INTRODUCTION
It has become increasingly clear that the disease process of Alzheimer’s disease (AD) is multifaceted. Because AD appears to be a complex disorder involving several genes interacting with environmental influences, it is difficult to single out any one factor as the root cause of the disease. Apart from the familial forms of the disease, in which the gene mutations have been elucidated, many post-translational factors are involved in the process of neurodegeneration, in the formation of plaques and tangles and in the development of an inflammatory state of the brain. Although some of these have been found to be altered in AD patients compared with controls, very few markers suitable for antemortem diagnostic purposes have emerged, since many of the alterations are not specific for AD, while others pertain only to subsets of AD1.
While it has been argued that the most powerful antemortem marker in AD is a clinical diagnosis based on an adequate range of observations2, such diagnosis is at present largely one of exclusion. An ideal biological marker would allow for greater specificity and sensitivity than a clinical diagnosis on its own, and be readily obtainable. While neuropathological biopsy diagnosis of AD allows high specificity and sensitivity, it is typically only available postmortem.
The neurobiological alterations present in AD may be reflected in changes in cerebrospinal fluid (CSF) neurotransmitters or neurochem-icals, or changes in systemic tissues including blood constituents. It should be borne in mind, however, that CSF measurements are influenced by a variety of factors, including CSF gradients, age, gen-der, diurnal and seasonal variations, state of the blood–brain barrier, blood contamination, contributions from the spinal cord, phase of illness, psychomotor activity, stress and diet. Measurement of blood constituents may also reflect concentration differences due to diurnal rhythms and other factors.
In this chapter on antemortem markers, we will briefly review neu-rotransmitters, neurochemistry and systemic pathology. We will also briefly address findings in brain imaging, and genomic and proteomic methods.
NEUROTRANSMITTERS AND NEUROCHEMISTRY
The Cholinergic System
Cholinesterase inhibitors (ChEIs) were introduced for the treat-ment of AD following the discovery that cholinergic neurons were depleted, and that cholinergic function was significantly decreased in the basal forebrain of AD patients3. Interestingly, the latter research group recently reported that ChEIs increased the phosphorylation of tau protein4, resulting in a possible decrease in long-term clinical responsiveness to ChEIs. The depletion of membrane choline may also play a role5. CSF markers of cholinergic function, as well as erythrocyte and plasma choline, have been studied as biomarkers for AD, but have not yielded consistent results6. Studies, however, indi-cate differences in the dynamics of RBC choline uptake, consistent with a vulnerability of cholinergic neurons in patients with AD7.
The Noradrenergic System
Autopsy studies of AD brains demonstrate that loss of cells in the locus coeruleus (LC), the major nucleus of origin of noradrener-gic fibres, may undergo even greater degeneration than the nucleus basalis of Meynert8. This raises the question whether the degener-ation of the noradrenergic system would provide markers for AD. Reduced noradrenaline (norepinephrine; NE) in autopsy samples of AD brains has been a fairly consistent finding, although it may be hypothesized that increased activity and turnover of the noradrener-gic system may compensate for cell loss and that a limited number of NE cells remain highly active in AD patients. Loss of NE inner-vation would in addition lead to peripheral effects, such as decreased control of vasoconstriction8. Some patients with advanced AD have biochemical and physiological indices of noradrenergic hyperactivity, including higher heart rate and blood pressure. Severe neuronal loss in advanced AD may lead to a compensatory increase in LC firing rate, contributing to symptoms such as pacing, agitation, insomnia and weight loss. Haglund etal.8 developed a scale for the evalu-ation of LC degeneration in patients with AD, vascular dementia and non-focal ischaemic deep white matter disease (WMD), as part of the ongoing Lund Longitudinal Dementia study. They found that LC degeneration was significantly higher in AD than in vascular dementia cases, and that there was a significant correlation with white matter pathology severity. However, there was no correlation between the degree of LC degeneration and duration of dementia or AD pathology8.
The Serotonergic System
Numerous autopsy studies of AD brains have suggested a serotoner-gic deficit. Although there have been reports that the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), is unchanged in the CSF of AD patients, most studies indicate a reduction in CSF 5-HIAA. In a study by Stuerenburg etal., CSF 5-HIAA correlated with CSF A?42, but not with CSF tau. There was also a signif-icant positive correlation between CSF 5-HIAA and homovanillic acid (HVA) in AD, but neither 5-HIAA nor HVA could differentiate between mild cognitive impairment (MCI), depression and AD9.
