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1.  Pinpointing key mechanisms in Alzheimer's disease development 
van Exel and colleagues present an elegant study testing relationships between vascular and inflammatory traits and the risk of Alzheimer's disease (AD) development. They compared middle-aged offspring of AD cases with similar offspring of nondemented parents and observed greater inflammatory response to challenge and increased hypertension in those at high genetic risk. These observations join a growing body of evidence implicating inflammation/innate immunity as a crucial component in disease development. Recent discoveries of new risk genes for Alzheimer's disease also implicate innate immunity and to some extent vascular health as potentially important in pathogenesis. Further identification and refinement of putative disease mechanisms is likely as the genetic architecture of AD is uncovered through current large-scale association and sequencing studies.
PMCID: PMC2876782  PMID: 20359316
3.  Role of structural MRI in Alzheimer's disease 
Atrophy measured on structural magnetic resonance imaging (sMRI) is a powerful biomarker of the stage and intensity of the neurodegenerative aspect of Alzheimer's disease (AD) pathology. In this review, we will discuss the role of sMRI as an AD biomarker by summarizing (a) the most commonly used methods to extract information from sMRI images, (b) the different roles in which sMRI can be used as an AD biomarker, and (c) comparisons of sMRI with other major AD biomarkers.
PMCID: PMC2949589  PMID: 20807454
4.  The role of animal models in advancing amyloid-beta immunotherapy to the clinic 
The amyloid-beta (Aβ) hypothesis of Alzheimer's disease (AD) causality is now well into its third decade and is finally entering a phase of rigorous clinical testing in numerous late stage clinical trials. The use of Aβ-based animal models of AD has been essential to the discovery and/or preclinical validation of many of these therapeutic approaches. While several neuropathologically based results from preclinical studies have translated nicely into AD patients, the full clinical value of Aβ-directed therapies awaits results from trials now in progress.
PMCID: PMC2949588  PMID: 20682084
5.  The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer's disease: oligomer size or conformation? 
Since the reformulation of the amyloid cascade hypothesis to focus on oligomeric aggregates of amyloid beta as the prime toxic species causing Alzheimer's disease, many researchers refocused on detecting a specific molecular assembly of defined size thatis the main trigger of Alzheimer's disease. The result has been the identification of a host of molecular assemblies containing from two up to a hundred molecules of the amyloid beta peptide, which were all found to impair memory formation in mice. This clearly demonstrates that size is insufficient to define toxicity and peptide conformation has to be taken into account. In this review we discuss the interplay between oligomer size and peptide conformation as the key determinants of the neurotoxicity of the amyloid beta peptide.
PMCID: PMC2949586  PMID: 20642866
6.  Advances in quantitative magnetic resonance imaging-based biomarkers for Alzheimer disease 
A critical goal of Alzheimer disease research is to identify disease biomarkers that can be used in clinical trials to assist in the adjudication of treatment effects. While clinical validation remains a goal for many potential Alzheimer disease biomarkers, the rapid proliferation of markers has sparked comparative efforts as well. New data acquisition methods and sophisticated image-processing algorithms are poised to make a substantial impact on our ability to make precise measurements of the structure and function of regions within the living human brain and their connections and chemical composition. This commentary provides a perspective on a recently published paper and how it illustrates progress and challenges in the field.
PMCID: PMC2949587  PMID: 20619002
7.  Con: Can biomarkers be gold standards in Alzheimer's disease? 
As Alzheimer's disease remains a clinical diagnosis, and as clinical diagnosis can be difficult, it makes sense to look for so-called biomarkers. A biomarker predicts who is likely to have the illness and who is not. Some biomarkers might even correlate with a clinically meaningful response to treatment. Developing biomarkers is often characterized as searching for a diagnostic gold standard that can seem appealing in its promise of certainty. Even so, considering both the economic history of the gold standard and the results of neuropathological studies, framing the search for measurable, biological correlates of dementia syndromes in this way is likely to be self-defeating. Instead of considering biomarkers as providing certainty through referent criterion validation, currently it makes more sense to test their construct validity and their predictive ability. This means that while biomarkers should inform, they will not dictate clinical meaningfulness. For the foreseeable future, even were they to inform diagnosis, biomarkers cannot substitute for understanding whether patients and caregivers find a given dementia treatment effective. Instead, clinicians should recognize their own determining role, both in dementia diagnosis and in the evaluation of treatment. These roles will best be executed by hearing what patients and caregivers tell us about dementia, and its response to treatment.
