, both bark, stem, leaves, and fruits.

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy.

Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (β = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

Analytical Methods for the determination of drugs used in Alzheimer's disease-A Review

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. Alzheimer's disease is the most common cause of dementia among elder adults. Till now there are no medications which cures Alzheimer's disease or alters the disease process in the brain. The exact causes of Alzheimer's disease are not understood. But scientists believe in most of the people, it is caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time. Problems with brain proteins leads to failure of normal functioning of brain which may disrupt the working of brain cells (neurons) which produces toxic events. Some of the drugs used are Donepezil, Rivastigmine, Galantamine, Memantine. A brief review of the analytical Methods developed for the estimation of the above drugs was discussed in the present study.

The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.

Alzheimer’s disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer’s disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer’s disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.

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The use of herbal medicine in Alzheimer's disease-a systematic review.

The treatments of choice in Alzheimer's disease (AD) are cholinesterase inhibitors and NMDA-receptor antagonists, although doubts remain about the therapeutic effectiveness of these drugs. Herbal medicine products have been used in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) but with various responses. The objective of this article was to review evidences from controlled studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the elderly. Randomized controlled studies assessing AD in individuals older than 65 years were identified through searches of MEDLINE, LILACS, Cochrane Library, dissertation (USA), ADEAR (Alzheimer's Disease Clinical Trials Database), National Research Register, Current Controlled trials, Centerwatch Trials Database and PsychINFO Journal Articles. The search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy. The crossover results were evaluated by the Jadad's measurement scale. The systematic review identified two herbs and herbal formulations with therapeutic effects for the treatment of AD: Melissa officinalis, Salvia officinalis and Yi-Gan San and BDW (Ba Wei Di Huang Wan). Ginkgo biloba was identified in a meta-analysis study. All five herbs are useful for cognitive impairment of AD. M. officinalis and Yi-Gan San are also useful in agitation, for they have sedative effects. These herbs and formulations have demonstrated good therapeutic effectiveness but these results need to be compared with those of traditional drugs. Further large multicenter studies should be conducted in order to test the cost-effectiveness of these herbs for AD and the impact in the control of cognitive deterioration.

Problems and Progress

### Contents #### News In Sickness or in Health? Future Brightening for Depression Treatments #### Reviews and Viewpoints Games Played by Rogue Proteins in Prion Disorders and Alzheimer's Disease A. Aguzzi and C. Haass Molecular Pathways of Neurodegeneration in Parkinson's Disease T. M. Dawson and V. L. Dawson The Genetics of Common Adult-Onset Neuropsychiatric Disease: Complexities and Conundra? J. L. Kennedy et al. Postnatal Neurodevelopmental Disorders: Meeting at the Synapse? H. Y. Zoghbi Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders S. T. DeKosky and K. Marek Immunotherapeutic Approaches to Alzheimer's Disease A. Monsonego and H. L. Weiner Related Science's SAGEKE and STKE material; related Brevia article by Singleton et al., related Reports by Mallucci et al., W.G. Chen et al., and Martinowich et al.; and related special Web supplement T his special issue of Science focuses on a wide range of brain diseases. The past years have seen tremendous progress in the battle against these diseases. Most promising in the long run, our understanding of the basic mechanisms underlying many of these diseases has grown. There have also been improvements in diagnostics and important additions to our arsenal of treatments and interventions. Our contributors describe some of the most exciting recent developments in the field and give a sense of the prospects for future prevention and therapy. Aguzzi and Haass (p. [814][1]) review the common features and the differences in the pathogenesis of Alzheimer's disease and prion disorders, both of which involve the accumulation of misfolded proteins. Dawson and Dawson (p. [819][2]) overview the present state of our knowledge of Parkinson's disease. Their main focus is on recent progress in the unraveling of the molecular pathways that cause neurodegeneration in this disease. Kennedy et al . (p. [822][3]) look at the complexities of the genetics underlying many neurodegenerative and neuropsychiatric disorders, such as schizophrenia or frontotemporal dementia. Zoghbi (p. 826) reviews recent developments in our understanding of autism and Rett syndrome, a developmental disorder in young children, and proposes a new model to explain the relation between these two diseases. DeKosky and Marek (p. 830) review the different imaging, biochemical, and clinical measures presently available for early detection of neurodegenerative disorders. This may trigger interventions, some of which slow the course of disease, before a large part of the damage has been done. Monsonego and Weiner (p. [834][4]) describe the promising concept of immunotherapeutic approaches to treat Alzheimer's disease. The News section focuses on mental illness. Psychiatrists are contemplating a major overhaul of the manual they use to define brain diseases (Helmuth, p. 808). One of the most problematic diagnoses is depression. While researchers explore possible causes of depression and associated brain dysfunction, several treatment options are wending their way through clinical trials (Holden, p. [810][5]). At Science 's Signal Transduction Knowledge Environment (STKE, ), Manji et al . discuss a possible role of the phosphatase calcineurin in schizophrenia; Robinson reviews contributions of neurotransmitter transporters in psychiatric disorders; and MacDonald examines evidence for the signaling functions of huntingtin, a protein altered in Huntington's disease. In the Science of Aging Knowledge Environment (SAGE KE, ), Groves et al . present the case of a 48-year-old man who suffered from Huntington's disease. The case study includes pathology slides and a movie of the patient's neurological testing. An updated introduction to Alzheimer's disease by Helmuth covers diagnosis, pathology, prevention, and treatment. [1]: /lookup/doi/10.1126/science.1087348 [2]: /lookup/doi/10.1126/science.1087753 [3]: /lookup/doi/10.1126/science.1092132 [4]: /lookup/doi/10.1126/science.1088469 [5]: /lookup/doi/10.1126/science.302.5646.810

