Alzheimer's Disease

Alzheimer’s disease is a progressive neurodegenerative disorder,
Alzheimer's disease is a very common memory disorder found in older adults and sometimes but very rarely found in young adults, affecting an estimated 15 million people world wide and 2.4 million americans. Performance of patients with mild to moderate Alzheimer’s disease was compared with the performance of age matched healthy adults. Researchers concluded the study with findings that showed reduced short-term memory recall for Alzheimer’s patients.
As the disorder progresses, some people with Alzheimer disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. People with this disease usually require total care during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting (inanition).
Alzhimers diseases is one of the most common causes of deterioration in the brain and is responsible for 50-60% of overall dementia among people of over 65 years of age(J Neurol Neurosurg Psychiatry 1999;66:137-147) The disease is expected to increase substantially over the next 20-30 years.
Alzheimer's disease has a mean duration of around 8.5 years between onset of clinical symptoms and death. Brain regions that are associated with higher mental functions, particularly the neocortex and hippocampus, are those most affected by the characteristic pathology of Alzheimer’s disease. This includes the extracellular deposits of β-amyloid (derived from amyloid precursor protein; APP). Alzheimer's disease pathogenesis is believed
to be triggered by an accumulation of the amyloid-β peptide (A-β), which is due to an overproduction of Aβ and/or the failure of clearance mechanisms. This β-amyloid forms diffuse and neuritic plaques in the parenchyma and blood vessels. Aβ self-agggerates into oligoers and plaques are potent synaptotoxins, block proteasome functions, inhibit mitochondrial activity, alter intercellular Ca^2+ levels and stimulate inflammatory processes.Loss of normal physiological functions of Aβ is also though to contribute to neuronal dysfunction.
Imaging technologies, including new amyloid imaging agents based on the chemical structure of histologic dyes, are now making it possible to track amyloid pathology along with disease progression in the living patient. Interestingly, these approaches indicate that the Abeta deposited in AD is different from that found in animal models. In general, deposited Abeta is more easily cleared from the brain in animal models and does not show the same physical and biochemical characteristics as the amyloid found in AD. This raises important issues regarding the development and testing of future therapeutic agents.
Cholinomimetic therapy in Alzheimer’s disease
A prediction of the cholinergic hypothesis is that drugs that potentiate central cholinergic function should improve cognition and perhaps even some of the behavioural problems experienced with Alzheimer’s disease. There are a number of approaches to the treatment of the cholinergic deficit in Alzheimer’s disease, most of which have initially focused on the replacement of ACh precursors (choline or lecithin) but these agents failed to increase central cholinergic activity. Other studies have investigated the use of ChE inhibitors that reduce the hydrolysis of ACh for example, physostigmine. More recent investigational compounds include specific M1 muscarinic or nicotinic agonists, M2 muscarinic antagonists, or improved “second generation” ChE inhibitors (table).

Most cases of early-onset Alzheimer disease are caused by gene mutations that can be passed from parent to child. Researchers have found that this form of the disorder can result from mutations in one of three genes: APP, PSEN1, or PSEN2. When any of these genes is altered, large amounts of a toxic protein fragment called amyloid beta peptide are produced in the brain. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer disease. A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder.
he systematic biochemical investigation of the brains of patients with Alzheimer’s disease began in the late 1960s and early 1970s. The hope was that a clearly defined neurochemical abnormality would be identified, providing the basis for the development of rational therapeutic interventions analogous to levodopa treatment of Parkinson’s disease. Support for this perspective came in the mid-1970s with reports of substantial neocortical deficits in the enzyme responsible for the synthesis of acetylcholine (ACh), choline acetyltransferase (ChAT). Subsequent discoveries of reduced choline uptake, ACh release and loss of cholinergic perikarya from the nucleus basalis of Meynert confirmed a substantial presynaptic cholinergic deficit.
These studies, together with the emerging role of ACh in learning and memory, led to the “cholinergic hypothesis of Alzheimers disease” (figure A). Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contributed significantly to the deterioration in cognitive function seen in patients with Alzheimer’s disease.

Neurochemical and histopathological changes in cholinergic and non-cholinergic neurons in Alzheimer’s disease