Although CSF measures of monoamines have not proven suffi-ciently specific and sensitive for clinical diagnosis, the degree of pineal calcification (DOC) can be used as an intra-individual mela-tonin deficit marker10. Melatonin, the pineal hormone biosynthesized from serotonin, declines with age and more so in AD patients due to calcification of the pineal gland. Mahlberg etal.10 measured the DOC, as well as the size of uncalcified tissue, with computed tomog-raphy (CT) in 279 consecutive memory clinic outpatients. The DOC was significantly higher in AD than in patients with other types of dementia, depression or controls, while the size of uncalcified pineal tissue in AD patients was significantly smaller than in patients of the other three groups10.
Wu and Swaab found that pineal melatonin secretion and pineal clock gene oscillation were disrupted in AD patients, as well as in non-demented controls with early signs of AD neuropathology (neuropathological Braak stages I–II), in contrast to non-demented controls without AD neuropathology11. Furthermore, a functional disruption of the suprachiasmatic nucleus (SCN) was observed from the earliest AD stages onwards, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN.
Taken together, measures of neurotransmitter systems have not provided sufficient sensitivity and specificity to be used for diagnostic purposes in the clinic. Nevertheless, such work has been useful in investigating the pathophysiology of AD.
It is possible to view AD as a systemic illness. Thus, if AD were a genetic disorder, then disturbances at the molecular level may be expressed in non-neural tissue, with systemic effects. Using blood cells for biomarkers has the added advantage of being relatively non-invasive, and techniques such as flow cytometry provide a convenient platform for such analyses. Uberti etal. found that the expression of a conformational mutant of p53 in mononuclear cells was significantly higher in AD patients compared to non-AD subjects. The expression of mutant p53 did not, however, correlate with the duration of illness or disease severity12.
Zainaghi etal. found that an alteration of amyloid precursor protein (APP) fragments in platelets, as measured by Western blot analysis, correlated with cognitive decline in patients with AD13. Platelets contain more than 95% of circulating APP and enzymatically produce both soluble APP and amyloid-beta peptides. It was found that the ratio of 130-to 110-kDa APP fragments in platelets from patients with AD was significantly lower compared to patients with mild cognitive impairment and elderly controls. There was no difference between the latter two groups. The alteration in APP also correlated with membrane fluidity of the platelets13.
Membrane fluidity of platelets as a biomarker for AD has been extensively studied. Increased fluidity was demonstrated in patients with AD compared to patients with vascular dementia and elderly controls. Only about 50% of AD patients, however, demonstrate this abnormality. Increased platelet membrane fluidity (PMF) appears to be a familial trait, and the subgroup of AD patients in whom it manifests suffers from an earlier onset and a more rapidly progressive decline. In a prospective longitudinal study evaluating PMF as a putative risk factor for AD, 9 of 330 people with increased PMF (initially asymptomatic first-degree relatives of probands with AD) developed AD after 7.5 years14. On a biochemical level, it was found that free radical induced lipid peroxidation increased the fluidity of platelet membranes, providing a possible mechanism underlying increased PMF15. This putative marker of AD would hence also be subject to modulation by environmental factors such as a diet rich in antioxidants.
In fibroblasts, abnormalities in enzymatic activity, glucose metabolism, abnormal calcium metabolism, impaired DNA repair as well as potassium channel dysfunction16 have been observed. While studies on blood cells and fibroblasts have advanced our understanding of the mechanisms relevant to AD, they are not sufficiently sensitive or specific for clinical use, once more raising the question of environmental influences.
Protein Abnormalities
The hallmark lesions of Alzheimer’s disease are neurofibrillary tangles, which contain tau protein, and the plaques with deposition of ?-amyloid (A?). Given that the clinical phase of AD may be preceded by a 15–30 year period of deposition of amyloid and tau protein, markers to predict the development of AD should ultimately be obtainable. Several studies have found increased levels of tau protein (total tau as well as phosphorylated tau) and decreased levels of A?(1–42) in CSF17, while the ratio of these two measures has been found to be a highly sensitive discriminator of AD from normal ageing. Maddalena etal. found that the ratio of CSF phospho-tau to A?42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%)18.
Inflammation
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