PMCID: PMC2919696  PMID: 20587007
8.  Pro: Can biomarkers be gold standards in Alzheimer's disease? 
Recent advances in biomarkers for Alzheimer's disease (AD) now allow the visualization of one of the hallmark pathologies of AD in vivo, and combination biomarker profiles can now approximate the diagnostic accuracy of autopsy in patients with dementia. Biomarkers are already employed in clinical trials in prodromal AD for both subject selection and in monitoring therapeutic response. Ultimately the greatest utility of biomarkers may be in the preclinical stages of AD, to identify and track progression of the disease prior to significant cognitive impairment, at the point when disease modifying therapies are likely to be most efficacious.
PMCID: PMC2919697  PMID: 20587006
9.  Mild traumatic brain injury: a risk factor for neurodegeneration 
Recently, it has become clear that head trauma can lead to a progressive neurodegeneration known as chronic traumatic encephalopathy. Although the medical literature also implicates head trauma as a risk factor for Alzheimer's disease, these findings are predominantly based on clinical diagnostic criteria that lack specificity. The dementia that follows head injuries or repetitive mild trauma may be caused by chronic traumatic encephalopathy, alone or in conjunction with other neurodegenerations (for example, Alzheimer's disease). Prospective longitudinal studies of head-injured individuals, with neuropathological verification, will not only improve understanding of head trauma as a risk factor for dementia but will also enhance treatment and prevention of a variety of neurodegenerative diseases.
PMCID: PMC2919698  PMID: 20587081
10.  Addressing the challenges to successful recruitment and retention in Alzheimer's disease clinical trials 
Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them.
PMCID: PMC3031880  PMID: 21172069
11.  A diverse portfolio of novel drug discovery efforts for Alzheimer's disease: Meeting report from the 11th International Conference on Alzheimer's Drug Discovery, 27-28 September 2010, Jersey City, NJ, USA 
While Alzheimer's disease researchers continue to debate the underlying cause(s) of the disease, most agree that a diverse, multi-target approach to treatment will be necessary. To this end, the Alzheimer's Drug Discovery Foundation (ADDF) recently hosted the 11th International Conference on Alzheimer's Drug Discovery to highlight the array of exciting efforts from the ADDF's funded investigators.
PMCID: PMC3031879  PMID: 21159211
12.  Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease? 
Should the apolipoprotein E (ApoE) genotype be a covariate for clinical trials in Alzheimer disease (AD)? ApoE is a transport protein for lipids, amyloid-beta proteins, and the different phenotypes differentially affect amyloid-beta deposition, neurofibrillary tangle formation, and microglial activation. The ApoE genotype has not affected efficacy in short symptomatic AD trials. ApoE4 has been associated with greater efficacy in at least two mild cognitive impairment studies. Vasogenic edema was more frequent in ApoE4 AD patients treated with a monoclonal antibody to amyloid beta. Since there is evidence that the ApoE genotype may differentially affect disease mechanisms, efficacy, and adverse effects in both AD and mild cognitive impairment trials, the ApoE genotype should be included as a covariate in future studies.
PMCID: PMC2919695  PMID: 20537201
13.  Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease 
In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.
PMCID: PMC3031878  PMID: 21122172
14.  The involvement of cell cycle events in the pathogenesis of Alzheimer's disease 
Most neurons undergo their last cell division within the first 1 to 2% of the lifespan of an organism. This has been interpreted to mean that adult neurons are permanently postmitotic, but Alzheimer's disease (AD) is an example of a late-onset neurodegenerative disease that challenges this concept. In AD, neurons in populations at risk for death reactivate their cell cycle and replicate their genome - but rather than complete the cycle with mitosis and cytokinesis, the neurons die. While opening new perspectives on the etiology of AD dementia, the simple linear model suggested by this description gains in complexity with the maturation of the adult brain. This complexity makes the full understanding of the relationship between cell division and cell death more difficult to achieve. The quest for understanding is worthwhile, however, as fresh avenues for therapeutic intervention are the prizes for success.