At postmortem, Alzheimer’s disease is characterised by neuronal loss and neurofibrillary tangle formation in circumscribed regions of the neocortex and hippocampus, primarily affecting pyramidal neurons and their synapses.10 11 Neurotransmitter specific subcortical nuclei that project to the cortex are also affected by neurodegenerative processes, including the cholinergic nucleus basalis of Meynert and medial septum, the serotonergic raphe nuclei, and the noradrenergic locus coeruleus.
Biochemical investigations of biopsy tissue taken from patients with Alzheimer’s disease 3.5 years (on average) after the onset of symptoms indicate that a selective neurotransmitter pathology occurs early in the course of the disease.12 Specifically, presynaptic markers of the cholinergic system appear uniformly reduced. This is exemplified by reductions in ChAT activity and ACh synthesis which are strongly correlated with the degree of cognitive impairment in patients with Alzheimer’s disease. Whereas serotonergic and some noradrenergic markers are affected, markers for dopamine, γ-aminobutyric acid (GABA), or somatostatin are not altered. When postmortem studies of Alzheimer’s disease brain are considered (typically representing a later stage of the disease) many more neurotransmitter systems are involved or are affected to a greater extent. These include GABA and somatostatin and may indicate that cortical interneurons, for which these are neurochemical markers, are affected later in the disease process. Based on postmortem studies, however, changes in serotonergic neurotransmission may be linked to the behavioural disturbances of Alzheimer’s disease such as depression, rather than cognitive dysfunction.
On the basis of the above evidence, neocortical cholinergic innervation is probably lost at an early stage of the disease, a conclusion substantiated by evidence for similar changes in patients that have displayed clinical symptoms for less than 1 year. However, although the loss of cholinergic function is correlated with the cognitive impairment in Alzheimer’s disease, an association between two such indices does not necessarily indicate a causal relation. Other indices also correlate with measures of cognitive decline in Alzheimer’s disease, such as loss of synapses and pyramidal cell perikarya. Moreover, a few patients with Alzheimer’s disease do not show large decreases in ChAT activity, albeit that a small reduction is found in the amygdala. In addition, patients with inherited olivopontocerebellar atrophy have diminished ChAT activity of a magnitude similar to that seen in Alzheimer’s disease in the absence of cognitive deficits. Thus, although diminished ChAT activity is a necessary correlate of Alzheimer’s disease, additional factors other than impaired cholinergic function are likely to participate in the decline in cognitive function. Other studies have demonstrated a reduction in the number of nicotinic and muscarinic (M2) ACh receptors in Alzheimer’s disease brains, most of which are considered to be located on presynaptic cholinergic terminals, but a relative preservation of postsynaptic muscarinic (M1, M3) receptors. However, there is some evidence for a disruption of the coupling between the muscarinic M1 receptors, their G-proteins, and second messenger systems.
In addition to cholinergic dysfunction, other strong correlates of dementia are the chemical and histopathological markers of excitatory amino acid (EAA) releasing cortical pyramidal neurons. These neurons, considered to contribute to normal cognitive function in their own right, also seem to have a pivotal role in cholinergic function as they are cholinoceptive. Although neurochemical studies of EAA neurotransmission have failed to show profound or extensive alterations in EAA neuronal indices, this may be related to the difficulty in distinguishing the transmitter pool of aspartate and glutamate from the metabolic pool. Nevertheless, glutamate concentration was reduced by 14% in temporal lobe biopsy samples of patients with Alzheimer’s disease. Greater reductions were evident at postmortem in regions enriched with EAA nerve terminals. Uptake of D-aspartate, a putative marker of EAA nerve endings, is also reduced in many cortical areas in Alzheimer’s disease brains.
Arguably, in vivo imaging studies of patients with Alzheimer’s disease also support the involvement of pyramidal neurons in the disease as the pattern of regional hypometabolism parallels neuronal loss/atrophy, tangle formation, and synapse loss. Loss of cortical pyramidal neurons, synapse loss and reduced glutamate concentration, together with the formation of neurofibrillary tangles, all correlate with the severity of dementia. These findings indicate that pyramidal neurons and their transmitter glutamate (and/or aspartate) play a part in the cognitive symptoms of Alzheimer’s disease and may therefore represent an additional therapeutic target. However, these neurons are cholinoceptive and it is reasonable to propose that one of the actions of cholinomimetic drugs for the treatment of Alzheimer’s disease is to increase the activity of EAA neurons through muscarinic and nicotinic receptors that are present on such cells. This is supported by electrophysiological studies showing the excitatory actions of cholinomimetic drugs in cortical pyramidal neurons from both rats and humans and microdialysis studies in rats. Clearly, as a result of cholinergic and other pyramidal neuronal loss, the profound reduction in EAA neurotransmission will lead to pyramidal hypoactivity compounded by maintained levels of inhibition by GABAergic neurons. Consequently, it may be hypothesised that in addition to the deleterious effects of neuronal loss and tangle formation, there is a change in the balance of neurotransmission in the Alzheimer’s disease brain favouring lower neuronal activity. This may be reflected in the hypometabolism in patients with Alzheimer’s disease seen with imaging techniques, although a component of this is also likely to be due to neuronal atrophy. Likewise, it is of interest that regional cerebral blood flow may be increased in patients with Alzheimer’s disease by cholinesterase (ChE) inhibitors such as physostigmine.

Cholinomimetic therapy in Alzheimer’s disease

A prediction of the cholinergic hypothesis is that drugs that potentiate central cholinergic function should improve cognition and perhaps even some of the behavioural problems experienced with Alzheimer’s disease. There are a number of approaches to the treatment of the cholinergic deficit in Alzheimer’s disease, most of which have initially focused on the replacement of ACh precursors (choline or lecithin) but these agents failed to increase central cholinergic activity. Other studies have investigated the use of ChE inhibitors that reduce the hydrolysis of ACh for example, physostigmine. More recent investigational compounds include specific M1 muscarinic or nicotinic agonists, M2 muscarinic antagonists, or improved “second generation” ChE inhibitors (table).