The majority of biochemical studies of AD have relied on informa tion derived from postmortem brain, which typically represents the late stage of the disease (8-10 years after onset of symptoms). In these studies there is considerable evidence of gross brain atrophy, histopathological features and multiple neurotransmitter abnormali ties affecting many brain regions. However, investigations of biopsy tissue taken from AD patients 3-5 years (on average) after the onset of symptoms indicate that a selective neurotransmitter pathology occurs early in the course of the disease².

Acetylcholine

Changes affecting many aspects of the cholinergic system in patients with AD have been reported since the initial discovery of deficits in choline acetyltransferase activity in postmortem brains^3-5. In biopsy samples from AD patients, presynaptic markers of the cholinergic system were also uniformly reduced². Thus, choline acetyltransferase activity, choline uptake and acetylcholine synthesis are all reduced to 30-60% of control values. The clinical correlate of this cholinergic deficit in AD was, until recently, considered to be cognitive dysfunction. Such a conclusion was supported by clinicopathological studies in AD and parallel experiments in non-human primates or rodents, which demonstrated disruptive effects of basal forebrain cholinergic lesions on cognitive functions. Furthermore, cholinergic deficits in AD occur to the greatest extent in cortical areas primarily concerned with memory and cognition – the hippocampus, adjacent temporal lobe regions and select frontal areas. Such studies led to the ,cholinergic hypothesis of geriatric memory dysfunction,⁶.

Neuropathologically, loss of neurons from the nucleus of Meynert (nbM; Ch4 cholinergic nucleus) is well documented in AD, although the extent of the loss reported varies from moderate to severe, and it has been suggested that in AD cholinergic dysfunction exceeds degeneration⁷. Detailed analysis of subpopulations of cholinergic perikarya in the nbM have been reported by Mesulam and Geula⁸, who identified selective cell loss in Ch4p (the posterior section pro jecting to temporal cortex). In the intermediate sector, Ch4id, which includes projections to the frontal cortex, neuron loss is not as exten sive, consistent with the moderate loss of cholinergic enzyme activity.

On the basis of the above evidence, neocortical cholinergic innervation appears to be lost at an early stage of the disease and this is supported by a study in which the cholinergic deficit (reduced ChAT activity) has been related to Braak stageing⁹. Braak stages I and II are considered to represent the earliest presentation of AD, with neurofibrillary tangles in the entorhinal cortex, and a 20-30% loss of ChAT activity was reported in brains from patients at these stages of AD¹⁰. However, another study using the Clinical Dementia Rating Scale (CDR) suggests that the greatest reduction in markers of the cholinergic system occurs between moderate (CDR 2.0) and severe (CDR 5.0) disease, with little change between non-demented and the mild stage (CDR 0-2)¹¹. Finally, tau and tangle pathology occurs in cholinergic neurons of the nbM during normal ageing and to a greater extent in patients with mild cognitive impairment (MCI), indicating functional changes in cholinergic neurotransmission¹².

There has been a recent shift of emphasis regarding the clinical sig nificance of cholinergic deficits. Non-cognitive or neuropsychiatric, in addition to cognitive, symptoms also appear to have a cholinergic component¹³. For example, visual hallucinations relate to neocortical cholinergic deficits¹⁴, such deficits (e.g. loss of ChAT) being greater in dementia of Lewy bodies (DLB), where hallucinations are common, than in AD, where they are less common¹⁵. Reductions in cortical ChAT activity in patients with dementia, in addition to cor relating with cognitive decline, are also related to overactivity and aggressive behaviour¹⁶.

Glutamate

Approximately 70% of cortical neurons use glutamate as a neuro transmitter and hence the glutamatergic system plays an important role in all regions of the cortex and hippocampus. Evidence for a piv otal role of glutamate in learning and memory is long-established²; indeed, it is likely that any function of a particular cortical region will depend on glutamate neurotransmission at some level. Loss of synapses and pyramidal cell perikarya (both considered to be mark ers of glutamatergic neurons) from the neocortex of AD patients correlate with measures of cognitive decline². From a biochemi cal perspective studying the glutamatergic system is more difficult since the amino acid is present at high concentrations in all cells. However, certain proteins related to glutamatergic neurotransmission provide vital clues to the status of this system in AD. For example, reduced glial glutamate uptake is reported in AD¹⁷, probably reflect ing oxidative damage to the transporters¹⁸,¹⁹. Additionally, there is loss of the vesicular glutamate transporter (VGluT) in several cor tical regions^20,21. Such changes are likely to generate an elevated baseline level of glutamate at the synapse, triggering inappropriate Ca²+ influx. These raised background levels of glutamate impair the usual detection of physiological signals (low signal-to-noise ratio), disrupting normal cognitive processes²². Furthermore, the disruption of vesicular glutamate transport results in less glutamate being stored in presynaptic vesicles, reducing the level of signal upon neurotrans mitter release²⁰.

In addition, soluble oligomers of beta amyloid (Aß) can reduce glutamatergic transmission by inducing the internalization of NMDA receptors²³. This pathological effect has been shown to disrupt NMDA-induced receptor currents, inhibiting long-term potentiation (LTP – synaptic plasticity) and signalling to downstream targets such as Akt (also known as protein kinase B)^23-25.

Other Neurotransmitters

Using biopsy samples from AD patients, serotonergic and some noradrenergic markers are affected, whereas markers for dopamine, Y-aminobutyric acid (GABA) or somatostatin are not altered. When postmortem studies of AD brain are considered, many neurotrans mitter systems, including GABA and somatostatin, are involved or are affected to a greater extent². Based on postmortem studies, how ever, changes in serotonergic neurotransmission may be linked to the behavioural disturbances of AD, such as depression, rather than cognitive dysfunction. For example, patients with AD who were also depressed had lower numbers of serotonin re-uptake sites in the neocortex than did patients without this symptom²⁶. Furthermore, both reduced serotonergic^27,28 and increased noradrenergic activities and sensitivity^29,30 have been linked to aggressive behaviour.

Neurotransmitter Receptors