Hans Förstl

What is AD ?

Gowers wrote in 1902  " in some people a premature aging or degeneration occurs, preferably affecting the central nervous system". When Alzheimer published his famous first case of " Alzheimer's disease" (AD) he was intrigued by the early-onset  of a dementia syndrome and the abundant intraneuronal neurofibrillary tangles in the patient's neocortex, which had never been seen before in a patient with such early onset of illness     . In this patient, the clinical course and the neuropathological changes, particularly the neuronal loss in the superficial layers of the neocortex were excessively severe. Kraepelin (1910)  decided that this presenile form of degenerative dementia with plaques and neurofibrillary tangles should bear Alzheimer's name. This term was reserved for severe forms of presenile dementia with abundant plaques and neurofibrillary tangles, until a number of researchers felt that the clinical and neuropathological differences between the presenile  and the senile manifestations of primary degenerative dementia were insufficient to define separate diagnostic entities (Albert, 1963; Lauter & Meyer, 1968; Corsellis, 1969)      . This new unitarian concept had a number of important implications. The concept of Alzheimer's disease once had a sharp focus and now became extended and softened. Senile dementia could no longer be accepted as the inevitable consequence of normal aging, but became a disease. The number of patients suffering from AD increased enormously. The economic burden and obligation became obvious. The main risk factor could be identified: age.

The size of the problem. The age – or aging –  -associated prevalence, incidence and lethality of AD are described elsewhere in this volume. Decreased mortality has led to a larger number of elderly people in our society, and decreased fertility has contributed to the higher proportion of old people. There are twice as many over 65-, four times as many over 80-, ten times as many over 90-year-olds in Germany today, as compared to the early years of the twentieth century . As age is the single most important demographic risk factor for AD, such considerations of demographic changes are relevant for the single most important mental health problem in our aging society. The growing importance of AD in the basic and clinical sciences is reflected by the growing number of publications (table 1)9. The exponential increase in publications on AD is unparalleled by research on other forms of dementia.

What Alzheimer's Disease is - Clinically

Diagnostic criteria. Clinically AD is a pure dementia without clinical evidence of another underlying specific disease relevant for the observed cognitive impairment. In the last decades, the cognitive paradigm of dementia has prevailed. Common elements of different diagnostic criteria for a dementia syndrome are: (1) secondary, (2) severe, (3) cognitive deficits. The deficits must not be pre-existent. They have to be severe enough  in order to cause a significant impairment of the usual activities of daily living. This secondary impairment must not be explained by physical handicaps, but has to be related to the cognitive deficits. Most diagnostic guidelines consider amnestic deficits as a core feature of the dementia syndrome. A common and critical basic dilemma of all guidelines is the definition of clear thresholds for the distinction between near normal and already pathological cognitive problems. This is an obvious, decisive and unresolved difficulty regarding the measurement of intellectual and behavioural disturbances which usually develop over long periods and on the basis of rather variable levels of premorbid functioning. Erkinjuntti et al. (1997)  demonstrated that different diagnostic criteria yield highly inconsistent results in the definition of the dementia syndrome in elderly individuals. These differences cannot exclusively be explained by different sensitivities of the examined criteria. This general difficulty is particularly pertinent in AD whose major defining criterion is the dementia syndrome. The criteria suggested by McKhann et al. (1984) , the ICD-10  and the DSM-IV  criteria are given in tables 2, 3 and 4. The daily use of such criteria and diagnostic categories misleads us to believe that they stand for natural facts, for nosological entities. But the authors of these operational guidelines clearly stated that they are tentative and in need of further revisions. Their major drawback is a focus on the dementia syndrome instead of the underlying neurobiological disease process. Their advantage is that they state exactly what I am supposed to describe in this chapter.

Clinical symptoms. AD frequently takes a typical clinical course which reflects the underlying neuropathology. The length of the pre-dementia phase cannot be reliably established with today's clinical research tools. Theoretical considerations based on  neuropathological and molecular-biological findings suggest that this subclinical stage of illness may extend over several decades. The clinical stages outlined in the present paper overlap, and patients gradually progress from the mildest to the most severe manifestations of illness.