The National Institute on Aging/Alzheimer's Association recommendations on the application of apolipoprotein E genotyping to Alzheimer's disease.

In a conference held in Chicago during October 1995, a working group of the National Institute of Aging (NIA) and the Alzheimer's Association (AlzA) drafted consensus recommendations on research and clinical applications of APOE genetic susceptibility testing for Alzheimer's disease (AD). The NIA/AlzA Working Group concluded that in considering future applications of APOE genotyping and other knowledge that has been gained about the genetic basis of AD, the interests of AD patients and their family members must be held paramount. The group acknowledged that a robust association exists between possession of the APOE epsilon 4 allele and the risk of late-onset AD and cited evidence that this allele is more strongly associated with AD than any other form of dementia. They recommended against the use of APOE genotyping to predict the-future development of AD in asymptomatic individuals at this time, and warned against the use of the test in isolation as the sole means for diagnosing AD. The group endorsed the concept of discretionary use of APOE genotyping as an adjunct to other AD diagnostic procedures. However, routine clinical use of the test for this purpose was not recommended at this time. Physicians were advised to weigh any potential benefits of testing against the possibility that genotype disclosure could adversely affect the insurability, employability, and social standing of AD patients and their family members. Adequate provisions for pre-test and post-test counseling and psychosocial support were advised for all future clinical and research applications of APOE genotyping. The group called for the development of improved protocols for AD genetic counseling as well as supplemental measures to assure genetic privacy for AD patients and their family members.

Anti-inflammatory drugs in the fight against Alzheimer's disease.

Lesions in Alzheimer disease are characterized by the assembly of a variety of cells and proteins associated with the immune system. Activated microglia express high levels of MHC glycoproteins and receptors for complement. Small numbers of T-lymphocytes infiltrate tissue. Proteins of the classical complement pathway are closely connected with beta-amyloid deposits. Several materials associated with senile plaques, including beta-amyloid protein itself, bind C1q in vitro and activate the pathway. The membrane attack complex of complement, as well as proteins which defend against that complex, colocalize with dystrophic neurites. These data imply that an autodestructive process is occurring in Alzheimer's disease, and that anti-inflammatory drugs might be an effective form of therapy. Some epidemiological evidence and results of a pilot clinical trial support this hypothesis.