Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Hypothesis on the regulation of cytosol calcium concentration and the aging brain.

This commentary proposes that neurobiology of aging must look beyond the issue of age related changes in calcium concentrations within the cytosol. The more important question is what causes these changes. Studies of structure, function, and dynamics of membranes may begin to give a better clue about underlying mechanisms of these changes.

Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities.

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.

Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: a study utilizing lead-exposed rats.

The effects of methylphenidate (MPH) and the cholinergic agonists nicotine and oxotremorine were tested on the spontaneous multiple unit activity in the mesencephalic reticular formation of two groups of rats. In control rats i.v. MPH (1 mg/kg), nicotine (0.125 mg/kg), and oxotremorine (0.5 mg/kg) all attenuated the unit activity with latencies of less than 10 min. In another group of rats, exposed to lead acetate since birth, the extent of attenuation of unit activity induced by MPH and nicotine was reduced and the latency of effect was delayed by 45--50 min. The latency of the oxotremorine effect was not changed but the attenuation of unit activity was more pronounced in the lead-treated group. Pretreatment with spiroperidol, to inhibit the aminergic receptors, diminished the inhibitory effect of MPH in the control group but not in the lead-treated group, whereas the attenuating effect of oxotremorine was not affected in either group. These data support our previous evidence that MPH exerts its action in the central nervous system by a cholinergic pathway in addition to published catecholaminergic pathways. Furthermore, the present findings indicate that chronic lead-exposure in rats results in cholinergic hypofunction and supersensitivity at central cholinergic receptor sites. This alteration of central cholinergic function may be partially attributed to the malnutrition observed in the lead-exposed animals.

Toward a comprehensive theory of Alzheimer's disease--challenges, caveats, and parameters.

The task of developing a unifying theory of Alzheimer's disease faces several impediments. The most difficult include: the impact of scientific orthodoxy on the acceptance of new ideas; the uncertain relationship between aging and disease(s); the long time course of the degenerative process; the heterogeneity in the genotype and phenotype of the disease; the complex interactions among genetic and other risk factors (many of which are not yet known); the poorly understood nonlinear relationships between the neurobiological and the clinical phenotypes of the disease--namely, viewing clinical symptoms as emergent behavior(s) of a complex system; and the paucity of appropriate models or modeling systems for human disease(s) such as Alzheimer's.

Prospects of developing interventions to prevent Alzheimer's disease.

Based largely on recommendations of scientists from around the world, it is possible to discover treatments designed to maintain independent functioning of patients with Alzheimer's disease. It is hoped that discussion of critical targets for intervention, and possible strategies for altering the degenerative course of the disease will spur interested groups into action.

A proposed strategy for international collaborative research in brain aging and Alzheimer's disease.

A description and discussion are given of several of the programmes initiated by the United States' National Institute on Aging that could be expanded to facilitate multicentre collaboration studies. It includes: the Alzheimer's Disease Research Centers; the Alzheimer's Disease Patient Registry Program; the World Health Organization Special Programme for Research on Aging; and how collaborative links with scientists working on this disease in other countries may be established.

Report of the task force on designing clinical trials in early (predementia) AD.

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD. RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods. CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.