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Cognitive NeurologyA clinical textbook$

Stefano Cappa, Jubin Abutalebi, Jean-Francois Demonet, Paul Fletcher, and Peter Garrard

Print publication date: 2008

Print ISBN-13: 9780198569275

Published to Oxford Scholarship Online: March 2012

DOI: 10.1093/acprof:oso/9780198569275.001.0001

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Alzheimer's disease

Alzheimer's disease

(p.199) Chapter 11 Alzheimer's disease
Cognitive Neurology

Andrew J. Larner

Oxford University Press

Abstract and Keywords

The diagnosis of Alzheimer's disease (AD) may be possible, probable, or definite. In clinical practice, most diagnoses are of probable AD: dementia is established on the basis of clinical examination and neuropsychological testing, and there is evidence of progressive worsening of memory and other cognitive functions without disturbance of consciousness. Supportive features include impaired activities of daily living (ADL), behavioural changes, and a positive family history of similar disease, particularly if confirmed by neuropathology. Supportive investigations include a normal cerebrospinal fluid (CSF), normal or non-specific electroencephalographic (EEG) changes, and cerebral atrophy on computerized tomography (CT) with progression documented by serial observation. Other features deemed consistent with probable AD include plateaus in the course of the illness, various associated behavioural features, and certain neurological signs including myoclonus and seizures. Features that make the diagnosis uncertain or unlikely include sudden onset, focal neurological findings, or seizures early in the course, though none of these excludes the diagnosis.

Keywords:   Alzheimer's disease, dementia, neuropsychological testing, cognitive functions, neuropathology, cerebrospinal fluid

11.1 Definition

The development of clinical diagnostic criteria for AD under the auspices of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA; McKhann et al. 1984) has rightly been hailed as a major landmark in dementia research. These criteria have become widely accepted because of their validity, reliability, and utility to research. Although the sensitivity and specificity of the criteria for a diagnosis of AD are good (e.g. 87% and 83%, respectively; McKeith et al. 2000), likelihood ratios (the comparison of post-test odds to pre-test odds, and hence a measure of ‘diagnostic gain’) are only modest (Chui and Lee 2002). Guidelines to assist clinicians in making the diagnosis of AD have been issued by both European and North American neurological societies (Waldemar et al. 2000; Knopman et al. 2001). The criteria are relatively easy to use, being clinically based, and do not require expensive investigations.

The diagnosis of AD may be possible, probable, or definite. In clinical practice, most diagnoses are of probable AD: dementia is established on the basis of clinical examination and neuropsychological testing, and there is evidence of progressive worsening of memory and other cognitive functions without disturbance of consciousness. Supportive features include impaired activities of daily living (ADL), behavioural changes, and a positive family history of similar disease, particularly if confirmed by neuropathology. Supportive investigations include a normal cerebrospinal fluid (CSF), normal or non-specific electroencephalographic (EEG) changes, and cerebral atrophy on computerized tomography (CT) with progression documented by serial observation. Other features deemed consistent with probable AD include plateaus in the course of the illness, various associated behavioural features, and certain neurological signs including myoclonus and seizures. Features that make the diagnosis uncertain or unlikely include sudden onset, focal neurological findings, or seizures early in the course, though none of these excludes the diagnosis.

A diagnosis of possible AD may be made when the onset, presentation, or clinical course is atypical, or when a second pathology—sufficient to cause dementia but which is not considered to be the cause of dementia—is present. A diagnosis of definite AD may be made when the clinical criteria for probable AD are met and when histological criteria are seen on a biopsy or autopsy specimen. Agreement between ante-mortem clinical and post-mortem neuropathological diagnosis is usually 80% or better, though lower when considering mild or early stage disease.

(p.200) Cases with age at onset ≤ 65 years may be labelled as early-onset AD (EOAD), and those with age of onset 〉 65 years as late-onset AD (LOAD) (McKhann et al. 1984). Whilst this is probably an arbitrary distinction, the differentiation of sporadic (i.e. no family history of the condition) from familial AD (one or more similarly affected first-degree relatives) is of crucial biological significance (see Section 11.3.1). Moreover, the reliability of such labels depends on the available information. Family pedigrees in a late-onset disease such as AD may be censored by early death from other causes.

A Lewy body variant of Alzheimer's disease (LBVAD) has been proposed (Hansen et al. 1990) based on the finding of neuropathological changes sufficient to meet criteria for AD together with Lewy body pathology (Mirra et al. 1991). Whether this represents a variant of AD or a separate disorder is debated, but most authorities would probably now label this as the ‘common form’ of dementia with Lewy bodies (DLB).

Individuals who have mild memory difficulties but are not functionally impaired have been recognized clinically for many years. Since their deficits are insufficient to fulfil the clinical diagnostic criteria for AD, various other terms have been used to describe them, with recent consensus developing around the idea of mild cognitive impairment (MCI; Petersen 2003, 2004), though this may simply represent ‘prodromal AD’. The identification of such patients is important since 10–15% of them progress to AD per year and most, though not all, will ultimately convert. Therapeutic intervention at the MCI stage may therefore prevent or retard the onset of AD.

11.2 Epidemiology

Numerous studies of the epidemiology of AD have been undertaken, with the dual aims of social planning and identifying potentially modifiable risk factors for the development of the disease (Jorm 1990). The most important risk factor for AD is increasing age, with incidence rising exponentially at least up to the age of 90 years (Jorm and Jolley 1998), by which time as many as one in four individuals may be affected. The hypothetical issue of whether everyone would develop AD if they lived long enough remains unresolved. There is a higher prevalence of AD among women than men, due either to a higher incidence or to longer survival after development of the disease (Launer et al. 1999). Studying disease prevalence and incidence across national and racial boundaries poses difficult methodological issues, but there is some evidence that AD has a higher incidence in developed compared to developing nations (Hendrie et al. 2001). Epidemiological studies have also identified other possible risk factors and also protective factors for AD (see below).

11.3 Aetiological factors

11.3.1 Genetic

Alzheimer's disease with a familial component was recognized as early as the 1920s, but Lowenberg and Waggoner (1934) were the first to report in detail an autosomal dominant (p.201) pedigree with neuropathological confirmation. Elucidation of the kindred of Alzheimer's second patient, Johann F., suggests an autosomal dominant disorder with variable penetrance and age of onset between the 30s and mid 60s (Klünemann et al. 2002), though the index case showed only plaques and was negative for APP gene mutations (Graeber et al. 1997). To date, three genes have been described in which mutations may be deterministic for AD, usually of early-onset. These mutations, namely, amyloid precursor protein (APP) presenilin-1 (PS1) and presenilin-2 (PS2), are discussed in more detail in Chapter 15.

The only genetically determined risk factor to have been demonstrated relates to allelic variation in the apolipoprotein E (ApoE) gene (Roses 1996; Saunders 2001). Other genetic loci of possible interest have been identified, particularly those on chromosomes 12 and 10, the former possibly associated with genes encoding α2-macroglobulin and low-density lipoprotein receptor (Bertram and Tanzi 2005). Rarely, kindreds with tau gene mutations, which typically present with fronto-temporal dementia (FTD), may have an AD-like presentation (Doran et al. in preparation). Amyloid precursor protein (APP)

The first APP mutation, V717I, was identified in 1991 (Goate et al. 1991). Around 20 further genomic mutations have since been reported, an up-to-date record of which is held on the Alzheimer Disease and Frontotemporal Dementia Mutation Database (www.molgen.ua.ac.be/Admutations). Mutations are located in proximity to the α-, β-, and γ-secretase cleavage sites of APP, and many have been shown to increase production of amyloid β-peptides (Aβ or βA4) in stably transfected cell lines (Scheuner et al. 1996), particularly of the longer variant (Aβ42), which has a particular propensity to aggregate and is more toxic to neurons (Jarrett et al. 1993). Mutations in the APP gene have also been found in hereditary cerebral haemorrhage with amyloidosis Dutch type (HCHWA-D), a rare familial form of cerebral amyloid angiopathy whose chief clinical features are recurrent cerebral haemorrhages and early death, with dementia occurring in only a minority of patients. Presenilin 1 and presenilin 2 (PS1, PS2)

A missense mutation in a gene on chromosome 14 that was deterministic for autosomal dominant EOAD was reported in 1995 (Sherrington et al. 1995). A homologous gene was identifed on chromosome 1, and found to bear mutations in the Volga-German AD kindred (Levy-Lahad et al. 1995; Rogaev et al. 1995). The two genes were named presenilin-1 and presenilin-2.

PS1 mutations are the commonest identified genetic cause of AD, with well over 100 different genomic mutations reported to date (Larner and Doran 2006; www.molgen.ua.ac.be/Admutations). In a study of 31 families fulfilling strict criteria for autosomal dominant EOAD, the PS1 mutation frequency for probable and definite AD was 77% and 82%, respectively (Janssen et al. 2003). PS2 mutations are less common, with only 10 mutations and 18 families reported at the time of writing.

As with APP, most PS mutations are associated with increased production of Aβ42 both in vitro and in vivo (Scheuner et al. 1996; Mehta et al. 1998). Although these findings bear out the predictions of the amyloid hypothesis, the mechanism(s) by which Aβ causes AD remains a subject of debate. Certainly Aβ is toxic to neurons in high concentration, possibly through enhanced levels of oxidative stress and deregulation of intracellular calcium ion concentrations (Iversen et al. 1995), but Aβ is also found in tissue fluids of normal individuals, suggesting a physiological role, perhaps as an inhibitor of neurite growth (Larner 1995a, 1997a), which becomes dystrophic with abnormal Aβ levels, leading to synaptic alterations, neuronal degeneration, and clinical dementia (Larner 1997b).