The pre-dementia stage. Meticulous neuropsychological investigation may reveal very mild cognitive impairment 5 years before the clinical diagnosis of a dementia syndrome can be established according to contemporary diagnostic standards (Linn et al., 1995) . The pattern of the subdiagnostic difficulties includes mild impairment in acquiring new information. Other demanding cognitive tasks, including the ability to plan or to access the semantic memory store, can also be compromised causing similar cognitive problems. The differentiation between incipient AD and a reversible condition (e.g. dementia syndrome of depression) or benign, non-progressive memory impairment is unreliable.  At the pre-dementia stage of AD, patients do not show a significant deterioration in Activities of Daily Living (ADL). At this stage, individuals may take advantage of memory aids and of other supportive strategies to overcome or compensate  their cognitive deficits. The performance of complex work tasks may be reduced. Patients tend to avoid difficult challenges and downplay or dissimulate their problems. In addition, non-cognitive alterations of behaviour, including social withdrawal and depressive dysphoria, may be present 5 years before a clinical diagnosis is made (Jost & Grossberg, 1995) .
Mild dementia stage. In most patients, a significant impairment of learning and memory is the outstanding clinical feature. In some individuals, however, aphasic or visuconstructional deficits may prevail. Short term memory, old declarative memory from the patient's earlier years and implicit memory are affected to a much lesser degree than the declarative recent memory. Memory impairment usually interferes with various cognitive domains and usually plays a key role in the patient's difficulties with ADL. The patient's reduced ability to plan, judge, and organise may not only show in complex tasks, but also in more difficult household chores (managing bank account; preparing meals, ...). Communication may begin to suffer from shrinking vocabulary, decreasing word fluency and less precise expressive language, even though a patient may still appear eloquent, "fluent" and even verbose on casual inspection. An impairment of object naming and semantic difficulties with word generation can be demonstrated by means of neuropsychological tests (Chobor & Brown, 1990; Locascio et al.,1995)   . Constructional apraxia can be revealed on drawing tasks (Moore & Wyke, 1984) . Spatial disorientation frequently causes major problems in driving, as patients are less capable of estimating distances and speed. Because they have an increased risk of accidents, patients with a diagnosis of AD should not be allowed to drive a vehicle (Trobe et al., 1996) . At the mild stage of AD, patients may still be able to live independently for most of the time. But due to the significant cognitive difficulties in several domains, they will need support with a variety of organisational matters. If a patient wishes to remain at home, arrangements for a support system should be made at this stage before a more intensive or permanent supervision is necessary. Non-cognitive disturbances in AD are more frequent than previously thought (Haupt et al., 1992) . Symptoms of depression may prevail in the early stage of illness (Burns et al., 1990) . These emotional disturbances are typically mild and fluctuating, but also full-blown depressive episodes can occur. They may partly represent understandable emotional reactions to reduced cognitive and ADL skills or to reduced social contacts while the patient's insight is, at least, partly retained. Patients with severe depressive disturbances may show reduced cell counts in the locus coeruleus and other aminergic brain stem nuclei (Förstl et al., 1992; Zubenko et al., 1989)   . A reduced dorsofrontal blood flow can be shown in patients with severe apathy (Craig et al., 1996) .
Subtle impairment of complex motor tasks may remain unnoticed on standard neurological examination (Kluger et al., 1997) .