PMCID: PMC2919693  PMID: 20497605
15.  Increasing incidence of dementia in the oldest old: evidence and implications 
The oldest old are the fastest growing segment of the US population but accurate estimates of the incidence of dementia in this age group have been elusive. Corrada and colleagues present data on the 5-year age-specific rates of dementia incidence in persons 90 years and older from The 90+ Study. Their findings show a continued exponential increase in dementia incidence after age 90 that mirrors the increase observed in persons aged 65 to 90, with a doubling every 5.5 years. This contrasts with previous smaller studies reporting a slowing of the increase in incidence after age 90. If confirmed, the continued increase, rather than a plateau, in the incidence of dementia in the oldest old has implications for proper healthcare planning. Strategies for prevention and treatment will require more information regarding risk factors and the etiopathogenesis of dementia in the oldest old.
PMCID: PMC2919692  PMID: 20497589
16.  Pro: Can neuropathology really confirm the exact diagnosis? 
Recent advances in the clinical diagnostic instruments for diagnosing Alzheimer's disease (AD) and in neuroimaging may cast doubt in the minds of some practitioners about the continued need for neuropathology to provide the ultimate diagnosis. Certainly the majority of cases of AD can be clinically correctly diagnosed by experienced clinicians but many cases are given this label by less experienced practitioners. Even after the most thorough work-up, a few cases of confidently diagnosed AD turn out to be something else when microscopy of the brain is undertaken. Even for neuropathologists, however, it can be difficult to correctly assign cognitive decline to the various pathological processes that can be found together in an older brain. We need further clinicopathogical study to enlighten us about, for example, the contribution of commonly found cerebrovascular disease to dementia. Human studies are also needed to explore the changes in pathology that new treatments for AD may produce.
PMCID: PMC2876787  PMID: 20497619
17.  Con: Can neuropathology really confirm the exact diagnosis? 
Clinical diagnostic accuracy using revised consensus criteria and newly developed biomarkers ranges from 65 to 96% for Alzheimer's disease (AD), with a diagnostic specificity versus other dementias of 23 to 88%. Neuropathological assessment using molecular biology and immunohistochemistry, homogeneous definitions, harmonized interlaboratory methods, and assessment standards can identify 54 to 97% of AD cases and can eliminate 62 to 100% of nondemented subjects, but only between 8 and 42% of non-AD dementias, without, however, being able to clarify the etiology of most of these disorders. The value and pitfalls of pathological diagnostic criteria are critically discussed.
PMCID: PMC2876788  PMID: 20497615
18.  Is it time for biomarker-based diagnostic criteria for prodromal Alzheimer's disease? 
Drug candidates targeting amyloid-β (Aβ) pathology in Alzheimer's disease are in different phases of clinical trials. These treatments will probably be most effective in the earlier stages of the disease, before neurodegeneration is too severe, but at the same time symptoms are vague and the clinical diagnosis is difficult. Recent research advances have resulted in promising biomarkers, including cerebrospinal fluid analyses for tau and Aβ, magnetic resonance imaging measurement of atrophy, and positron emission tomography imaging of glucose metabolism and Aβ pathology, which allow identification of prodromal Alzheimer's disease. More details are needed, however, on how these biomarkers can be standardized, to allow a general implementation in the clinical routine diagnostic work-up of patients with cognitive disturbances.
PMCID: PMC2876786  PMID: 20441609
20.  Herbal therapy: a new pathway for the treatment of Alzheimer's disease 
It has been a clinical challenge to treat Alzheimer's disease (AD). In the present commentary we discuss whether herbal therapy could be a novel treatment method for AD on the basis of results from clinical trials, and discuss the implications for potential therapy for AD pathophysiology. There is evidence to suggest that single herbs or herbal formulations may offer certain complementary cognitive benefits to the approved drugs. The current evidence supporting their use alone, however, is inconclusive or inadequate owing to many methodological limitations. Herbal mixtures may have advantages with multiple target regulation compared with the single-target antagonist in the view of traditional Chinese medicine. Several clinical trials using herbal mixtures are being conducted in China and will hopefully show promising results for treating AD in the near future.