(p.202) Apolipoprotein E (ApoE)

Apolipoprotein E, a lipid transport molecule, has been identified as a genetically determined risk factor for the development of AD (Roses 1996; Saunders 2001). The protein has three isoforms, E2, E3, and E4, encoded by alleles ε2, ε3, and ε4. In patients with late-onset AD the ε4 allele is found with much greater frequency than in controls (e.g. 52% versus 16%; Saunders 2001). Hence, possession of an ε4 allele, though neither necessary nor sufficient for the development of AD, increases the risk. This increase is of the order of twofold in heterozygotes, and between six-and eightfold in homozygotes (Corder et al. 1993). ApoE genotype also appears to modulate the age of onset in patients with EOAD related to APP mutations (Saunders et al. 1993), but not PS (van Broeckhoven et al. 1994, though see Larner and Doran 2006 for some possible exceptions).

The mechanism by which the ApoE ε4 genotype increases risk is uncertain. A number of possibilities exist, of which increase in amyloid deposition may be the most important (Polvikoski et al. 1995), though ApoE also has roles in synaptogenesis and neurite growth (Poirier 1994; Roses 1996; Saunders 2001).

11.3.2 Acquired

Epidemiological studies have suggested a number of possible risk factors for the development of AD. In terms of the potential for modification, perhaps the most important of these are hypertension and hypercholesterolaemia in mid-life (Kivipelto et al. 2001). Vascular risk factors, once thought of greater importance in vascular dementia (VaD), are now widely acknowledged to be risk factors for AD (Shobab et al. 2005; Stewart 2005) and there is often significant cerebrovascular disease in addition to typical AD pathology in the brains of elderly demented individuals (see Section 11.8). A number of studies have suggested that treatment of hypertension may reduce the risk of dementia in general, including AD (Forette et al. 1998, 2002; Lithell et al. 2003; Tzourio et al. 2003), but in none of these studies was cognition the primary outcome measure.

The possible roles of education and recreation in the pathogenesis of AD are subjects of much current interest. Low levels of education seem to be a risk factor for AD (Launer et al. 1999). In the religious orders (‘nun’) study, verbal ability in young adulthood, as evidenced by idea density and grammatical complexity in written work, correlated with cognitive function in old age, low verbal ability being related to AD pathology (Snowdon et al. 1996). There is some evidence that AD patients engage in fewer physical and recreational activities in midlife (Friedland et al. 2001), and regular recreational activities, both physical and intellectual, may be protective (Wilson et al. 2002; Verghese et al. 2003).

Diet has also been investigated. In view of the possible importance of oxidative stress in neurodegenerative pathogenesis, use of vitamin supplements has been studied, with the finding that combined use of vitamin E and vitamin C (ascorbic acid) was associated with reduced prevalence and incidence of AD. However, the effect was not observed for either vitamin in isolation nor for multivitamin supplements (Zandi et al. 2004). Data on smoking have been inconsistent, with both increased and decreased risk reported (Launer et al. 1999). Alcohol in moderate amounts may be protective (Huang et al. 2002).

Epidemiological studies have suggested possible beneficial effects of a number of drug classes in preventing AD, including: nonsteroidal anti-inflammatory drugs (NSAIDs); lipid-lowering agents, particularly statins (HMG CoA reductase inhibitors); and oestrogens, all of which are associated with biologically plausible explanations. In several cases, however, controlled clinical trials of these agents have proved negative. NSAID use has repeatedly been found to offer a protective effect (McGeer et al. 1996; In't Veld et al. 2001; Etminan et al. 2003), a finding buttressed by the observation of an inflammatory response in AD brain tissue. However, clinical (p.203) trials of NSAIDs in established AD have been repeatedly disappointing, though there may be valid reasons for the failure to observe any benefit (van Gool et al. 2003). Likewise, observational studies have suggested that statin therapy is associated with a lower prevalence of AD (Wolozin et al. 2000; Rockwood et al. 2002) and may slow progress of established disease (Masse et al. 2005), while others have found no association between statin use and subsequent AD (Zandi et al. 2005). A brief trial of the HMG CoA reductase inhibitor simvastatin in AD patients had no effect on CSF Aβ levels and, although there was a favourable difference between the Mini-Mental State Examination (MMSE) scores of treated and placebo groups, this was not reflected in the functional outcome (Simons et al. 2002). Epidemiological evidence suggesting a protective effect of hormone replacement therapy in postmenopausal women (Henderson 1997; Zandi et al. 2002) prompted a clinical trial, but this was stopped because of excess dementia in the treatment group (Shumaker et al. 2003). Hence, to date, none of these agents can be recommended in established disease, though a role in primary prevention remains possible (Doraiswamy and Xiong 2006).

Exposure to metals, particularly aluminium, was once believed to be relevant (Doll 1993), in part because of the phenomenon of‘dialysis dementia’ that occurred in renal patients exposed to dialysate with high concentrations of aluminium. Although these patients have neurofibrillary pathology typical of AD (Harrington et al. 1994), aluminium is no longer perceived as aetiologi-cally important. Likewise zinc can induce Aβ aggregation in vitro (Bush et al. 1994), but evidence for a role of zinc in AD is equivocal (Nachev and Larner 1996). In an intriguing contrast to the trial data discussed above, however, the metal chelator clioquinol has produced encouraging results in a preliminary trial in AD (Ritchie et al. 2003).

Head injury with loss of consciousness has been found to increase Aβ expression in the brain (Roberts et al. 1991, 1994), and boxers are at risk of dementia pugilistica, which shares some neu-ropathological features with AD. The results of epidemiological studies on the risks of AD after head injury are equivocal, largely because of methodological difficulties (Launer et al. 1999; Fleminger et al. 2003), though there is an interaction between head injury and ApoE genotype in increasing risk of developing AD pathology (Nicoll et al. 1995).

11.4 Clinical features

11.4.1 Typical presentations

Forgetfulness is usually the earliest symptom of AD, commonly manifesting as repetitive questioning. Day-to-day, events or appointments may also be forgotten, pointing to a problem with the episodic or autobiographical component of memory. Difficulty in mastering new routines or household appliances (i.e. acquisition and retention of new information) is another reflection of this anterograde amnesic syndrome. In contrast, personal events of long ago may be readily recalled, indicating a temporal gradient of memory impairment. These remote memories are assumed to have become part of the semantic component of declarative memory which, though not normal (Garrard et al. 2004), is rarely as profoundly impaired as new learning. Difficulty with the production of names (of both people and objects) is probably an early reflection of semantic memory impairment (Garrard et al. 2005), while aspects of implicit (non-declarative) memory function are relatively preserved.

(p.204) 11.4.2 Atypical presentations

Although slowly progressive anterograde amnesia is the commonest clinical presentation of AD, ‘variant’ presentations in which cognitive symptoms other than amnesia are prominent or even isolated (e.g. agnosia, aphasia, apraxia, or behavioural and psychological features) are well recognized. These are not ‘subtypes’, a term that implies a different causative factor (Jorm 1985), but simply reflections of the clinical heterogeneity of AD, due to variation in the distribution of pathology. Such variants are not uncommon, accounting for just under 10% of AD presentations over a 6-year period in the author's cognitive function clinic (though specialist clinics are subject to selection bias in favour of atypical cases). Visual disruption

Posterior cortical atrophy (PCA; Benson et al. 1988) and visual variant of AD (Levine et al. 1993) are names given to AD with predominantly visuospatial dysfunction as the presenting feature, such as visual agnosia, alexia, and Balint's syndrome. Diagnostic criteria for PCA have been proposed (Mendez et al. 2002), and most cases presenting in this way turn out to have AD as their neuropathological substrate, though other disorders are occasionally encountered (Pantel and Schröder 1996). The heterogeneity of clinical features reflects the different ways in which visual processing may be disrupted in both sporadic and familial AD (Cronin-Golomb and Hof 2004), though it should be noted that visual agnosia is an uncommon feature in AD due to PS1 mutations (Larner and Doran 2006). Progressive apraxia

Slowly progressive apraxia with the neuropathological substrate of AD has been described, as a unilateral or bilateral parietal lobe syndrome (Crystal et al. 1982; Mackenzie Ross et al. 1996; Galton et al. 2000). Difficulty with manual tasks and apraxic agraphia may be accompanied with visuospatial difficulties akin to those of Balint's syndrome, hence prompting the suggestion that this disorder reflects disconnection of the parietal (‘where’) visual pathway, whereas PCA affects the occipitotemporal (‘what’) visual pathway (Mackenzie Ross et al. 1996; Galton et al. 2000). AD cases have also been described that overlap clinically with, and may be mistaken for, corticobasal degeneration (Boeve et al. 1999; Doran et al. 2003), sometimes with the alien limb phenomenon (Ball et al. 1993). AD with progressive frontal gait disturbance (gait apraxia) has also been reported (Rossor etal. 1999). Progressive aphasia

Slowly progressive aphasia is recognized to be a presenting feature of neurodegenerative disease, and may either remain focal, as in primary progressive aphasia (Mesulam 2001), or presage a more generalized dementia (Pogacar and Williams 1984; Mendez and Zander 1991; Galton et al. 2000). Non-fluent aphasia has been described as the presenting feature of AD due to PS1 gene mutation (Godbolt et al. 2004). Fluent aphasia with characteristics more in keeping with transcortical sensory aphasia may also occur in AD (Galton et al. 2000). Occasionally aphasia of acute onset, mimicking cerebrovascular disease, may be the first sign of AD (Larner 2005a). Frontal AD

A frontal variant of AD (fvAD) was described by Johnson et al. (1999). Among 63 patients with pathologically confirmed AD, 19 had greater neurofibrillary pathology in frontal as compared to entorhinal cortex, and 3 had disproportionately severe impairment on two neuropsychological tests of frontal executive function. The term fvAD may also be used for inherited AD cases with a clinical phenotype reminiscent of the behavioural or frontal variant of frontotemporal dementia (p.205) (fvFTD), sometimes even fulfilling suggested clinical diagnostic criteria for FTD, and is seen in association with certain mutations in the PS1 gene (Larner and Doran 2006). Rarely, sporadic early-onset AD may present with a behavioural phenotype suggestive of FTD (Larner 2006a). Evidence from neuropsychological assessments of a subgroup of AD patients with executive dysfunction early in the disease and apparently without behavioural dysfunction has been reported (Binetti et al. 1996; Royall 2000). Psychiatric presentations

Behavioural and psychological symptoms of dementia (BPSD)—such as depression—are common in the later stages of AD (Burns et al. 1990; Ballard et al. 2001) but may sometimes be prominent presenting signs (Alzheimer 1907; Doran and Larner 2004). The difficult differential diagnosis of AD from ‘depression associated with dementia’ or ‘depressive pseudodementia’ is familiar to all who work in the field. Vigorous use of antidepressant medication with monitoring of cognitive function may be undertaken, but passage of time may be the only investigation that permits a definitive diagnosis.