Moderate dementia stage. Due to the severe impairment of recent memory, patients may appear to "live in the past"  (Beatty et al., 1988) . Logical reasoning, planning and organising significantly deteriorate at this stage. Language difficulties become more obvious as word finding difficulties, paraphasia and circumstanciality increase (Romero et al., 1995) . Reading skills deteriorate and the comprehension of texts can be incomplete (Cummings et al., 1986) . Writing becomes increasingly insecure with an increasing number of mistakes and omissions (Neils et al.,1989) . Patients become distractible and gradually lose insight into their condition. Longer (ideomotor) sequences of action can no longer be organised, until finally the skills of using household appliances, dressing, and eating are lost. The patient's spatial disorientation increases (Haupt et al.,1991; Liu et al., 1990)    Cortical visual agnosia is often present and can include the inability to recognise familiar faces (prosopagnosia). One third of AD patients at this stage develop illusionary misidentifications and other delusional symptoms which are triggered by their cognitive deficits, but also the underlying disease process (Förstl et al., 1993; Reisberg et al., 1996)   . Up to 20% of the patients develop hallucinations, mostly of visual quality, which may be associated with a particularly severe cholinergic deficit (Lauter, 1968; 1970; Perry et al., 1990)   . At this stage, anosognosia prevails, but residues of insight may contribute to "catastrophic reactions" following minor distress. Patients often lose emotional control and develop temper tantrums which may be accompanied by physical or verbal aggression. Aimless and restless activity like wandering, hoarding, etc. are common (Devanand et al., 1997) . Patients in this moderate state of illness cannot survive in the community without close supervision. They are incapable of managing financial or legal matters. Household gas or electrical appliances are a constant source of danger to the patients, but also to their carers. Hospital or nursing home admission  may be delayed or even avoided, if a closely knit support system is in place. During this phase, there is a maximum strain on partners and other carers due to the patient's non-cognitive behavioural problems and somatic symptoms (Jost et al., 1995; Steele et al., 1990)15   Restlessness, aggression, disorientation and incontinence are the most frequent factors which precipitate the breakdown of family support (Haupt & Kurz, 1993; Stern et al., 1997)   . Sphincter control is insufficient and can be aggravated by "pseudo-incontinence" as a consequence of spatial disorientation and clumsy handling of clothes. Many patients are at an increased risk of falls provoked by a hesitant, festinating gait and a stooped posture (Förstl et al., 1992)22.
Severe dementia stage. Specific modular cognitive deficits cannot be teased apart at that late stage of illness, when almost all cognitive functions are severely impaired. Even early biographical memories can be lost. Language is reduced to simple phrases or even single words. Patients are increasingly unable to articulate the most simplest of needs. However, many patients can receive and return emotional signals long after the loss of language skills. This emotional receptiveness has to be remembered while the patient is completely dependent on comprehensive nursing care.
Patients often misunderstand and misinterpret nursing interventions, and this may lead to aggressive reactions. Subgroups of patients may develop stereotyped motor programmes like yelling or wandering. Restlessness and aggression may also be an expression of pain or the consequence of a profoundly disturbed circadian rhythm. A large proportion of patients shows extreme apathy and exhaustion. Patients need support while eating, and even the most basic motor functions (chewing and swallowing) may be impaired as an expression of extreme apraxia. Double incontinence is frequent (Franssen et al., 1993) . Other motor disturbances (e.g.  rigidity and primitive reflexes) may interfere with nursing support. Extrapyramidal motor symptoms are usually due to a comorbidity with Parkinson's disease. Snouting and grasping reactions are the most frequent primitive reflexes and are associated with frontal lobe atrophy (Förstl et al., 1992)22. Myoclonus and epileptic seizures can be observed in a smaller proportion of patients with severe AD, but are more frequent as compared with the general elderly population (Förstl et al., 1992; Romanelli et al., 1990)22  . Many bedridden patients develop decubital ulcerations, contractions and infections. Pneumonia followed by myocardial infarction and septicaemia are the most frequent causes of death in AD (Förstl & Hewer, 1993) .

What Alzheimer's Disease is - Basically
Neurophysiology and neuroimaging. Neither cranial Computed (CT) nor Magnetic Resonance Tomography (MRT) or Single Photon Emission Computed Tomography (SPECT), nor Positron Emission Tomography (PET), not even electroencephalography (EEG) and its quantitative analysis (qEEG) are appropriate tools for diagnosing AD. Each of these methods can, however, contribute to a clinical diagnosis, (1) by excluding other specific causes of dementia which are incompatible with AD and, (2) by documenting functional and morphological changes which are characteristic of AD.
