Current Alzheimer Research - Volume 8, Issue 4, 2011

Alzheimer disease (AD), a complex neurodegenerative disorder, has become a major public health concern given its rapidly increasing prevalence and the long duration coupled with high cost of care. Successful disease-modifying therapy is still lacking, despite a decade of remarkable advances in our understanding of both the pathology and the risks associated with AD. In recent years, it has become obvious that neuritic plaques and neurofibrillary tangles, the neuropathological hallmarks of AD, are not exclusive to demented individuals. In fact, as many as 30% of individuals older than 75 years of age who are considered clinically normal at the time of death will receive a post-mortem diagnosis of possible or probable AD based on neuropathological findings - a condition we define as Asymptomatic AD (ASYMAD). This realization certainly poses a challenge to the neuropathological diagnosis, which is still considered the gold standard. In addition, the recognition of ASYMAD has begun to shift the focus of research from risk and pathology to the identification of protective factors, and thereby the prevention of disability and disease which have been relatively understudied. Much of our recent efforts have focused on what might be allowing these older individuals to remain resilient to pathology compared to many who have succumbed to it. Most of our investigations to date have centered on the Baltimore Longitudinal Study of Aging. Here, we provide a historical background and highlight the combined clinical, pathologic and morphometric findings related to ASYMAD. We believe that a better understanding of changes occurring during this apparently asymptomatic state may be seminal to our understanding of the mechanisms that underlie the maintenance of cognitive health or halt the progression of the disease. Based on their findings from two large communitybased, cohort studies, the Religious Orders Study and the Rush Memory and Aging Project, Negash and colleagues propose a provocative paradigm shift in consideration of the neurobiology of healthy aging and dementia. They highlight the need for research identifying factors that promote resistance to age-related pathology. Within the framework of cognitive reserve, many factors thought to modify or mediate the association between neuropathology and cognition are also discussed. Vascular dementia is also challenging field, and O'Brien reviews the relationship among Alzheimer's brain pathology, cerebral infarcts and cerebral atherosclerosis, all of which are common in autopsy brains of patients enrolled in longitudinal prospective cohorts. The relative contribution of each of these factors to overall cognitive function or dementia is unclear. O'Brien offers that each seems to be an independent predictor of dementia and that individual's ability to withstand the toxic effects of amyloid deposition might be due to the lack of additional coexisting pathologies....

Neuritic plaques and neurofibrillary tangles, the neuropathological hallmarks of AD, are not limited to individuals with dementia. These pathologic changes can also be present in the brains of cognitively normal older adults - a condition we defined as Asymptomatic AD (ASYMAD). Although it remains unclear whether these individuals would remain clinically normal with longer survival, they seem to be able to compensate for or delay the appearance of dementia symptoms. Here, we provide a historical background and highlight the combined clinical, pathologic and morphometric evidence related to ASYMAD. Understanding the nature of changes during this apparently asymptomatic state may shed light on the mechanisms that forestall the progression of the disease and allow for maintenance of cognitive health, an important area of research that has been understudied relative to the identification of risks and pathways to negative health outcomes.

It is increasingly recognized that the correlation between neuropathological lesions and cognition is modest and accounts for about a quarter of the variance of cognition among older adults. Some individuals maintain normal cognitive functioning amidst significant brain pathology, while others suffer varying degrees of cognitive and neurological deterioration that render them dependent and frail. We present data from the Religious Orders Study and the Memory and Aging Project pertaining to pathology and cognition, and propose a paradigm shift in consideration of the neurobiology of healthy aging and dementia. Factors that modify or mediate the association between neuropathology and cognition are also discussed. It is hypothesized that the concept of resilient aging can serve as a useful entity in understanding mechanisms that underlie healthy aging amidst disease-related pathology.