PMCID: PMC2983439  PMID: 21067555
21.  Inflammation in the Alzheimer's disease cascade: culprit or innocent bystander? 
The strongest known risk factors for late-onset Alzheimer disease (LOAD) remain a positive family history and the APOE ε4 allele. van Exel and colleagues used these known risk factors to identify high- and low-risk samples of middle-aged persons in whom they compared levels of inflammatory and vascular risk factors. They observed that, compared with controls, middle-aged offspring of families with a parental history of LOAD had higher blood pressures, lower ankle-brachial indices (measure of peripheral atherosclerosis), and increased production of proinflammatory cytokines in lipopolysaccharide-stimulated whole blood samples, associations that were independent of APOE genotype. This study adds to the growing body of evidence linking inflammatory mechanisms to Alzheimer disease risk and, especially when considered in light of the recently described association of genetic variation in the complement receptor 1 (CR1) gene with LOAD, suggests that inflammatory biomarkers (whether causal or incidental) could be measured and perhaps used to risk-stratify middle-aged persons for early preventive and therapeutic interventions.
PMCID: PMC2876784  PMID: 20388190
22.  Can novel therapeutics halt the amyloid cascade? 
The amyloid hypothesis provides a basis for the development of new therapeutic strategies in Alzheimer's disease. Two large trials have recently been published. The first is a phase 2 study of passive immunotherapy with bapineuzumab, a humanized anti-Aβ monoclonal antibody directed against the N-terminus of Aβ. This trial showed no differences within dose cohorts on the primary efficacy analysis. Exploratory analyses showed potential treatment differences on cognitive and functional endpoints in study completers and apolipoprotein E ε4 noncarriers. A safety concern was the occurrence of reversible vasogenic edema. The second study is a phase 3 trial of tarenflurbil, a modulator of the activity of γ-secretase. Tarenflurbil had no beneficial effect on the primary or secondary outcomes. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. Possible explanations for the negative results of these trials may be related to the study design or the choice of dosage. However, it may also be that these negative findings reflect our still incomplete understanding of, at least part of, the pathogenesis of Alzheimer's disease.
PMCID: PMC2876783  PMID: 20388189
23.  Assessing the progression of mild cognitive impairment to Alzheimer's disease: current trends and future directions 
With the advent of advances in biomarker detection and neuropsychological measurement, prospects have improved for identifying and tracking the progression of Alzheimer's disease (AD) from its earliest stages through dementia. While new diagnostic techniques have exciting implications for initiating treatment earlier in the disease process, much work remains to be done to optimize the contributions of the expanding range of tools at the disposal of researchers and clinicians. The present paper examines recent work in cerebrospinal fluid biomarkers, magnetic resonance imaging, positron emission tomography, neuropsychological measures, and functional assessment. The strengths and weaknesses of current methodologies are explored and discussed. It is concluded that AD from its mild cognitive impairment state through dementia represents a continuous process, and that progression over time can best be accomplished by interval-level variables. Biomarkers that are most sensitive to early AD may not be the most optimal for monitoring longitudinal change, and it is likely that multivariate models incorporating cognitive measures, functional variables and biomarker data will be the most fruitful avenues for future research.
PMCID: PMC2983437  PMID: 20920147
24.  Obesity and the brain: a possible genetic link 
Structural brain deficits have been repeatedly linked to body mass index and obesity, which itself is controlled by the effects of a number of independent genetic loci. One of the most consistently replicated of these putative obesity genes is fat mass and obesity-associated protein (FTO). A recent study by investigators from the Alzheimer's Disease Neuroimaging Initiative set out to assess whether polymorphisms in FTO are directly correlated with brain volume in a collection of over 200 healthy older individuals. The authors found a modest but significant reduction in brain volume in the frontal and occipital lobes exerted by the same FTO alleles that also predispose to obesity. Although potentially providing a novel genetic link between obesity and brain structure, the relevance of these findings for normal brain function and disease remains to be determined.
PMCID: PMC2983436  PMID: 20875147
25.  From model system to clinical medicine: pathophysiologic links of common proteinopathies 
Recent clinical evidence suggests that Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB), though distinct neurological disorders, have some common pathological features that may have an impact on the clinical characteristics of these diseases. However, the question of whether these disorders have a common pathophysiology remains. Clinton and colleagues recently reported a mouse model that exhibits the combined pathologies of AD, PD, and DLB, a finding that may shed some light on this issue. Using this mouse model, the authors demonstrate that the pathogenic proteins amyloid beta, tau, and alpha-synuclein interact synergistically to enhance the accumulation of one another and accelerate cognitive decline. These data indicate shared pathogenic mechanisms and suggest the possibility that therapeutic interventions successfully targeting one of these pathogenic proteins have implications for a number of related neurodegenerative disorders.
PMCID: PMC2983435  PMID: 20854651

Results 1-25 (35)