AD is recognized as predisposing to an acute confusional state, and occasionally delirium may be the presenting feature. Certainly, elderly patients presenting de novo with delirium should be followed up since some will show evidence of progressive cognitive decline (Robertson et al. 1998; Rockwood et al. 1999). Myoclonic jerks and epileptic seizures become more prevalent with disease duration (Mendez and Lim 2003), though patients with new seizure onset and cognitive decline in whom no symptomatic cause for seizures other than AD is discovered are occasionally encountered (Lozsadi and Larner 2006). Seizures are usually of partial onset type, with or without secondary generalization, and are usually easily to control, seldom requiring more than one anti-epileptic drug. A small number of cases progresss rapidly from early on and, if myoclonic jerks are present, AD may be mistaken for prion disease (Tschampa et al. 2001; Larner and Doran 2004). EEG periodic sharp waves and CSF 14-3-3 protein may even be present (Reinwald et al. 2004).

11.4.3 Examination

The general examination in patients with AD may be entirely normal, though weight loss is sometimes evident, perhaps related to inadequate food intake due to forgetfulness, apathy, or lack of initiative (Cronin-Stubbs et al. 1996). Patients often have a perplexed, bemused air, and there may be a lack of attention to appearance and personal hygiene.

Neurological examination may reveal primitive reflexes, such as the palmomental, grasp, and pout, though these are also seen in normal ageing (Hodges 1994; Larner 2006c) and may therefore be incidental to a diagnosis of AD. Testing of olfaction is seldom undertaken in the neurological examination, but hyposmia seems to be an early and consistent change in AD (Graves et al. 1999). The irregular shock-like jerks of myoclonus may be seen, becoming more prevalent with AD duration (Chen et al. 1991), and may lead to diagnostic confusion with sporadic Creutzfeldt-Jakob disease (sCJD). Extrapyramidal signs, particularly rigidity and bradykinesia, are not infrequent in AD: one study found a prevalence of 50% six years after symptom onset (Chen et al. 1991) though, as with frontal release signs, they may simply reflect the increased prevalence of these features with normal ageing (Bennett et al. 1996; Larner 2006c).

Neurological signs that are seen uncommonly in AD, such as cerebellar ataxia, spastic paraparesis, and slowly progressive hemiparesis, prompt a broader differential diagnosis. Although neuropathological changes may be seen in the cerebellum in AD (Larner 1997c), cerebellar ataxia is not generally a feature, other than in occasional pedigrees of autosomal dominant AD associated with PS1 gene mutations (Martin et al. 1991, Larner and Doran 2006; though see Huff et al. 1987 for an alternative view). Spastic paraparesis was first described in association with AD in (p.206) 1913 (Barrett 1913) and is now recognized as associated with the exon 9 deletion in PS1 (Crook et al. 1998; Larner and Doran 2006) and with the neuropathological observation of cotton wool type amyloid plaques (Tabira et al. 2002). Slowly progressive hemiparesis has been reported with the pathological substrate of AD (Jagust et al. 1990), and may be similar to the syndrome first described by Mills (1900).

The most commonly used, brief (ca. 10 minutes), bedside test of cognitive function is the Mini-Mental State Examination (MMSE) of Folstein et al. (1975), a well-established instrument for testing cognitive function, with subtests of attention, memory, language, and visuospatial skills. However, there is no specific cutoff score that defines dementia in general or AD in particular. Moreover, test results are subject to educational bias. Nonetheless, MMSE scores do correlate with neuropathological markers of AD such as synaptic density (Terry et al. 1991). The suggestion that a subscore of the MMSE may be useful in the differential diagnosis of AD from DLB, based on the greater attentional and visuospatial deficits in DLB (Ala et al. 2002), has not proved specific in a prospective study (Larner 2003a, 2004b). The clock drawing test is also a popular brief screening test for AD, since it requires a mix of cognitive abilities to execute correctly (Shulman and Feinstein 2003).

Longer bedside batteries (ca. 20–45 minutes) that address some of the shortcomings of the MMSE (i.e. perfunctory testing of memory, visuospatial, and executive function) without becoming unwieldy have been developed. Of these, the Alzheimer's Disease Assessment (p.207) Scale—Cognitive Section, ADAS-Cog (Rosen et al. 1984), has become widely used, including as a measure of drug efficacy in clinical trials. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery incorporates the MMSE and other subtests including tests of memory, naming, and verbal fluency (Morris et al. 1989). In the UK, the Addenbrooke's Cognitive Examination (ACE; Mathuranath et al. 2000) has become popular. As with the MMSE, it has good sensitivity and specificity for the diagnosis of dementia using particular cutoffs, although likelihood ratios (a measure of change in pre-test to post-test odds, hence of‘diagnostic gain’) have not been overly impressive (Larner 2005b), but these may be improved in the revised version, ACE-R (Mioshi et al. 2006). ACE may be responsive to cognitive change, and hence useful in tracking progression from MCI to AD (Larner 2006d). The suggestion that a subscore of the ACE may be useful in the differential diagnosis of AD from frontotemporal dementia (FTD) has been largely borne out in practice (Mathuranath et al. 2000; Larner 2005b). Other widely used scales (for details see Burns et al. 1999), such as the Clinical Dementia Rating and the Mattis Dementia Rating Scale, are more global scales, incorporating functional (ADL) as well as cognitive assessments. Such measures, along with the Clinician's Interview-Based Impression of Change, without or with caregiver input (CIBIC, CIBIC+), are desirable in clinical trials methodology. Informant-based instruments, such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) may also afford useful information. Specific assessment of behavioural features may be undertaken with instruments such as the Neuropsychiatric Inventory (NPI).

11.5 Neuropsychology

The battery of tests used in formal neuropsychological assessment varies from centre to centre, dependent upon local preference and familiarity with tests. Measures of IQ (verbal, performance, full scale) can be obtained with the Wechlser Adult Intelligence Scale Revised (WAIS-R). The National Adult Reading Test (NART) can be used to obtain a measure of premorbid IQ, provided there is no confounding by marked aphasia, thus allowing comparison of present and premorbid IQ to see whether there is evidence for generalized intellectual loss. Individual tests may then be used to probe specific cognitive functions, such as language (Graded Naming Test, Boston Naming Test), memory (Hopkins Verbal Learning Test, Camden Recognition Memory Tests, California Verbal Learning Test), visuoperceptual and visuospatial skills (Rey-Osterreith figure, Visual Object and Space Perception battery), and executive function (Stroop colour-word test, verbal fluency tests, Wisconsin Card Sorting test). Since affective disorders may impact on cognitive performance, some assessment of this domain is also advisable (Beck Depression Inventory, Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale). Such a battery may take 2 hours or more, and patients may become fatigued requiring a break or return on another day to complete testing.

The profile on neuropsychological assessment in AD varies according to stage, but typically there will be evidence of memory impairment, particularly learning and recalling new information (e.g. word lists). This may occur in isolation, but often by the time of presentation there will be additional language deficits, evident as word-finding and naming difficulties, sometimes with circumlocutions and sometimes phonological errors. Visuospatial and visuoperceptual difficulties may also be apparent, for example, in clock drawing or copying the Rey figure. Executive dysfunction, as evidenced by difficulties with the Stroop test or verbal fluency, may be apparent in some patients in the early stages. The neuropsychological profile is often the most helpful way to differentiate AD from other conditions such as DLB and semantic dementia. The role of computerized test batteries (e.g. CANTAB-PAL) is still being evaluated.

(p.208) 11.6 Imaging correlates

11.6.1 Structural

Guidelines for the diagnosis of AD (Waldemar et al . 2000; Knopman et al. 2001) recommend use of some form of structural brain imaging, either with CT or, preferably, magnetic resonance imaging (MRI). These modalities may display the consequences of AD: brain atrophy with an increase in CSF spaces on visual inspection of scans (Fig. 11.1). As such, these changes are rathern

                      Alzheimer's disease

Fig. 11.1 Coronal MR images. (a) Healthy control. (b) Bilateral hippocampal atrophy in moderate AD; MMSE = 20. (c) Repeat imaging of patient in (b) at 1 year follow-up: 2% loss of brain volume. (Courtesy of Professor N.C. Fox, Dementia Research Group, Institute of Neurology Queen Square, London.)