EEG. Hans Berger's original observation of a slowed background activity in the EEG of demented patients was repeatedly confirmed with modern quantitative methods. This slowing exceeds the changes observed in elderly individuals without cognitive changes, but is significantly less severe than in patients with reversible confusional states. The decrease of alpha-power and the increase of  slow theta- and delta-activity are correlated with the severity of illness (Schreiter-Gasser et al., 1994) . The dimensional complexity and the synchronicity (coherence) of the EEG signals are significantly reduced in clinically manifest AD (Besthorn et al., 1994, 1995)   . A statistical discrimination of patients from elderly controls can be achieved in more than 80% (Besthorn et al., 1997) .
SPECT and PET. Numerous SPECT studies demonstrated a typical asymmetric temporoparietal hypoperfusion in a large proportion of patients with AD (Burns et al, 1989; McMurdo et al., 1994)   . A decrease of temporoparietal perfusion is an important sign of AD and this typical perfusion pattern represents a valuable aid for the differentiation of AD from vascular forms of dementia and from frontal or frontotemporal brain degenerations. PET methods are possibly more sensitive for the early observation of characteristic functional changes (Massa et al., 1994) . The correlations between reduced perfusion or reduced metabolism with cognitive deficits, stage or duration of illness are statistically significant (Bartenstein et al., 1997; Stoppe et al., 1995)   . Similar to qEEG, SPECT and PET allow a statistical discrimination of patients with AD from elderly controls in more than 80%.
CT/MRT. The intracranial cerebrospinal fluid spaces show an age-related increase. A significant AD-associated atrophy is superimposed on this age-related effect (Förstl et al., 1995; Fox et al., 1996; Kidron et al., 1997)     . The corresponding decrease of brain volume is significantly correlated with the decrease of cognitive performance (Murphy et al., 1993; Kumar et al., 1994; Förstl et al., 1995)    25.  As the hippocampus is an early target for Alzheimer plaques, neurofibrillary tangles, neuronal and gross volume loss, it should be visualised accurately at the first occasion for a thorough clinical and neuroradiological examination. The demonstration of an increasing volume loss in the medio-temporal cortex is of diagnostic importance (Jobst et al., 1992; Fox et al., 1996)  26. Similar to qEEG, SPECT and PET, planimetric and volumetric estimates of brain atrophy permit a statistical discrimination between patients with AD and elderly controls in more than 80% (Sandor et al., 1992) .

Neuropathology. Some authors have argued that plaques and neurofibrillary tangles could also be found in the brains of non-demented persons who appeared clinically intact until their death and that their pathophysiological significance was, therefore, doubtful (e.g. Rothschild, 1937) . Blessed et al. (1968)  established a statistical correlation between the severity of cortical plaque depositions and the activities of daily living and also of cognitive performance. This approach reintroduced reason, or at least common sense into the scientific investigation of the mind-brain relationship of dementing patients. Brun & Gustafson (1976)  pointed out the typical distribution of cerebral degeneration in AD, which is usually most pronounced in the mediotemporal limbic area, the posterior inferior temporal areas, adjoining parieto-occipital lobes and posterior cingulate gyrus. The frontal lobes are less severely involved. The primary projection areas are typically spared. Braak & Braak (1991)  elaborated a topographic distribution of neuritic plaques, neurofibrillary tangles and neuropil threads, including non-demented individuals in their studies. In stages I and II, the transentorhinal cortex is affected; the neurofibrillary tangles extend into the entorhinal cortex in stages III and IV, the hemispheral isocortex shows neurofibrillary and plaque depositions in stages V and VI, when patients typically develop clinical deficits. The clinical validity of Braak & Braak's stageing has been confirmed by Bancher et al. (1996)  and Gertz et al. (1996)  . Delacourte et al. (1998)  have recently established the correlation between clinical deficits and the extension of neurofibrillary changes in a meticulous study.
