The pharmacogenomics of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder mostly affecting geriatric patients worldwide. The high emotional and economic impact of AD on patients, families, and the society has made AD one of the paramount geriatric syndromes. Efforts to find disease-modifying therapy have not yet been rewarding. Despite our increasing appreciation of the role of genetics in AD pathogenesis, pharmacogenomic approaches to uncover drug targets have not been extensively explored. The current knowledge of the genetics of both familial and non-familial (sporadic) AD, and the emerging data on the effect of Apolipoprotein E (ApoE) alleles on the response to AD therapeutic agents, is evidence that the potential utility of pharmacogenomics may not be limited to the familial AD (FAD) but provide answers for AD as a whole. The apparent inability of presently available drugs to alter the course of AD could be a signal that it is time to change the way we think about AD therapeutics.     

The role of inflammasome in Alzheimer's disease

Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease with clinical characteristics of memory loss, dementia and cognitive impairment. Although the pathophysiologic mechanism is not fully understood, inflammation has been shown to play a critical role in the pathogenesis of AD. Inflammation in the central nervous system (CNS) is characterized by the activation of glial cells and release of proinflammatory cytokines and chemokines. Accumulating evidence demonstrates that inflammasomes, which cleave precursors of interleukin-1β (IL-1β) and IL-18 to generate their active forms, play an important role in the inflammatory response in the CNS and in AD pathogenesis. Therefore, modulating inflammasome complex assembly and activation could be a potential strategy for suppressing inflammation in the CNS. This review aims to provide insight into the role of inflammasomes in the CNS, with respect to the pathogenesis of AD, and may provide possible clues for devising novel therapeutic strategies.     

The presenilins and Alzheimer's disease

The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi. The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-beta42(43) being produced from the metabolism of the amyloid protein precursor. Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis. Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.      

The EEG spectra of Alzheimer's disease

Sixteen Alzheimer's and 16 non-Alzheimer's dementia patients, the two groups being matched for dementia, as well as 10 normal controls were given an EEG examination with 12 monopolar leads during an awake-resting condition. Power spectra (16 s) were obtained in 12 brain areas for 18 frequency bands (0–36 Hz). An 11-point dementia scale furnished the dementia scores. Analyses of variance were performed. Data confirmed earlier findings of an increase in slow activity and a decrease in fast activity for the demented groups. It further demonstrated that these EEG features were not related to dementia per se since the Alzheimer's group (matched for dementia) exhibited a spectral curve having a maximum at 1 Hz and an exponential asymptotic power characterized by decreasing power with increasing frequency without additional features or remnant of dominant activity. The study demonstrated that the decrease in frequency of alpha activity is perhaps more significant in identifying dementia of the non-Alzheimer type even though this characteristic may be present in the earlier stages of Alzheimer's dementia. It is hypothesized that the characteristics shown by the Alzheimer's group may be related to the presence of neurofibrillary tangles and plaques which are more prevalent in Alzheimer's patients.     

The role of innate immunity in Alzheimer's disease

The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain-resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.     

The cause of neuronal degeneration in Alzheimer's disease

Alzheimer's disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration and the progressive development of dementia. Pathological hallmarks common to the disease include beta-amyloid plaques, dystrophic neurites associated with plaques and neurofibrillary tangles within nerve cell bodies. The exact relationship between these pathological features has been elusive, although it is clear that beta-amyloid plaques precede neurofibrillary tangles in neocortical areas. Examination of the brains of individuals in the preclinical stage of the disease have shown that the earliest form of neuronal pathology associated with beta-amyloid plaques resembles the cellular changes that follow structural injury to axons. Thus, the development of beta-amyloid plaques in the brain may cause physical damage to axons, and the abnormally prolonged stimulation of the neuronal response to this kind of injury ultimately results in the profound cytoskeletal alterations that underlie neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of the neuronal reaction to physical trauma may be a useful neuroprotective strategy in the earliest stages of Alzheimer's disease.     