(p.209) non-specific, also occurring in normal ageing; overreliance on such features may lead to misdiagnosis (Larner 2004a). Moreover, in early AD scans may be judged normal for age, as acknowledged in diagnostic criteria (McKhann et al. 1984). Disproportionate loss of medial temporal lobe volume may be useful although this may also be seen in DLB.

Serial measurement of hippocampal volume using volumetric imaging techniques (Fig. 11.1(b), (c)) may be particularly helpful (Fox et al. 1996a). Presymptomatic individuals with deterministic AD mutations may show hippocampal volume loss before clinical deficits become apparent (Fox et al. 1996b). This imaging modality also has the capacity to be a surrogate marker for drug efficacy.

Imaging of AD pathology per se may become a reality in the future using ligands that bind specifically to pathological structures. One such compound, Pittsburgh compound B, is an 11C-labelled positron emission tomography (PET) tracer compound that binds with high affinity to fibrillar amyloid plaques, allowing in vivo quantification of amyloid burden (Klunk et al. 2004). This compound has generated much excitement, offering the possibility not only of diagnosis of AD (and MCI) but also as a surrogate marker for monitoring the efficacy of AD disease-modifying therapies.

11.6.2 Functional

Single photon emission computed tomography (SPECT) is both sensitive and specific for the diagnosis of AD compared to controls, the typical signature being bilateral hypoperfusion of the temporal and parietal cortices (Dougall et al. 2003), although clinical variants may differ, such as the occipital hypoperfusion in PCA. SPECT may also be useful in differential diagnosis of dementia syndromes, particularly AD and FTD (Talbot et al. 1998; Doran et al. 2005).

Other functional imaging modalities include positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), typically proton MRS (1H-MRS), although these are not as widely available as SPECT. PET typically shows hypometabolism in those regions showing hypoperfusion on SPECT and shows a good correlation with brain pathology (Silverman et al. 2001). Decrease of N-acetyl aspartate (NAA), a neuronal marker, and elevation of myoinositol in occipital voxels, or equivalent changes in their ratios with creatine, are changes observed with 1H-MRS consistent with the diagnosis of AD.

11.7 Other investigations

A number of other investigations may be undertaken in patients with suspected AD, as recommended by diagnostic guidelines (Waldemar et al. 2000; Knopman et al. 2001), largely to exclude other disorders rather than to confirm AD. They may be deemed unnecessary in cases where the diagnosis is established with confidence on the basis of clinical, neuropsychological, and neu-roimaging information.

Blood tests may include vitamin B12, thyroid function, and syphilis serology, although the pick-up rate of potentially reversible dementia syndromes is extremely low and the number that actually reverse even lower (Clarfield 2003).

Neurogenetic testing for mutations in the APP, PS1, and PS2 genes is potentially diagnostic, but cases of genetically determined AD are rare. Hence, testing, with appropriate genetic counselling to patient and family, is best reserved for those with an autosomal dominant pattern of inheritance (Cruts et al. 1998; Janssen et al. 2003). ApoE genotyping in isolation has no role as a diagnostic test.

The role of electroencephalography (EEG) in the diagnosis of AD has lessened with the advent of neuroimaging. Generally, there is a slowing of the alpha frequency, amplitude, and relative (p.210) power; decrease in relative and absolute beta power; and increasing predominance of diffuse and symmetrical theta and delta waves in posterior regions (Knott et al. 2001). Although the EEG may be normal in the early stages of AD, it would be very unlikely to remain so throughout the course of the disease. The persistent normality of the EEG in FTD may help in differential diagnosis. Periodic sharp wave complexes, typical of sCJD, have been described on occasion in AD (Tschampa et al. 2001; Reinwald et al. 2004).

Analysis of the CSF contents is usually normal; a modest elevation of protein may be seen. An elevated white cell count would argue against a diagnosis of AD. Likewise, the finding of oligo-clonal bands (OCB) would be more suggestive of an inflammatory disorder, although cases of pathologically proven AD with OCB for which no other cause could be identified have been reported (Janssen et al. 2004), indicating that a central immune response may occur in AD, albeit uncommonly. Measurement of CSF total tau, phospho-tau, and Aβ42 is not widely available but may help in making a diagnosis (Andreasen and Blennow 2005)

Brain biopsy for diagnostic purposes is seldom resorted to in patients with dementia, its use being largely confined to younger patients with atypical presentations, and where a suspicion of a potentially remediable inflammatory or infective aetiology is ranked high in the differential diagnosis. In reported series, where a specific diagnosis can be made, AD is one of the commonest findings (Warren et al. 2005), presumably reflecting the very high prevalence of AD in comparison to other dementing conditions.

11.8 Pathology

The hallmark lesions in the AD brain are amyloid (senile) plaques and neurofibrillary tangles (Fig. 11.2), although neither is unique to AD. Various other neuropathological changes have also been reported. A number of criteria have been developed to grade AD type pathology (Mirra et al. 1991; Braak and Braak 1991; National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease 1997).

11.8.1 Macroscopic appearances

Macroscopically there may be obvious brain atrophy, often with a frontal, temporal, and parietal bias. On brain slicing there may be obvious thinning of gyri and widening of sulci, with ventricular enlargement and sometimes visible hippocampal atrophy. Depigmentation of the locus ceruleus may be apparent.

11.8.2 Microscopic Amyloid pathology: plaques and angiopathy

Amyloid plaques, originally named because of their propensity to take up stains for starch, are proteinaceous (Aβ) deposits in the extracellular space that may have various morphologies (Wisniewski et al. 1996). The classic neuritic or senile plaque is an amyloid core surrounded by neuritic (axonal and dendritic) processes, glial cell processes, and microglia (Fig. 11.2(a), (b)). Other proteins may co-localize with Aβ including ApoE, ubiquitin, inflammatory markers such as complement, and acute phase proteins (C-reactive protein, α1-antichymotrypsin). (p.211)

                      Alzheimer's disease

Fig. 11.2 (a) Neocortex showing a high density of silver staining amyloid plaques. Diffuse, primitive and mature/neuritic plaques (arrows) are evident. (Modified Bielchowsky stain, 100 × original magnification.) (b) Neocortex containing diffuse, primitive and mature/neuritic amyloid plaques (arrows). The neuritic plaques consist of an amyloid core surrounded by a corona of silver staining thickened, distorted dystrophic neurites. (Modified Bielchowsky stain, 400 × original magnification.) (c) Hippocampal pyramidal neurons containing silver staining neurofibrillary tangles (arrows). The neurons also show granulovacuolar degeneration. (Modified Bielchowsky stain, 630 × original magnification.) (d) Neocortex containing a high density of tau-immunopositive neurofibrillary tangles, neuropil threads, and neuritic plaques, the latter delineated by immunopositive dystrophic neurites. (Tau-immunostaining, 200 × original magnification.) (e) Cortex showing prominent leptomeningeal and intracortical amyloid angiopathy (arrows), the latter often extending into the surrounding parenchyma. Numerous dense cortical amyloid plaques, some vessel-derived. (Beta A4 amyloid immunohistochemistry, 50 × original magnification.) This is a black and white version of Plate 8. (Courtesy of Dr D.G. DuPlessis, Greater Manchester Neurosciences Centre, Salford.)

(p.212) Following the characterization of Aβ from amyloid deposits, the development of Aβ antibodies permitted immunohistochemical studies of AD brain, which have revealed additional plaque morphologies. Diffuse plaques, composed mostly of Aβ42 and lacking a neuritic halo, are more widespread, and may be forerunners of neuritic plaques (Wisniewski et al. 1996). Cotton wool plaques are large (100–120 μm diameter) eosinophilic structures without surrounding neuritic or glial responses, first described in a Finnish pedigree with the PS1 exon 9 deletion mutation (Crook et al. 1998) and subsequently seen in various other PS1 mutations (Larner and Doran 2006).

Cerebral amyloid angiopathy (CAA), also known as congophilic angiopathy, is the deposition of amyloid in the walls of small parenchymal and leptomeningeal arterioles. Sometimes it extends around vessel walls into the surrounding brain parenchyma (dyshoric angiopathy).

Despite the association of APP mutations with AD, and the finding that virtually all genetic mutations deterministic for AD increase Aβ42 production, nonetheless the correlation between amyloid plaque burden and severity of cognitive impairment in AD is less impressive than for neurofibrillary tangles (McKee et al. 1991; Terry et al. 1991; Arriagada et al. 1992). Better correlation has been established with brain levels of soluble Aβ (Näslund et al. 2000). A contribution of Aβ per se to cognitive impairment is also suggested by the observation of dementia in some cases of HCHWA-D, independent of neurofibrillary pathology and without a clinical history of stroke or focal radiological lesions (Natté et al. 2001). Neurofibrillary tangles

Neurofibrillary tangles (NFTs) are argyrophilic structures seen predominantly within the soma and apical dendrites, but not the axon, of pyramidal neurons in AD brain (Fig. 11.2(c), (d)). Extracellular or ghost tangles are occasionally seen, thought to be markers for dead neurons. Ultrastructurally, NFTs are composed of paired helical filaments (PHFs) 8–20 nm in width with a periodicity of about 80 nm (Kidd 1963; Terry 1963). Purification of the highly insoluble proteins composing PHFs revealed them to be composed of the microtubule-associated protein tau (Wischik et al. 1988), which is present in a hyperphosphorylated state (Goedert et al. 1992). Silver stains and tau immunohistochemistry also reveal dystrophic neurites as a halo around neuritic amyloid plaques and also distributed throughout the cortical neuropil (first described by Simchowicz 1911), the latter variously known as neuropil threads, curly fibres, or cortical neuritic dystrophy (Braak et al. 1986; Larner 1995b).