Both Alzheimer's disease type pathology (neuritic plaques and neurofibrillary tangles) and evidence of atherosclerosis and infarcts are common in autopsy specimens from the brains of patients enrolled in longitudinal prospective cohorts; the relative contribution of each of these to overall cognitive function is unclear. In addition whether each of these two forms of brain pathology can accelerate the appearance of the other is also unclear. In this paper we examine the relationship among Alzheimer's brain pathology, cerebral infarcts and cerebral atherosclerosis. We conclude that each is an independent predictor of dementia. Moreover we do not find that atherosclerosis increases Alzheimer's type brain pathology or vice versa.

A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, such as the specificity of risk for AD vs. other forms of dementia, and the specific links between premorbid intelligence and development of the neuropathology characteristic of AD. Lower premorbid intelligence has also emerged as a risk factor for greater mortality across myriad health and mental health diagnoses. Genetic covariance contributes importantly to these associations, and pleiotropic genetic effects may impact diverse organ systems through similar processes, including inefficient design and oxidative stress. Through such processes, the genetic underpinnings of intelligence, specifically, mutation load, may also increase the risk of developing AD. We discuss how specific neurobiologic features of relatively lower premorbid intelligence, including reduced metabolic efficiency, may facilitate the development of AD neuropathology. The cognitive reserve hypothesis, the most widely accepted account of the intelligence-AD association, is reviewed in the context of this larger literature.

Cognitive reserve explains why those with higher IQ, education, occupational attainment, or participation in leisure activities evidence less severe clinical or cognitive changes in the presence of age-related or Alzheimer's disease pathology. Specifically, the cognitive reserve hypothesis is that individual differences in how tasks are processed provide reserve against brain pathology. Cognitive reserve may allow for more flexible strategy usage, an ability thought to be captured by executive functions tasks. Additionally, cognitive reserve allows individuals greater neural efficiency, greater neural capacity, and the ability for compensation via the recruitment of additional brain regions. Taking cognitive reserve into account may allow for earlier detection and better characterization of age-related cognitive changes and Alzheimer's disease. Importantly, cognitive reserve is not fixed but continues to evolve across the lifespan. Thus, even late-stage interventions hold promise to boost cognitive reserve and thus reduce the prevalence of Alzheimer's disease and other agerelated problems.

Changes in regional activity levels and network connectivity occur across the lifespan within the default mode network (DMN) of resting brain function. Changes with age are noted in most components of the DMN, especially in medial frontal/anterior cingulate and posterior cingulate/precuneus regions. Individuals with age-related disease such as mild cognitive impairment (MCI) and Alzheimer's disease (AD) demonstrate additional default-related changes particularly in posterior cingulate/precuneus and hippocampal regions. As these regions are areas of known pathologic change in both normal aging and age-related disease, examining DMN activity may allow future studies to more fully assess the relationship between pathology and function in these regions. The ability to form this structure-function link could allow us to determine critical factors involved in the decline or preservation of function in the presence of age-related neuropathology.

PET imaging agents such as Pittsburgh compound B (PiB) allow detection of fibrillar β-amyloid (Aβ) in vivo. In addition to quantification of Aβ deposition in mild cognitive impairment and Alzheimer's disease, PiB has also increased our understanding of Aβ deposition in older adults without cognitive impairment. In vivo Aβ deposition has been studied in relation to genotype, structural and functional brain changes, as well as alterations in biomarker levels. To date, several studies have reported changes in Aβ burden over time. This, together with investigation of the relationship between Aβ deposition and cognition, sets the stage for elucidation of the temporal sequence of the neurobiological events leading to cognitive decline. Furthermore, correlation of Aβ levels detected by PiB PET and those obtained from biopsy or postmortem specimens will allow more rigorous quantitative interpretation of PiB PET data in relation to neuropathological evaluation. Since the first human study in 2004, in vivo amyloid imaging has led to advances in our understanding of the role of Aβ deposition in human aging and cognitive decline, as well as provided new tools for patient selection and therapeutic monitoring in clinical trials.