The role of cerebral ischemia in Alzheimer's disease

The Alzheimer type of dementia and stroke are known to increase at comparable rates with age. Recent advances suggest that vascular risk factors linked to cerebrovascular disease and stroke in the elderly significantly increase the risk of developing Alzheimer's disease (AD). These include atherosclerosis, atrial fibrillation, coronary artery disease, hypertension, and diabetes mellitus. Moreover, review of various autopsy series shows that 60-90% of AD cases exhibit variable cerebrovascular pathology. Although some vascular lesions such as cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions are evident in most cases of AD, a third will exhibit cerebral infarction. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that the co-existence of stroke and AD occurs more than by chance alone. Strokes known to occur in patients with Alzheimer syndrome and most frequently in the oldest old substantially worsen cognitive decline and outcome, implicating some interaction between the disorders. Nevertheless, the nature of a true relationship between the two disorders seems little explored. What predisposes to strokes in underlying cognitive decline or AD? Is it possible that cerebral ischemia is a causal factor for AD? I examined several vascular factors and the vascular pathophysiology implicated in stroke and AD, and propose that cerebral ischemia or oligemia may promote Alzheimer type of changes in the aging brain. Irrespective of the ultimate pathogenetic mechanism, these approaches implicate that management of peripheral vascular disease is important in the treatment or prevention of Alzheimer's disease or mixed dementia.     

Alzheimer's disease

The primary degenerative dementia of Alzheimer type, present denomination, represents a medical, social and economical problem. The early diagnosis, based on medical criteria, might improve some aspects of the expected evolution of these, up to date, hopeless patients.     

The neuropsychology of hydrocephalus.

The relationship between neuropsychological impairment and hydrocephalus is reviewed and three case studies presented. Current brain imaging technology provides a method for detailed quantification of ventricular expansion and alteration or loss of cortical tissue in hydrocephalus. However, there appears to be little systematic relationship between ventricular size in hydrocephalus and the type or degree of neuropsychological impairment. As a group, hydrocephalic patients do demonstrate a variety of cognitive and perceptual-motor deficits, but there does not appear to be a common diagnostic neuropsychological pattern in hydrocephalus although perceptual-motor/manipulo-spatial deficits appear to predominate. It appears that there is considerable neural plasticity that occurs in some patients with congenital hydrocephalus and much of this functional reorganization may take place at subcortical and subtentorial levels. Clinical guidelines for the neuropsychological assessment of hydrocephalus are given.     

The coming problem of HIV-associated Alzheimer's disease

BACKGROUND: Dementia associated with human immunodeficiency virus (HIV) is a subcortical neuropathology that does not resemble Alzheimer's disease. However, several lines of evidence suggest that in the future there may be significant numbers of long-term HIV survivors with true Alzheimer's disease. Age is itself a risk factor Alzheimer's disease, and an aging population and widespread use of highly active antiretroviral therapy (HAART) means more elderly HIV patients. Immune reconstitution inflammatory syndrome, lypodystrophic effects of HAART medications, HIV-induced amyloid deposition and excitotoxic effects of gp120 and TAT protein all could be risk factors for subsequent Alzheimer's disease. Finally, HIV patients will have greater vulnerability to common non-HIV pathogens that may contribute to development of Alzheimer's disease. PRESENTATION OF THE HYPOTHESIS: It is predicted that in the future there will be seen measurable numbers of long-term HIV survivors on HAART who have Alzheimer's disease, with a cortical deficit profile on neuropsychological tests, pronounced cerebral atrophy seen on brain MRI, and neurofibrillary tangles, senile plaques and neuronal loss in post-mortem brain tissue. VALIDATING THE HYPOTHESIS: The hypothesis could be validated through case reports, longitudinal clinical studies, brain bank programs and animal models. IMPLICATIONS OF THE HYPOTHESIS: Management of HIV may become more difficult, requiring greater provisions for long-term care of HIV patients with chronic dementia. However, it may be possible to reduce or prevent HIV-associated Alzheimer's disease through early use of cholinesterase inhibitors, glutamate-blocking drugs, insulin sensitizing agents, statins and anti-oxidants.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.     

The capillary dysfunction hypothesis of Alzheimer's disease

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.     

Acetylcholinesterase in Alzheimer's disease

Since the discovery of the cholinergic deficit in Alzheimer disease (AD), acetylcholinesterase (AChE) has been widely investigated in tissues involved in the disease. These studies showed modifications in AChE activity and changes in its polymorphism in brain as well as in cerebro-spinal fluid (CSF) and blood. The co-localization of the enzyme in the senile plaque provided evidence of its anomalous features. It has been also shown that AChE forms a stable complex with senile plaque components through its peripheral anionic site. Moreover, the neurotoxicity of amyloid components is increased by the presence of AChE. The occurrence of an altered glycosylation of some AChE forms in AD is closely related to the presence of amyloid formations. Literature on expression, relationships and modifications in the molecular polymorphism of AChE, in brain, CSF and blood in AD is reviewed.