Neurofibrillary pathology follows a relatively stereotyped pattern of development in the AD brain, spreading from transentorhinal cortex to entorhinal cortex and hippocampus, and lastly to association cortex (Arnold et al. 1991; Braak and Braak 1991). This correlates with progressive cognitive decline (Braak and Braak 1991; Arriagada et al. 1992; Bierer et al. 1995; Delacourte et al. 1999). The presence of dystrophic neurites also correlates with cognitive decline (McKee et al. 1991). Neuronal and synaptic loss

Selected populations of neurons undergo disproportionate decreases in the AD brain. Examples include pyramidal neurons in the hippocampus (Ball 1977) and neocortex, especially frontal and temporal regions (Mountjoy et al. 1983), and noradrenergic neurons in the locus ceruleus. However, the loss of the cholinergic forebrain projection neurons from the nucleus basalis of Meynert (Whitehouse et al. 1982), resulting in reduced cortical cholinergic supply and choline acetyltransferase, is perhaps of the greatest functional importance, and the stimulus for the development of cholinergic therapies in AD. Whether neuronal death is by a process of apoptosis remains unclear. Loss of neocortical neurons (Gomez-Isla et al. 1997) and of synaptic connections in the frontal lobe (Terry et al. 1991) has been shown to correlate with the severity of dementia.

(p.213) Cerebrovascular disease

In addition to CAA (Fig. 11.2(e)), cerebrovascular disease is very commonly observed in the AD brain. In one community-based study, most patients with dementia coming to autopsy had mixed disease (MRC CFAS 2001) and, in a series of patients with a clinical diagnosis of VaD, most had either AD alone or mixed disease (Nolan et al. 1998). Considering the shared vascular risk factors of AD and VaD, this is perhaps not surprising. Moreover, double pathology may lower the threshold for clinically manifest deficits (Snowdon et al. 1997). Granulovacuolar degeneration, Hirano bodies

Granulovacuolar degeneration, first described by Simchowicz (1911), is the name given to abnormal cytoplasmic structures found in hippocampal pyramidal neurons (Fig. 11.2(c)), consisting of vacuoles containing a single granule that are thought to be autophagosomes. Hirano bodies are also seen in hippocampal neurons as homogeneous, spindle-shaped inclusions that are bright pink on haematoxylin and eosin staining. Hirano bodies may also be seen in normal ageing. Glial reaction

As mentioned, glial elements are associated with plaques. A generalized glial cell reaction, as judged by upregulation of expression of glial fibrillary acidic protein (GFAP) is found throughout the AD brain (Delacourte 1990). Activated microglia are also found in association with plaques. Lewy bodies, Pick bodies

Although typical of other neurodegenerative disorders, the inclusion bodies of Lewy and Pick may occasionally be seen in the AD brain. Although cases labelled as the Lewy body variant of AD now fall under the rubric of DLB (McKeith et al. 2000), nonetheless Lewy bodies containing ot-synuclein may be seen in some cases of AD with APP or PS1 mutations (Lippa et al. 1998). In one PS1 mutation, AT440, the clinical features fulfilled diagnostic criteria for DLB (Ishikawa et al. 2005). The precise interrelationship of AD and DLB remains to be defined.

The inclusion bodies, which are typical of tau-positive ubiquitin-positive FTD (Pick bodies), have been reported in some patients with AD associated with PS1 mutations (Larner and Doran 2006), for example M146L (Halliday et al. 2005), suggesting that their formation may be a downstream event of aberrant APP processing. In one family with the PS1 G183V mutation, the clinical phenotype was of FTD and the pathology was that of Pick's disease without amyloid plaques, even though cell lines transfected with this mutation did produce increased Aβ42 (Dermaut et al. 2004).

11.9 Clinical course and prognosis

(p.214) Epidemiological studies suggest that patients destined to develop AD on long-term follow-up have poorer cognitive performance at baseline, and this may affect not only episodic memory but other cognitive domains as well (Amieva et al. 2005). Whether such pre-morbid individuals can be reliably identified prospectively is still open to question, but if so they would be appropriate targets for future preventive therapies. Likewise, patients with MCI.

The clinical course of established AD is one of insidious progression, but this is not necessarily linear. Following diagnosis patients may enter a prolonged plateau phase before declining once again (Stern et al. 1994). MMSE scores in untreated patients may decline, remain stable, or improve during the first years of follow-up (Holmes and Lovestone 2003), indicating how unreliable the use of MMSE scores may be as a method for assessing drug efficacy, and hence pointing to the need for assessment of other (functional, global) domains when making decisions about drug continuation or withdrawal (Larner and Doran 2002). AD progression over time can be modelled using a cubic or logarithmic function of MMSE score (Mendiondo et al. 2000).

Longitudinal studies indicate the increasing prevalence of psychiatric symptoms with disease duration (Chen et al. 1991). These include the misidentification syndromes—delusional conditions in which patients incorrectly identify and reduplicate people, places, objects, or events (Larner 2006b), for example, the belief that a close relation has been replaced by an exact alien or double (illusion of doubles) or that the house is not one's own (Capgras' syndrome, or reduplicative paramnesia). Patients may mistake their own mirror reflection for that of a stranger (‘mirror sign’), leading to the belief that someone else is staying in the house (‘phantom boarder sign’). This stranger may be blamed for lost items, which may in turn lead to involvement of the police. Visual hallucinations are more typical of dementia with Lewy bodies/Parkinson's disease dementia (DLB/PDD).

Other distinctive behavioural features, again commoner in the later stages of AD, include ‘shadowing’ (a tendency to follow the spouse or carer around the house) and ‘sundowning’ (increased confusion, agitation, or disorientation at the end of the day). There may be complete reversal of sleep-wake cycle with daytime somnolence and nocturnal wakefulness, resulting in getting up and dressed in the small hours, making telephone calls to relatives or walking the dog in the middle of the night. Sundowning and reversal of sleep-wake pattern may reflect a disorder of circadian rhythms related to pathology in the supraoptic nuclei (Volicer et al. 2001). Wandering, restlessness, abnormal vocalizations, and verbal and physical aggression may also occur (Ballard et al. 2001).

ADL gradually become more restricted, progressing from instrumental to basic activities. A common complication is the development of BPSD, which, along with urinary incontinence, is associated with increased likelihood of nursing home placement. Survival time from symptom onset is usually of the order of 10–15 years, but in some cases the course is more rapid.

11.10 Management strategies

Ideally, AD should be identified in its earliest stages. This may be facilitated through the development of the concept of MCI, or with new imaging techniques. In the absence of reliable biomark-ers, however, the diagnosis remains clinical, with the risk of false negative and false positive diagnoses (Larner 2004a). Once established, it is now generally accepted that, unless there are exceptional reasons, patients should be told the diagnosis. Although relatives may prefer their loved ones not to be told, they themselves expect to be informed and would expect to be told if they had AD (Maguire et al. 1996). Knowing the diagnosis allows appropriate arrangements to be made, such as settling financial matters, allocating enduring power of attorney, applying for financial benefits, and making a living will.

(p.215) Guidelines for the management of established AD have been published (Doody et al. 2001), encompassing both non-pharmacological and pharmacological treatments, although these predate the introduction of memantine. Certainly the age of therapeutic nihilism is over and, although curative treatment is not on the horizon, nonetheless amelioration of the lives of patients and their carers is possible.

11.10.1 Non-pharmacological management

The diagnosis of AD carries with it implications for employment and lifestyle. Employment issues are particularly relevant in younger individuals who may have young dependents and significant financial liabilities (Baldwin and Murray 2003). Advice is also required on activities such as driving: in the UK there is a statutory requirement for patients to inform the Driver and Vehicle Licensing Authority (O'Neill 2005). Appropriate restrictions to ensure safety must be counterbalanced by encouraging patients to maintain other interests and activities, if necessary with supervision, such as gardening (Larner 2005c) or other exercise in order to avoid any lapse into apathy, itself one of the neuropsychiatric symptoms of AD. Simple external memory aids and a regular routine may be helpful in the early stages of disease. Quality of life measures are increasingly important as outcome measures in intervention trials, although reliable measurement presents difficulties in dementia.

A multidisciplinary approach to management is advisable, including occupational therapists, social workers, and speech and language therapists, particularly as the disease progresses and problems become more prevalent. Support for patients may take various forms including assistance from a carer at home for a number of hours per week, attendance at a day care centre, and intermittent admission for respite care where resources permit. This will also impact on carers, often elderly, who are often subject to significant caregiver burden, including financial costs. Long-term nursing home care may eventually become necessary, BPSD and urinary incontinence being the symptoms that most often precipitate institutionalization. Urinary incontinence may be treated with behaviour modification, scheduled toileting, or prompted voiding (Doody et al. 2001). Education of caregivers is recommended (Doody et al. 2001), as this in itself may reduce placement of patients in nursing homes (Brodaty et al. 2003). Families are often keen for information, and may use telephone helplines (Harvey et al. 1998) or the internet (Larner 2003b). Alzheimer associations are active in many countries.

11.10.2 Pharmacological treatments

There are many possible pharmacological treatments for AD (Jones 2000; Larner 2002; see also the Cochrane Library for up-to-date meta-analysis), targeting both cognitive and non-cognitive (behavioural and psychological) symptoms. To date, however, the only anti-dementia drugs of proven, albeit limited, efficacy are cholinomimetics, specifically cholinesterase inhibitors (ChEI), and memantine, an uncompetitive antagonist at the NMDA subtype of ionotropic glutamate receptors.