Diagnostic confirmation. According to the clinical-pathological  paradigm, a histopathological confirmation of clinically suspected AD is still considered the gold standard. The clinical diagnosis of AD can be confirmed by the neuropathological work-up in 80% or more similar to qEEG, SPECT, PET, CT and MRT studies. This high percentage is often mistaken as a proof of our clinical skills and may mislead to undue complacency. It must not be forgotten that the a priori probability of choosing the right diagnosis is higher than 60%, simply due to the high prevalence of AD. The probability that a patient who satisfies clinical diagnostic criteria for AD will also satisfy neuropathological criteria for Alzheimer's disease is -–according to the Bayes-theory – directly proportional to the prevalence of AD (i.e.critical levels of plaques and neurofibrillary tangles according to standard neuropathological criteria) in the study population. In dealing with prevalent brain changes, highly sensitive – and highly unspecific – diagnostic criteria will inevitably lead to a frequent diagnostic confirmation. Numerous selection mechanisms lead to strongly biased patient samples in memory clinics and in scientific long-term studies which lead to these high, impressive validation rates. The patients have usually undergone repeated examinations; many reached a severe stage of illness before death; cases difficult to examine and with evidence of mixed pathology had been eliminated from these studies at an earlier stage. Such samples have little to do with the normal clinical situation and the diagnostic difficulties at early and mild stages of illness when diagnostic certainty is much lower. Recent studies, using operational, clinical and neuropathological criteria have shown that the presence of Alzheimer-type changes in the brains of demented patients can be predicted with a rather high reliability (due to their prevalence), but that the admixture of other pathologies is not infrequent (Bowler et al., 1998; Holmes et al., 1998)   . Modern neuropathological criteria (Hymen & Trojanowksi, 1997)  do not offer a categorical "yes-or-no decision" for the verification of AD, but yield an estimate for the likelihood that the observed plaque – and tangle counts and their distribution explain the clinical deficits (table 5).
It remains questionable whether it is appropriate for clinicians to speculate about the exclusive presence of Alzheimer-type plaques and tangles in their patients' brains, or whether it would be more adequate to aim at identifying as many treatable pathogenic co-factors as possible.

The Functional Neuroanatomy of Alzheimer's Disease.
Cortico-cortical disconnection. Blessed et al. (1968)33 confirmed a relationship between the isocortical plaque density and the clinical deficits. This is illustrated by the severity and extension of  primarily temporoparietal hypoperfusion and hypometabolism in SPECT and PET studies. Brun & Gustafson (1976)34 pronounced  the plausible correlation between the pattern of neuropsychological deficits and the topographical pattern of the brain changes. Delacourte et al. (1998)38 observed that cognitive deficits are inevitably associated with neurofibrillary changes in the polymodal isocortical association areas. Neurofibrillary and plaque depositions in the isocortical layers III and V are associated with a degeneration of glutamatergic pyramidal cells responsible for cortico-cortical and cortico-subcortical projections (Arendt et al., 1999; Pearson et al., 1985)   . Up to 50% of the neocortical neurons can be lost (Gomez-Isla et al., 1997) . This leads to a functional impairment of feedforward loops from the lower to the higher association areas, and of feedback systems from higher to lower association areas. Its cognitive consequence is an increased noise due to disturbed amplification and filtering of information. A decreased electroencephalographic coherence can be considered as a neurophysiological result of this disconnection (Besthorn et al., 1994; Wada et al., 1998)17  . A callosal atrophy is evidence for cortico-cortical axons (Hampel et al., 1998) . The cortical localisation of the process can be associated with the clinical symptoms: a disruption of cortical pathways mediating visuo-spatial cognition is associated with constructional apraxia; damage of high order visual association areas with apperceptive agnosia (Giannakopoulos et al., 1998; 1999)   .
