Here you'll find links to a selection of recent papers on Alzheimer's disease with no particular central thesis: merely a sampling of representative research results. Alzheimer's research is as much investigation of cellular metabolism and the biochemistry of the brain as it is research into the disease itself. Scientists strive to understand everything that might put the mechanisms of disease development into context. Our neural biochemistry is enormously complex, and thus so is any form of dysfunction in the many interacting systems of the brain. Since there is still so much blank space still left on the comprehensive map of human biochemistry, there are many competing theories to explain the development and pathology of Alzheimer's disease (AD), in part or in whole. Theories proliferate in times of uncertainty, and since therapies emerging from the dominant branch of theories based on amyloid accumulation are still in search of meaningful results, there is plenty of room for heresy, hypothesis, and debate.
It is perhaps ironic that aging has such simple and well-cataloged roots, a few forms of cell and tissue damage that occur as a result of the normal operation of metabolism, and yet the research community spends all of its time working backwards from enormously complicated end states of diseases, where a great deal of time and money are required to make even modest advances in understanding. This makes more sense if one assumes that the goal is less one of treatment and more one of understanding human biochemistry: Alzheimer's disease is the narrow end of the wedge to obtain funding to develop that understanding. That may be part of the problem, that the incentives and the goals for much of the research establishment are not necessarily aligned with rapid progress towards effective treatments. The output of traditional investigation followed by drug discovery is almost entirely marginal treatments that tinker with some aspect of cellular behavior in the late-stage disease process, a far cry from the most effective approach of tackling root causes.
Yet at the same time Alzheimer's research is actually one of the few fields where it is possible to say that at least some within the community work on ways to attack fundamental forms of damage, in the form of amyloid clearance. With enough money and enough different competing research groups, someone somewhere will be close to doing the right thing. Clearance of amyloid is a capability that will be needed for rejuvenation therapies, since the presence of amyloid is a distinguishing difference between old tissues and young tissues. A robust way to clear amyloid in Alzheimer's should require little work to adapt to other forms of amyloid in the body, at which point we might start to see a greater understanding developed as to exactly how and why these deposits contribute to degenerative aging. The fastest way to enlightenment and practical results is often to remove the potential cause of a problem, rather than to keep analyzing the system as it is.
The papers below are illustrative of these points, being representative of several types of output generated by the Alzheimer's research community. Theories abound, as do suggested forms of compensatory treatment, and books can be written to provide an overview of even just aspects of Alzheimer's development in the full context of how the brain works. It is a very complicated business, and some of the approaches to treating Alzheimer's patients are now more than a decade old, still gathering data in search of any benefit.
In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.
Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side. Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.
These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.
Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects.
In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.
Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by aging and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease.
Oxidative stress (OS) has been demonstrated to be involved in the pathogenesis of the two major types of dementia: Alzheimer's disease (AD) and vascular dementia (VaD). Evidence of OS and OS-related damage in AD is largely reported in the literature. Moreover, OS is not only linked to VaD, but also to all its risk factors. Several researches have been conducted in order to investigate whether antioxidant therapy exerts a role in the prevention and treatment of AD and VaD. Another research field is that pertaining to the heat shock proteins (Hsps), that has provided promising findings. However, the role of OS antioxidant defence system and more generally stress responses is very complex. Hence, research on this topic should be improved in order to reach further knowledge and discover new therapeutic strategies to face a disorder with such a high burden which is dementia.
Mitochondrial dysfunction and neuroinflammation occur in Alzheimer's disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While, mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.