Cholinesterase inhibitors (ChEIs), specifically donepezil, rivastigmine, and galantamine, have been the principal focus of AD treatment since their widespread licensing in the late 1990s, based on clinical trial results and subsequent meta-analyses demonstrating efficacy (e.g. Lanctôt et al. 2003; Ritchie et al. 2004), although there have been dissenting voices (AD2000 Collaborative Group 2004; Kaduszkiewicz et al. 2005). There seems little doubt that ChEIs as a class do produce a modest benefit in some, but not all patients, not only in terms of cognition but also for BPSD (Holmes et al. 2004). ChEIs do not seem to slow the rate of conversion of MCI to AD (Salloway et al. 2004; Petersen et al. 2005). Generally they are well tolerated although gastrointestinal (p.216) side-effects may be limiting. In clinical practice, very high retention rate (〉 90% at 1 and 2 years) may be seen (Larner 2004c), contrary to the expectations of the national guidelines (National Institute for Clinical Excellence 2001). Few head-to-head studies of ChEIs have been performed, showing little clinical evidence of differential efficacy (Wilcock et al. 2003; Bullock et al. 2005), despite possible differences in pharmacological actions (dual inhibition of both acetyl- and butyryl-cholinesterase by rivastigmine; allosteric nicotinic receptor agonism by galantamine). Nonetheless, switching between different ChEIs when lack or loss efficacy becomes apparent may be attended with further response, albeit modest (Gauthier et al. 2003). The combination of ChEI and meman-tine (‘dual therapy’) may offer additional benefits over monotherapy (Tariot et al. 2004), in part because of memantine's different mode of action as a non-competitive NMDA receptor antagonist, which may protect against glutamate-mediated neurotoxocity (Wilcock 2003). Although trial data on memantine is sparse (Winblad and Poritis 1999; Reisberg et al. 2003), the reported beneficial effects in moderate to severe AD have been sufficient to gain product licence, although use of this drug is not reimbursed in some jurisdictions, leading to patchy uptake (‘postcode prescribing’).

A variety of other medications has been used for symptomatic treatment of AD based on limited trial data, although without being licensed for this purpose. These include anti-oxidants (vitamin E, selegiline), ginkgo, and piracetam. A controlled trial of vitamin E (ot-tocopherol) in moderate to severe AD did show a delay in clinical progression to certain time points, such as institutionalization, but no effect on cognition. The monoamine oxidase-B inhibitor selegiline had a similar effect (Sano et al. 1997). However, a trial of vitamin E in patients with MCI showed no slowing of conversion to AD over a 3 year period (Petersen et al. 2005). A meta-analysis of selegiline trials suggested short term improvements in cognition and ADLs but no evidence for long term effects (Wilcock et al. 2002). Extracts from the leaves of the maidenhair tree, Ginkgo biloba, have been a popular treatment for AD. Initially these were difficult to standardize but the component EGb761 may have some effects as an anti-oxidant. One meta-analysis found ginkgo to have moderate beneficial effects, but it is telling that of 50 trials analysed only four were deemed of sufficient quality to be included (Oken et al. 1998). Piracetam, 2-oxo-1-pyrrolidine acetamide, a cyclic derivative of gamma aminobutyric acid (GABA), marketed as a nootropic, may have a modest impact on cognitive impairment (Waegemans et al. 2002).

The treatment of BPSD remains a most difficult therapeutic area (Ballard et al. 2001) due to a relative paucity of clinical trials, and the risk of side-effects of medications. A variety of medications may be used including typical and atypical antipsychotics, anxiolytics and sedatives, antidepressants, anticonvulsants (for their mood-stabilizing, rather than their anti-epileptic, action), and β-blockers, although options have contracted recently with the finding of an association between atypical antipsychotics and cerebrovascular events. ChEIs and memantine may also have a place in the treatment of BPSD (Holmes et al. 2004; Gauthier et al. 2005). One school of thought attempts to match the behaviour syndrome to standard therapy (the ‘psychobehavioural metaphor’); hence agitation with dysphoria might be treated with an antidepressant, agitation with increased activity with a mood stabilizer, and aggression with delusions with an antipsychotic (Profenno et al. 2005). Another approach is case-specific, causality-targeted, largely psychosocial interventions, with or without pharmacotherapy; sometimes caregivers rather than patients may be the focus of the treatment plan (Bird 2005).

Other symptomatic features of AD may merit treatment. Seizures may be treated with standard anti-epileptic drugs, and are usually easily controlled (Mendez and Lim 2003). Myoclonus may require treatment with agents such as clonazepam, sodium valproate, or piracetam.

Many drugs are reported to cause confusion in the elderly, and hence may be best avoided in AD. It has been suggested that anticholinergic drugs accelerate cerebral amyloidosis and plaque pathology (Perry et al. 2003).

(p.217) 11.10.3 Future therapy

Although ChEIs are licensed as symptomatic treatment for mild-to-moderate AD, there is some evidence that they may have disease-modifying effects, perhaps most strikingly illustrated in an observational study suggesting reduced prevalence of institutionalization in treated patients (Lopez et al. 2002). Similar low levels of nursing home placement have been noted elsewhere (Larner, in preparation). However, the principal hope for future disease-modifying therapy for AD rests with agents that target the key pathophysiological pathways, specifically amyloid deposition.

The observation that transgenic mice bearing human APP mutations, animals destined to develop amyloid pathology, had a reduced burden of pathology following immunization with A peptides, in association with the production of high titres of anti-Aβ antibodies (Schenk et al. 1999), stimulated the development of human ‘amyloid vaccines’, or immunotherapy (Heppner et al. 2004). The pivotal clinical trial had to be halted because some patients (6%) developed meningoencephalitis. Nonetheless, trial data suggested some clinical benefit (Gilman et al. 2005). Perhaps surprisingly, the neuroradiological arm of the study showed evidence of increased brain shrinkage in treated as compared to placebo patients (Fox et al. 2005). One possible explanation of this observation is that it reflects removal of amyloid from the brain, which may correlate with limited neuropathological evidence of reduced amyloid burden in vaccine-treated patients (Nicoll et al. 2003). Future trials of new immunotherapeutic agents seem likely. Administration of antibodies against Aβ, which may be found in some commercially available intravenous immunoglobulin preparations, has also been suggested (Dodel et al. 2002).

Aβ biosynthesis from APP requires the action of β- and γ-secretase enzymes. Inhibitors of these enzymes, or modulators of α-secretase, might thus have a therapeutic role; various agents have been designed for this purpose (Larner 2004d). Endoproteolytic cleavage of Aβ has also been considered as a therapeutic approach, although the possibility that N-terminally truncated Aβ peptides may be of pathogenetic significance (Larner 1999, 2001) may limit this approach. Anti-apoptotic agents currently remain experimental (Larner 2000), as do cell transplantation and regeneration strategies (Larner and Sofroniew 2003).

Epidemiological data suggest that delaying the onset of AD by 5 years would lead to a dramatic reduction in the incidence and prevalence of AD (Jorm and Jolley 1998). The increased societal burden of AD consequent upon an ageing population demands continued efforts to define disease-modifying agents.


Thanks to my colleagues Paula Hancock, Mark Doran, and Eric Ghadiali.


Bibliography references:

AD2000 Collaborative Group (2004). Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 363, 2105–15.

Ala, T.A., Hughes, L.F., Kyrouac, G.A., Ghobrial, M.W., and Elble, R.J. (2002). The Mini-Mental State exam may help the differentiation of dementia with Lewy bodies and Alzheimer's disease. Int. J. Geriatr. Psychiatry 17, 503–9.

Alzheimer, A. (1907). Über eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatrie Psychisch-Gerichtlich Med. 64, 146–8.

Amieva, H., Jacqmin-Gadda, H., Orgogozo, J-M., et al. (2005). The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain 128, 1093–101.

Andreasen, N. and Blennow, K. (2005). CSF biomarkers for mild cognitive impairment and early Alzheimer's disease. Clin. Neurol. Neurosurg. 107, 165–73.

(p.218) Arnold, S.E., Hyman, B.T., Flory, J., Damasio, A.R. and Van Hoesen, G.W. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1, 103–16.

Arriagada, P.V., Growdon, J.H., Hedley White, E.T., and Hyman, B.T. (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631–9.

Baldwin, R. and Murray, M. (eds.) (2003). Younger people with dementia: a multidisciplinary approach. Martin Dunitz, London.

Ball, J.A., Lantos, P.L., Jackson, M., Marsden, CD., Scadding, J.W., and Rossor, M.N. (1993). Alien hand sign in association with Alzheimer's histopathology J. Neurol. Neurosurg. Psychiatry 56, 1020–3.

Ball, M.J. (1977). Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia: a quantitative study. Acta Neuropathol. (Berl.) 37, 111–18.

Ballard, C.G., O'Brien, J., James, I., and Swann, A. (2001). Dementia: management of behavioural and psychological symptoms. Oxford University Press, Oxford.

Barrett, A. (1913). A case of Alzheimer's disease with unusual neurological disturbances. J. Nerv. Ment. Dis. 4, 361–74.

Bennett, D.A., Beckett, L.A., Murray, A.M., et al. (1996). Prevalence of parkinsonian signs and associated mortality in a community population of older people. N. Engl. J. Med. 334, 71–6.

Benson, D.F., Davis, R.J., and Snyder, B.D. (1988). Posterior cortical atrophy. Arch. Neurol. 45, 789–93.

Bertram, L. and Tanzi, R.E. (2005). Genetics of Alzheimer's disease. In Neurodegenerative diseases. Neurobiology, pathogenesis and therapeutics (ed. M.F. Beal, A.E. Lang, and A. Ludolph), pp. 441–51. Cambridge University Press, Cambridge.