Hippocampal de-afferentiation and de-efferentiation. Hyman et al. (1984)  demonstrated an isolation of the hippocampal formation due to a cell-specific pathology in layers II and IV of entorhinal cortex and the subiculum, normally responsible for the connection with basal forebrain, thalamus, hypothalamus and association cortices. This leads to a perforant pathway destruction with consecutive glutamate depletion in the dentate gyrus (Hyman et al., 1987) . It is now well-known that the transentorhinal followed by the entorhinal regions are early targets of neurofibrillary tangle formation and neuronal degeneration in Alzheimer's disease (Braak & Braak, 1991; Delacourte et al., 1998)35  . Intact hippocampal pyramidal cells ("index-neurons") are part of extensive hippocampal-neocortical neuronal networks and represent essential prerequisites for the storage and retrieval of declarative memories in adult individuals. Deficits of recent episodic memory are frequent presenting symptoms in AD. According to Ribot's law, recent declarative memory functions are more severely impaired than older episodic and semantic memories which are affected in the course of illness. The volume amygdala-hippocampus complex is positively correlated with the performance on memory tasks and inversely correlated with the severity of dementia (Fama et al., 1997; Mori et al., 1997; Pantel et al., 1997)     . There is a close association between  the severity of mediotemporal lobe atrophy and hypoperfusional hypometabolism of the temporoparietal neocortex (Lavenu et al., 1997; Yamaguchi et al., 1997)   . The severity of mediotemporal degeneration increases while the disease process  extents over the isocortex. The individual contribution of the archicortical and isocortical changes to the clinical deficits are, therefore, difficult to disentangle. The situation is further complicated by severe alterations in the upper brain stem.
Cholinergic denervation. As explained in other chapters of this volume, the basal nucleus of Meynert and other cholinergic nuclei in the basal forebrain are the only sources of acetylcholine for the isocortex and the hippocampus. Acetylcholine in the neocortex reduces the potassium resting potential, thereby increasing neuronal excitability, and also stimulates the activity of GABAergic interneurons allowing a focused cortical excitation. In addition, acetylcholine reduces the activity of thalamic pacemaker neurons. This is how acetylcholine increases attention and allows the organised processing of information in the neocortex and limbic system (Arendt, 1991; 1999)42  . In summary, acetylcholine reduces the resistance in  hippocampo-neocortical oscillating circuits responsible for the formation and retrieval of memories. Acetylcholinesterase-inhibitors temporarily reduce the resistance in these circuits.
Heterogeneity. There are presenile and senile, sporadic and familial forms of AD. The patients are examined at different stages of illness; and the topographic patterns – reflected by the clinical symptoms –  may show some heterogeneity and deviate from the standard course of illness described above. Most of these heterogeneous patterns are not sufficiently distinctive and stable over time to warrant the definition of a meaningful subtype of AD. Few patients have been described in whom an atypical pattern of deficit, related to plaque and tangle pathology, persisted over a longer period of time, e.g. in progressive biparietal atrophy (Förstl & Fischer, 1994; Ross et al., 1996)   . As mentioned above, Alzheimer pathology does not protect against other forms of neuropathological change. In old age, the admixture of other pathologies, e.g. of vascular changes, Lewy-bodies, etc., is not infrequent. Some neuropathological changes would be extremely difficult to detect under the cover of plaques and tangles, e.g. brain degenerations with focal cortical onset, lacking distinctive histopathology.

What Could Be Alzheimer's Disease
What is (probably) not AD. "AD" should not be considered as a synonym for normal aging.
Also, AD is not a synonym for dementia; this is often forgotten, even in diagnostic guidelines.
AD is not just the clinical Alzheimer dementia syndrome, but the underlying disease process together with its typical clinical manifestation. AD is not (only) presenile, but also a senile form of degenerative dementia. AD is more severe than age-associated memory impairment, benign senescent forgetfulness and the like. AD is more than an amnestic syndrome, even if deficits of episodic memory may frequently represent the core symptom of AD. AD is not a confusional state, but a confusional state may represent a first transient manifestation of a subclinical cholinergic deficit and the threshold for confusional states is reduced in patients who are cholinergically challenged due to Lewy-body and/or plaque and tangle pathology in the basal forebrain nuclei.