Background: The Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) is the most widely used cognitive outcome measure in AD trials. Although errors in administration and scoring have been suggested as factors masking accurate estimates and potential effects of treatments, there have been few formal examinations of errors with the ADAS-cog. Methods: We provided ADAS-cog administration training using standard methods to raters who were designated as experienced, potential raters by sponsors or contract research organizations for two clinical trials. Training included 1 hour sessions on test administration, scoring, question periods, and required that raters individually view and score a model ADAS-cog administration. Raters scores were compared to the criterion scores established for the model administration. Results: A total of 108 errors were made by 80.6% of the 72 raters; 37.5% made 1 error, 25.0% made 2 errors and 18.0% made 3 or more. Errors were made in all ADAS-cog subsections. The most common were in word finding difficulty (67% of the raters), word recognition (22%), and orientation (22%). For the raters who made 1, 2, or ≫ 3 errors the ADAS-cog score was 17.5 (95% CI, 17.3 - 17.8), 17.8 (17.0 - 18.5), and 18.8 (17.6 - 20.0), respectively, and compared to the criterion score, 18.3. ADAS-cog means differed significantly and the variances were more than twice as large between those who made errors on word finding and those who did not, 17.6 (SD=1.4) vs. 18.8 (SD=0.9), respectively (χ2 = 37.2, P<001). Conclusions: Most experienced raters made at least one error that may affect ADAS-cog scores and clinical trials outcomes. These errors may undermine detection of medication effects by contributing both to a biased point estimate and increased variance of the outcome.

Basal synaptic transmission and activity-dependent synaptic plasticity were evaluated in superior cervical sympathetic ganglia (SCG) of amyloid-β rat model of Alzheimer's disease (Aβ rat) using electrophysiological and molecular techniques. Rats were administered Aβ peptides (a mixture of 1:1 Aβ1-40 and Aβ1-42) by chronic intracerebroventricular infusion via 14-day mini-osmotic pumps (300 pmol/day). Control rats received Aβ40-1 (inactive reverse peptide: 300 pmol/day). Ganglionic compound action potentials were recorded before (basal) and after repetitive stimulation. In isolated SCG, ganglionic long-term potentiation (gLTP) was generated by a brief train of stimuli (20Hz for 20s) and ganglionic long-term depression (gLTD) was produced with trains of paired pulses. The input/output (I/O) curves of ganglia from Aβ rats showed a marked downward shift along all stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission. In addition, repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals, but, the same protocols failed to induce gLTP or gLTD in ganglia from Aβ rats indicating impairment of activity-dependent synaptic plasticity in these animals. Western blotting of SCG homogenate from Aβ rats revealed reduction in the ratio of phosphorylated-/total-CaMKII and in calcineurin protein levels. Although other mechanisms could be involved, these changes in signaling molecules could represent an important molecular mechanism linked to the failure to express synaptic plasticity in Aβ rat ganglia. Results of the current study could explain some of the peripheral nervous system manifestations of Alzheimer's disease.

Amyloid beta (Aβ) peptides are related to the pathogenesis of Alzheimer's disease (AD). The search for therapeutic strategies that lower these peptides has mainly focused on the proteolytic processing of the β-amyloid precursor protein (APP), and other post-transcriptional pathways. The transcription factor specificity protein 1 (Sp1) is vital for the regulation of several genes involved in AD including APP and the beta site APP cleaving enzyme 1 (BACE1). We have previously reported that tolfenamic acid promotes the degradation of Sp1 protein (SP1) in pancreatic human cancer cells and mice tumors. This study examines the ability of tolfenamic acid to reduce SP1 levels, and thereby decrease APP transcription and Aβ levels in rodent brains. Tolfenamic acid was administered by oral gavage to C57BL/6 mice at variable dosages and for different time periods. Results have shown that tolfenamic acid was able to downregulate brain protein levels of SP1, APP, and Aβ. These findings demonstrate that interference with upstream transcriptional pathways can lower pathogenic intermediates associated with AD, and thus tolfenamic acid represents a novel approach for the development of a therapeutic intervention for AD.

Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.

It has been demonstrated that the onset and progression of Alzheimer's disease (AD) are associated with inflammatory disorders in the brain. Although the interactions of inflammatory cytokines with neurotrophins have been reported in vitro, the balance change between inflammatory cytokines and neurotrophic factors (NTFs), such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), due to amyloid β (Aβ) chronic administration in vivo is still unclear. The hypothesis of the present study was that the accumulation of Aβ activated glial cells to produce inflammatory mediators and NTFs to maintain the neurons survival, however the failure of crosstalk between NTFs and inflammatory cytokines might occur in the brain and the NTFs expressions would decrease after Aβ chronic treatment, which, therefore, would contribute to the neuronal death and memory impairments. Thus, the present study measured the learning and memory behavior, glial cells activities, cytokines (IL-1α, IL-1β and TNF-α) concentrations and NTFs (NGF, BDNF and GDNF) gene and protein levels in rats after i.c.v injection of Aβ25-35 for 14 days. The results showed that Aβ25-35-treated animals exhibited failure of balance between inflammatory cytokines and NTFs system (increased cytokines levels, decreased NGF protein expression and reduced NTFs gene transcriptions), which might contribute to the cognitive impairments. The findings from this study provide valuable evidence that correct regulation of the crosstalk between inflammatory cytokines and NTFs could be a direction for AD therapy in the future.

Missing data are frequent in Alzheimer's disease (AD) trials due to the age of participants and the nature of the disease. This can lead to bias and decreased statistical power. We assessed the level and causes of missing data in a 2-year randomised trial of an AD patient management program (PLASA study), and conducted sensitivity analyses on the primary endpoint (functional decline), using various methods for handling missing data: complete case, LOCF, Z-score LOCF, longitudinal mixed effects model, multiple imputation. By 2 years, 32% of the 1131 subjects had dropped out, with the commonest reasons being death (28% of dropouts) and refusal (22%). Baseline cognitive and functional status were predictive of dropout. All sensitivity analyses led to the same conclusion: no effect of the intervention on the rate of functional decline. All analyses demonstrated significant functional decline over time in both groups, but the magnitude of decline and between-group (intervention versus usual care) differences varied across methods. In particular, the LOCF analysis substantially underestimated 2-year decline in both groups compared to other methods. Our results suggest that data were not “missing completely at random”, meaning that the complete case method was unsuitable. The LOCF method was also unsuitable since it assumes no decline after dropout. Methods based on the more plausible “missing at random” hypothesis (multiple imputation, longitudinal mixed effects models, z-score LOCF) appeared more appropriate. This work highlights the importance of considering the validity of the underlying hypotheses of methods used for handling missing data in AD trials.

Alzheimer's disease, one of the most common forms of dementia, is a neurodegenerative disorder characterized by progressive cognitive decline and affects as many as 5.3 million people in United States alone. Both Alzheimer's and dementia have tripled the cost of health care for elderly people, amounting to about $148 billion each year. Although there have been numerous drugs designed so far, no ideal or successful drug treatment for Alzheimer's and dementia has been translated into clinical setups. One of the most widely accepted theories of Alzheimer's pathology is the aggregation of amyloid-beta (Aβ) into extracellular cortical and hippocampal plaques. It has also been postulated that excessive cholesterol build-up in the brain plays an integral role in Aβ aggregation, and using HMG-coA reductase inhibitors may reduce Aβ accumulation by lowering brain cholesterol levels. Based on the success of animal studies and phase II clinical trials, HMG-coA reductase inhibitors may provide a viable alternative therapy in AD treatment. This review highlights the results of both pre-clinical and clinical trials on HMG-coA reductase inhibitors in order to give a comprehensive overview of their recent progress in Alzheimer's disease research.