Bierer, L.M., Hof, PR., Purohit, D.P., et al. (1995) Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease. Arch. Neurol. 52, 81–8.

Binetti, G., Magni, E., Padovani, A., Cappa, S.F., Bianchetti, A., and Trabucchi, M. (1996). Executive dysfunction in early Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 60, 91–3.

Bird, M. (2005). A predominantly psychosocial approach to behaviour problems in dementia: treating causality. In Dementia, 3rd edn (ed. A. Burns, J. O'Brien, and D. Ames), pp. 499–509. Hodder Arnold, London.

Boeve, B.F., Maraganore, M.D., Parisi, J.E., et al. (1999). Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53, 795–800.

Braak, H. and Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82, 239–59.

Braak, H., Braak, E., Grundke-Iqbal, I., and Iqbal, K. (1986). Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside the neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65, 351–5.

Brodaty, H., Green, A., and Koschera, A. (2003). Meta-analysis of psychosocial interventions of caregivers of people with dementia. J. Am. Geriatr. Soc. 51, 657–64.

Bullock, R., Touchon, J., Bergman, H., et al. (2005). Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period. Curr. Med. Res. Opin. 21, 1317–27.

Burns, A., Jacoby, R., and Levy, R. (1990). Psychiatric phenomena in Alzheimer's disease: IV. Disorders of behaviour. Br. J. Psychiatry 157, 86–94.

Burns, A., Lawlor, B., and Craig, S. (1999). Assessment scales in old age psychiatry. Martin Dunitz, London.

Bush, A.I., Pettingell, W.H., Multhaup, G., et al. (1994). Rapid induction of Alzheimer Aβ amyloid formation by zinc. Science 265, 1464–7.

Chen, J-Y., Stern, Y., Sano, M., etal. (1991). Cumulative risk of developing extrapyramidal signs, psychosis or myoclonus in the course of Alzheimer's disease. Arch Neurol. 48, 1141–3.

Chui, H. and Lee, AY (2002). Clinical criteria for dementia subtypes. In Evidence-based dementia practice (ed. N. Qizilbash etal), pp. 106–13. Blackwell, Oxford.

(p.219) Clarfield, A.M. (2003). The decreasing prevalence of reversible dementias: an updated meta-analysis. Arch. Intern. Med. 163, 2219–29.

Corder, E.H., Saunders, A.M., Strittmatter, W.J., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–3.

Cronin-Golomb, A. and Hof, P.R. (eds.) (2004). Vision in Alzheimer's disease. Karger, Basel.

Cronin-Stubbs, D., Beckett, L.A., Scherr, P.A., etal. (1996). Weight loss in people with Alzheimer's disease: a prospective population based analysis. Br. Med. J. 314, 178–9.

Crook, R., Verkkoniemi, A., Perez-Tur, J., et al. (1998). A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature Med. 4, 452–5.

Cruts, M., van Duijn, CM., Backhovens, H., et al. (1998). Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum. Mol. Genet. 7, 43–51.

Crystal, H.A., Horoupian, D.S., Katzman, R., and Jotkowitz, S. (1982). Biopsy-proved Alzheimer disease presenting as a right parietal lobe syndrome. Ann. Neurol. 12, 186–8.

Delacourte, A. (1990). General and dramatic glial reaction in Alzheimer brains. Neurology 40, 33–7.

Delacourte, A., David, J.P., Sergeant, ∼N., etal. (1999). The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52, 1158–65.

Dermaut, B., Kumar-Singh, S., Engelborghs, S., et al. (2004). A novel presenilin 1 mutation associated with Pick's disease but not β-amyloid plaques. Ann. Neurol. 55, 617–25.

Dodel, R., Hampel, H., Depboylu, C., et al. (2002). Human antibodies against amyloid β peptide: a potential treatment for Alzheimer's disease. Ann. Neurol. 52, 253–6.

Doll, R. (1993). Review: Alzheimer's disease and environmental aluminium. Age Ageing 22, 138–53.

Doody, R.S., Stevens, J.C., Beck, C., et al. (2001). Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56, 1154–66.

Doraiswamy, P.M. and Xiong, G.L. (2006). Pharmacological strategies for the prevention of Alzheimer's disease. Expert Opin. Pharmacother. 7, 1–10.

Doran, M. and Larner, A.J. (2004). Prominent behavioural and psychiatric symptoms in early-onset Alzheimer's disease in a sib pair with the presenilin-1 gene R269G mutation. Eur. Arch. Psychiatry Clin. Neurosci. 254, 187–9.

Doran, M., du Plessis, D.G., Enevoldson, T.P., Fletcher, N.A., Ghadiali, E., and Larner, A.J. (2003). Pathological heterogeneity of clinically diagnosed corticobasal degeneration. J. Neurol. Sci. 216, 127–34.

Doran, M., Vinjamuri, S., Collins, J., Parker, D., and Larner, A.J. (2005). Single-photon emission computed tomography perfusion imaging in the differential diagnosis of dementia: a retrospective regional audit. Int. J. Clin. Pract. 59, 496–500.

Dougall, N.J., Bruggink, S., and Ebmeier, K.P. (2003). The clinical use of 99mTc-HMPAO-SPECT in Alzheimer's disease a systematic review. In SPECT in dementia (ed. K.P. Ebmeier), pp. 4–37. Karger, Basel.

Etminan, M., Gill, S., and Samii, A. (2003). Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. Br. Med. J. 327, 128–31.

Fleminger, S., Oliver, D.L., Lovestone, S., Rabe-Hesketh, S., and Giora, A. (2003). Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on: a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–62.

Folstein, M.F., Folstein, S.E., and McHugh, P.R. (1975). ‘Mini-Mental State.’ A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–98.

Forette, F., Seux, M.L., Staessen, J.A., et al. for the Syst-Eur investigators (1998). Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 352, 1347–51.

(p.220) Forette, F., Seux, M.L., Staessen, J.A., et al. for the Syst-Eur investigators (2002). The prevention of dementia with anti-hypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch. Intern. Med. 162, 2046–52.

Fox, N.C., Freeborough, P.A., and Rossor, M.N. (1996a). Visualisation and quantification of atrophy in Alzheimer's disease. Lancet 348, 94–7.

Fox, N.C., Warrington, E.K., Freeborough, P.A., et al. (1996b). Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal study. Brain 119, 2001–7.

Fox, N.C., Black, R.S., Gilman, S., et al. (2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64, 1563–72.

Friedland, R.P., Fritsch, T., Smyth, K.A., et al. (2001). Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control group members. Proc. Natl. Acad. Sci. USA 98, 3440–5.

Galton, C.J., Patterson, K., Xuereb, J.H., and Hodges, J.R. (2000). Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 123, 484–98.

Garrard, P., Patterson, K., and Hodges, J.R. (2004). Semantic processing in Alzheimer's disease. In Cognitive neuropsychology of Alzheimer's disease, 2nd edn (ed. R.G. Morris and J.T. Becker), pp. 179–96. Oxford University Press, Oxford.

Garrard, P., Lambon Ralph, M.A., Patterson, K., Pratt, K., and Hodges, J.R. (2005). Semantic feature knowledge and picture naming in dementia of Alzheimer's type: a new approach. Brain Lang. 93, 79–94.

Gauthier, S., Emre, M., Farlow, M.R., Bullock, R., Grossberg, G.T., and Potkin, S.G. (2003). Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors. Curr. Med. Res. Opin. 19, 707–14.

Gauthier, S., Wirth, Y., and Möbius, H.J. (2005). Effects of memantine on behavioural symptoms in Alzheimer's disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled trials. Int. J. Geriatr. Psychiatry 20, 459–64.

Gilman, S., Koller, M., Black, R.S., et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–62.

Goate, A., Chartier, H.M., Mullan, M., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–6.

Godbolt, A.K., Beck, J.A., Collinge, J., et al. (2004). A presenilin 1 R278I mutation presenting with language impairment. Neurology 63, 1702–4.

Goedert, M., Spillantini, M.G., Cairns, N.J., and Crowther, R.A. (1992). Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–68.

Gomez-Isla, T., Hollister, R., West, H., et al. (1997). Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24.

Graeber, M.B., Kösel, S., Egensperger, R., et al. (1997). Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics 1, 73–80.

Graves, A.B., Bowen, J.D., Rajaram, L., etal. (1999). Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon 4 status. Neurology 53, 1480–7.

Halliday, G.M., Song-Yun, J.C., Lepar, G., et al. (2005). Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann. Neurol. 57, 139–43.

Hansen, L.A., Salmon, D., Galasko, D., et al. (1990). The Lewy body variant of Alzheimer's disease: a clinical and pathological entity. Neurology 40, 1–8.

Harrington, C.R., Wischik, C.M., McArthur, F.K., et al. (1994). Alzheimer's disease-like changes in tau protein processing: association with aluminium accumulation in brains of renal dialysis patients. Lancet 343, 993–7.

Harvey, R., Roques, P.K., Fox, N.C., and Rossor, M.N. (1998). CANDID—Counselling and Diagnosis in Dementia: a national telemedicine service supporting the care of younger patients with dementia. Int. J. Geriatr. Psychiatry 13, 381–8.

(p.221) Henderson, V.W. (1997). The epidemiology of estrogen replacement therapy and Alzheimer's disease. Neurology 48 (suppl. 17), S27–35.

Hendrie, H.C., Ogunniyi, A., Hall, K.S., et al. (2001). Incidence of dementia and Alzheimer disease in two communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. J. Am. Med. Assoc. 285, 739–47.

Heppner, F.L., Gandy, S., and McLaurin, J. (2004). Current concepts and future prospects for Alzheimer disease vaccines. Alzheimer Dis. Assoc. Dis. 18, 38–43.

