Toward a Unifying Hypothesis in the Development of Alzheimer's Disease

The thesis of the article by Martorana et al. [1] “Beyond the cholinergic hypothesis. Do current drugs work in Alzheimer’s disease? ” is that despite the observations showing an association between acetylcholine (ACH) deficiency and cognitive decline in Alzheimer’s disease (AD) patients, results of clinical trials studying the efficacy of agents which increase the availability of ACH demonstrate only temporary symptomatic relief. A further comment implicates dysfunction of other neurotransmitters as playing a role in the symptom complex observed in AD and recommends further exploration of these disturbed relationships as a future research direction. The identification of neurotransmitter dysfunction has resulted in a major focus on symptom relief, but the discussion should explain the initiation of the disease and account for the large population that develops the illness. The neurotransmitter model is based upon knowledge of specific brain function at specific anatomical sites. This provides a valuable clue in connecting structure to function and implicates basal forebrain nuclei in early deficits of the AD patient. This model does identify vulnerable anatomical sites but falls short in explaining why and how these sites are targeted in AD pathogenesis. Finding a solution to understanding Alzheimer’s disease requires a unifying hypothesis. Up to now, the leading hypotheses have focused on three major themes, neurotransmitter dysfunction, the amyloid cascade, and the role of tau in the formation of neurofibrillary tangles. Perhaps this reflects an over reliance on information derived from studies of genetically associated AD (∼5%), leading us to ignore environmental factors that may influence the course of the disease in the much more frequent sporadic form of the illness (∼95%). Prevailing thought indicates that amyloid deposition or failure to dispose of excess amyloid leads to dysfunction at the synapse and eventually to tangle formation. However, initiation of this sequence has not been explained and may be the reason effective therapy has not yet been developed despite decades of effort. The question that must be asked is “what trigger(s) lead to these events? ” There is growing interest in the concept which proposes that most sporadic AD is initiated long before evidence of cognitive decline becomes apparent. Under this concept, the complexity of the neurotransmitter dysfunction observed more likely represents individual variation in the response to a chronic process much as one would predict when a stochastic model is applied to the perturbation of an orderly system. Rather than focusing on symptomatic relief, consideration of a broader model that includes mechanisms of disease initiation and progression as well as early identification of high-risk patients supports the structure of a novel unifying hypothesis. This unified model opens the door to consider new approaches to prevention and therapy. A clue to the localization of damage and the sequence of events may come from the observed functional change in the sense of smell that often precedes loss of cognitive function [2,3]. Documentation of olfactory deficits in AD as well as in Parkinson’s disease demonstrates that the deficit precedes classical clinical signs by several years [4]. In fact, recognition that the loss of the sense of smell is an early symptom of AD suggests that the olfactory system may hold the key to the location and origin of triggering events leading to amyloid production/processing/deposition and secondarily to ACH neurotransmitter and other deficits. Experimental evidence in rodents has demonstrated that bulbectomy results in degeneration within the temporal cortex, hippocampus, and raphe nucleus, decreased numbers of cholinergic neurons in the basal forebrain, and increased levels of β-amyloid in limbic structures including the hippocampus [5–7]. ACH-producing cells in the basal nucleus as well as projections from the olfactory system innervate limbic regions of the brain including the amygdala and hippocampal formation demonstrated to have the earliest pathology in AD. Atrophy in the hippocampus and entorhinal cortex as demonstrated by MRI has been shown to correlate with changes in cognition [8]. The proposed model offers a contrast to the presumption that olfactory deficit is a result of disease rather than a precursor to it and furthermore incorporates the chronic nature of the disease process in the sequence of events leading to disease.