Can we prevent Alzheimer's disease? Secondary “prevention” trials in Alzheimer's disease

Current research including the basic biology of Alzheimer's disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimer's Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimer's dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimer's Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.     

Can we do better in developing new drugs for Alzheimer's disease?

The past 30 years have seen multiple attempts at demonstrating the safety and efficacy of drugs for Alzheimer's disease (AD), predominantly to improve symptoms. Only five drugs (tacrine, donepezil, rivastigmine, galantamine, memantine) have obtained regulatory approval in most countries. Their cost-effectiveness from a societal perspective has not been universally recognized, and anybody who thinks these drugs are useful for individual patients will have to agree that the improvement above the starting point of treatment is moderate. Most of the benefit has been in slowing down progression of symptoms rather than a readily detectable improvement above baseline. There have also been attempts at arresting progression of AD, but all have failed until now. Should we change our approach to developing new drugs for AD so as to move forward? This review will highlight some options to consider in the development of future drugs for AD, with emphasis on strategies to prevent AD or arrest its progression.     

Can mouse models mimic sporadic Alzheimer's disease?

Alzheimer's disease(AD) is a progressive neurodegenerative disorder and the most common form of dementia worldwide. As age is the main risk factor, 97% of all AD cases are of sporadic origin, potentiated by various risk factors associated with life style and starting at an age 60 years. Only 3% of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2, and symptoms already start at an age 30 years. In order to study progression of AD, as well as therapeutic strategies, mouse models are state-of-the-art. So far many transgenic mouse models have been developed and used, with mutations in the APP or presenilin or combinations(3×Tg, 5×Tg). However, such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop. Several risk genes, such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD, but also many risk factors associated with life style(e.g., diabetes, hypercholesterolemia, stress) may play a role. In this review we discuss the current situation regarding AD mouse models, and the problems to develop a sporadic mouse model of AD.     

Why have we failed to cure Alzheimer's disease?

There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.     

Can patients with Alzheimer's disease learn a category implicitly?

Can a person with a damaged medial-temporal lobe learn a category implicitly? To address this question, we compared the performance of participants with mild Alzheimer's disease (AD) to that of age-matched controls in a standard implicit learning task. In this task, participants were first presented a series of objects, then told the objects formed a category, and then had to categorize a long sequence of test items [Knowlton B. J., Squire L. R. (1993). The learning of categories: parallel brain systems for item memory and category knowledge. Science, 262, 1747-1749]. We tested the hypotheses that: (1) both Control and AD participants would show evidence for implicit learning after the unwanted contribution of learning during test is removed; (2) the degree of implicit learning is the same for AD and Control participants; (3) training with exemplars that are highly similar to an unseen prototype will lead to better implicit category learning than training with exemplars that are less similar to a prototype. With respect to the first hypothesis, we found that both AD and Control participants performed better on tests of implicit learning than could be attributed to just learning on test trials. We found no clear means for evaluating our second hypothesis, and argue that comparisons of the degree of implicit learning between patient and control groups in this paradigm are confounded by the contribution of other memory systems. In line with the third hypothesis, only training with similar exemplars resulted in significant implicit category learning for AD participants.     

Molecular genetics of Alzheimer's disease: what have we learned?

Alzheimer's disease (AD), by far the most common form of dementia in the elderly, is clinically characterized by gradual, progressive loss in cognitive functioning and changes in personality, ultimately leading to death. It is now well established that genetic factors play an important role in AD. So far, three genes have been identified in which mutations cause autosomal-dominant AD: the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the homologous presenilin 2 (PSEN2) gene on chromosome 1. A major susceptibility gene, the apolipoprotein E (APOE) gene, was identified on chromosome 19.     

Can episodic memory tasks differentiate semantic dementia from Alzheimer's disease?

The performance of two groups of patients with semantic dementia (SD), with predominant right (SDR) and left temporal lobe atrophy (SDL), was contrasted with that of cases with probable Alzheimer's disease (AD) on a range of standard episodic memory tasks. While the SDL group achieved a good score on a composite visual, but not a verbal, episodic memory measure, the AD and SDR groups were equivalently impaired at visual and verbal memory. The SD, but not the AD, groups were, by definition, impaired on simple tests of semantic memory. Standard verbal episodic memory tests, therefore, failed to discriminate patients with SD from those with probable AD and even visual memory tests may result in misclassification of SDR cases.     

Biomarkers in the diagnosis of Alzheimer's disease: are we ready?

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.     

Can Alzheimer's type pathology influence the clinical phenotype of Parkinson's disease?

OBJECTIVES: Patients with clinical and pathological diagnosis of Parkinson's disease (PD) may, at death, also be found to have the pathological changes of Alzheimer's disease (AD). With this study we aim to determine the influence of AD pathology on the clinical phenotype of PD. METHODS: We studied 64 patients who donated their brains to the University of Miami Brain Endowment Bank(TM) and fulfilled the clinical and pathological criteria for PD. For the evaluation of AD pathology we used the CERAD criteria. Dementia was diagnosed, in life, also using standard criteria. Case histories were abstracted and reviewed by one investigator (SP) who then made comparisons between patients. RESULTS: Patients with AD pathology (PD-AD) were older both at the time of diagnosis and death. The presence of AD pathology did not seem to influence disease duration in our cohort of PD patients. As expected there was a clear relation between AD pathology and dementia but not all PD-AD patients were demented. Psychosis and depression were also found to be more prevalent in the PD-AD patients. In the comparison between demented and non-demented PD-AD patients dementia was more likely to appear in patients with PD and definite criteria for AD. CONCLUSION: Apart from dementia AD pathology seems to be associated with a number of other clinical characteristics of PD.