AD is different from other forms of dementia with specific features that satisfy standard clinical and neuropathological criteria, e.g. Vascular dementia, dementia with Lewy-bodies, Pick's disease and other brain degenerations with focal cortical onset and characteristic histopathological hallmarks, Creutzfeldt-Jakob disease, AIDS-related complex, Huntington's disease, alcohol-related cognitive impairment, cognitive impairment and schizophrenia,
dementia syndrome of depression or other uncommon forms dementia.
What May Be Alzheimer's Disease. As mentioned earlier, patients satisfying clinical criteria for the diseases listed above may still have critical numbers of plaques and neurofibrillary tangles, and a cholinergic deficit, and may, therefore, benefit from cholinergic treatment. To date, there is no method for ruling out the presence of plaques and neurofibrillary tangles in the patients' brains with sufficient certainty during their lifetime, but there may be features which make the presence of significant Alzheimer pathology, a comorbidity, more likely, e.g.
- a slow onset of cognitive impairment before a stroke,
- a continuous progression of dementia after treatment for normal-pressure hydrocephalus,
- hippocampal atrophy,
- temporoparietal hypoperfusion and hypometabolism,
- molecular changes in the cerebrospinal fluid which are indicative of Alzheimer's disease,
-    a family history of Alzheimer dementia or
-    a molecular-genetic risk or diagnostic factor.
Double pathology decreases the threshold for the manifestation of deficits. Less severe vascular changes would be required for the manifestation of dementia, if a moderate amount of plaques and neurofibrillary tangles is already present. This appears to be confirmed by observations  from the nun study (Snowdon et al., 1997) . Therefore, a clinical deficit unexplained by the severity and extension of the observed specific brain changes suggests the presence of a double pathology.
Clinically any mild cognitive impairment, amnestic syndrome, confusional state, depression, etc. may represent an early preclinical stage of AD. Pathophysiologically, a low alpha-power, a discrete temporoparietal hypoperfusion or hypometabolism, early molecular cerebrospinal fluids’ alterations may herald incipient AD. Morphologically, anyone with mild brain atrophy, any person with subthreshold counts of plaques and neurofibrillary tangles would be a candidate for AD. Genetically, asymptomatic carriers of dominant mutations or risk factors are disposed to developing AD. To date, there is relatively little we know about potential protective factors.
Future diagnostic approaches. We are, presently, concentrating all our diagnostic and therapeutic efforts on the epiphenomena of AD. It is now known, that the disease process develops over many decades before it becomes clinically evident. It is hardly a rewarding exercise for patient and physician to establish the diagnosis of AD, once that significant  and irreversible brain changes have accrued. But this will be the case as long as a diagnosis relies on the manifestation of a clinical dementia syndrome and does not aim at pathophysiological factors which could represent the targets of an early intervention. Cumulative incidence and morbidity suggest that everyone runs a  remarkable risk of developing the symptoms of  AD in old age. Therefore,  the risk or chance models should help to plan the timing and intensity of early interventions. Such risk models will include genetic, sociodemographic, somatic and environmental protective and risk factors together with the “early” psychological and biological epiphenomena of illness (fig.1). Most of these factors are discussed elsewhere in this volume. The genetic factors are currently frequently discussed. Several sociodemographic factors are of self-explanatory importance (age, life expectancy, cognitive reserve). The influence of somatic and environmental co-factors is usually disregarded because their are not considered part of the Alzheimer pathophysiology. Some of them are now getting increasing attention (estrogen, cholesterol, cortisone; vascular comorbidity; Hénon et al, 1998; Snowdon et al, 1997; Stewart, 1998)  59  . Subclinical changes which can  occur in the course of the biological disease process and be discovered with special laboratory methods before the patient develops clinical symptoms can be considered as “ early epiphenomena”. These can be discrete cognitive, predominantly amnestic deficits (Fabrigoule et al., 1998; Fox et al, 1998; Hodges, 1998)     , associated functional brain changes (Desgranges et al., 1998; Minoshima et al., 1997)    discrete morphological alterations in the mediotemporal lobe (Reiman et al., 1998)  and early alterations of cerebrospinal fluid. Numerous gaps in figure 1 will be filled within the next decade.

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