Hodges, J.R. (1994). Neurological aspects of dementia and normal aging. In Dementia and normal aging (ed. F.A. Huppert, C. Brayne, and D.W. O'Connor), pp. 118–29. Cambridge University Press, Cambridge.

Holmes, C. and Lovestone, S. (2003). Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications. Age Ageing 32, 200–4.

Holmes, C., Wilkinson, D., Dean, C., et al. (2004). The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63, 214–19.

Huang, W., Qiu, C., Winblad, B., and Fratiglioni, L. (2002). Alcohol consumption and incidence of dementia in a community sample aged 75 years and older. J. Clin. Epidemiol. 55, 959–64.

Huff, F.J., Boller, F., Luchelli, F., Querriera, R., Beyer, J., and Belle, S. (1987). The neurologic examination in patients with probable Alzheimer's disease. Arch. Neurol. 44, 929–32.

In't Veld, B.A., Ruitenberg, A., Hofman, A., et al. (2001). Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515–21.

Ishikawa, A., Piao, Y.S., Miyashita, A., et al. (2005). A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann. Neurol. 57, 429–34.

Iversen, L.L., Mortishire-Smith, R.J., Pollack, SJ., and Shearman, M.S. (1995). The toxicity in vitro of Pamyloid protein. Biochem. J. 311, 1–16.

Jagust, W.J., Davies, P., Tiller-Borcich, J.K., and Reed, B.R. (1990). Focal Alzheimer's disease. Neurology 40, 14–19.

Janssen, J.C., Beck, J.A., Campbell, T.A., et al. (2003). Early onset familial Alzheimer's disease. Mutation frequency in 31 families. Neurology 60, 235–9.

Janssen, J.C., Godbolt, A.K., Ioannidis, P., Thompson, EJ., and Rossor, M.N. (2004). The prevalence of oligoclonal bands in the CSF of patients with primary neurodegenerative dementia. J. Neurol. 251, 184–8.

Jarrett, J.T., Berger, E.P., and Lansbury, P.T Jr. (1993). The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–7.

Johnson, J.K., Head, E., Kim, R., Starr, A., and Cotman, C.W. (1999). Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch. Neurol. 56, 1233–9.

Jones, R. (2000). Drug treatment in dementia. Blackwell Science, Oxford.

Jorm, A.F. (1985). Subtypes of Alzheimer's dementia: a conceptual analysis. Psychol. Med. 15, 543–53.

Jorm, A.F. (1990). The epidemiology of Alzheimer's disease and related disorders. Chapman and Hall, London.

Jorm, A.F. and Jolley, D. (1998). The incidence of dementia: a meta-analysis. Neurology 51, 728–33.

Kaduszkiewicz, H., Zimmermann, T., Beck-Bornholdt, HP, and van den Bussche, H. (2005). Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. Br. Med. J. 331, 321–3.

Kidd, M. (1963). Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197, 192–3.

Kivipelto, M., Helkala, E-L., Laakso, M.P., et al. (2001). Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. Br. Med. J. 322, 1447–51.

Klünemann, H.H., Fronhöfer, W., Wurster, H., Fischer, W., Ibach, B., and Klein, H.E. (2002). Alzheimer's second patient: Johann F. and his family. Ann. Neurol. 52, 520–3.

(p.222) Klunk, W.E., Engler, H., Nordberg, A., et al. (2004). Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann. Neurol. 55, 306–19.

Knopman, D.S., DeKosky, S.T., Cummings, J.L., et al. (2001). Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56, 1143–53.

Knott, V., Mohr, E., Mahoney, C, and Ilivitsky, V. (2001). Quantitative electroencephalography in Alzheimer's disease: comparison with a control group, population norms and mental status. J. Psychiatry Neurosci. 26, 106–16.

Lanctôt, K.L., Herrmann, N., Yau, K.K., et al. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Can. Med. Assoc. J. 169, 557–64.

Larner, A.J. (1995a). Hypothesis: physiological and pathological interrelationships of amyloid P peptide and the amyloid precursor protein. BioEssays 17, 819–24.

Larner, A.J. (1995b). The cortical neuritic dystrophy of Alzheimer's disease: nature, significance, and possible pathogenesis. Dementia 6, 218–24.

Larner, A.J. (1997a). Neurite growth-inhibitory properties of amyloid Ppeptides in vitro: Aβ25–35, but not Aβ1–40, is inhibitory. Neurosci. Res. Commun. 20, 147–55.

Larner, A.J. (1997b). The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J. Neuropathol. Exp. Neurol. 56, 214–15.

Larner, A.J. (1997c). The cerebellum in Alzheimer's disease: a review. Dementia Geriatr. Cogn. Dis. 8, 203–9.

Larner, A.J. (1999). Hypothesis: amyloid β-peptides truncated at the N-terminus contribute to the pathogenesis of Alzheimer's disease. Neurobiol. Aging 20, 65–9.

Larner, A.J. (2000). Neuronal apoptosis as a therapeutic target in neurodegenerative disease. Expert Opin. Therapeutic Patents 10, 1493–518.

Larner, A.J. (2001). N-terminally truncated amyloid β-peptides and Alzheimer's disease. Neurobiol. Aging 22, 343.

Larner, A.J. (2002). Alzheimer's disease: targets for drug development. Mini Rev. Medicinal Chem. 2, 1–9.

Larner, A.J. (2003a). MMSE subscores and the diagnosis of dementia with Lewy bodies. Int. J. Geriatr. Psychiatry 18, 855–6.

Larner, A.J. (2003b). Use of the internet and of the NHS Direct telephone helpline for medical information by a cognitive function clinic population. Int. J. Geriatr. Psychiatry 18, 118–22.

Larner, A.J. (2004a). Getting it wrong: the clinical misdiagnosis of Alzheimer's disease. Int. J. Clin. Pract. 58, 1092–4.

Larner, A.J. (2004b). Use of MMSE to differentiate Alzheimer's disease from dementia with Lewy bodies. Int. J. Geriatr. Psychiatry 19, 1209–10.

Larner, A.J. (2004c). Cholinesterase inhibitor use at a cognitive function clinic. Prog. Neurol. Psychiatry 8 (4), 14, 18, 20.

Larner, A.J. (2004d). Secretases as therapeutic targets in Alzheimer's disease: patents 2000–2004. Expert Opin. Therapeutic Patents 14, 1403–20.

Larner, A.J. (2005a). ‘Dementia unmasked’: atypical, acute aphasic, presentations of neurodegenerative dementing disease. Clin. Neurol. Neurosurg. 108, 8–10.

Larner, A.J. (2005b). An audit of the Addenbrooke's Cognitive Examination (ACE) in clinical practice. Int. J. Geriatr. Psychiatry 20, 593–4.

Larner, A.J. (2005c). Gardening and dementia. Int. J. Geriatr. Psychiatry 20, 796–7.

Larner, A.J. (2006a). ‘Frontal variant Alzheimer's disease’: a reappraisal. Clin. Neurol. Neurosurg. 108 (7), 705–8.

Larner, A.J. (2006b). A dictionary of neurological signs, 2nd edition. Springer, New York.

Larner, A.J. (2006c). Neurological signs of aging. In Principles and practice of geriatric medicine, 4th edn (ed. M.S.J. Pathy, A.J. Sinclair, and J.E. Morley), pp. 743–50. Wiley, Chichester.

Larner, A.J. (2006d). An audit of the Addenbrooke's Cognitive Examination (ACE) in clinical practice. 2. Longitudinal change. Int. J. Geriatr. Psychiatry 21 (7), 698–9.

(p.223) Larner, A.J. and Doran, M. (2002). Broader assessment needed for treatment decisions in AD. Prog. Neurol. Psychiatry 6 (3), 5–6.

Larner, A.J. and Doran, M. (2004). Prion disease at a regional neuroscience centre: retrospective audit. J. Neurol. Neurosurg. Psychiatry 75, 1789–90.

Larner, A.J. and Doran, M. (2006). Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J. Neurol. 253, 139–58.

Larner, A.J. and Sofroniew. M.V. (2003). Mechanisms of cellular damage and recovery. In Handbook of neurological rehabilitation, 2nd edn (ed. R.J. Greenwood, M.P. Barnes, T.M. McMillan, and CD. Ward), pp. 71–98. Psychology Press, Hove.

Launer, L.J., Andersen, K., Dewey, M.E., et al. (1999). Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work groups. European Studies of Dementia. Neurology 52, 78–84.

Levine, D.N., Lee, J.M., and Fisher, C.M. (1993). The visual variant of Alzheimer's disease: a clinicopatho-logic case study. Neurology 43, 305–13.

Levy-Lahad, E., Wasco, W, Poorkaj, P., et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973–7.

Lippa, C.F., Fujiwara, H., Mann, D.M.A., et al. (1998). Lewy bodies contain altered OC-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am.J. Pathol. 153, 1365–70.

Lithell, H., Hansson, L., Skoog, I., et al. for the SCOPE Study Group (2003). The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J. Hypertens. 21, 875–86.

Lopez, O.L., Becker, J.T., Wisniewski, S., Saxton, J., Kaufer, D.I., and DeKosky, S.T (2002). Cholinesterase inhibitor treatment alters the natural history of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 72, 310–14.

Lowenberg, K. and Waggoner. R.W (1934). Familial organic psychosis (Alzheimer's type). Arch. Neurol. Psychiatry 31, 737–54.

Lozsadi, D.A. and Larner, A.J. (2006). Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer's disease. Dementia Geriatr. Cogn. Dis. 22, 121–4.

Mackenzie Ross, S.J., Graham, N., Stuart-Green, L., et al. (1996). Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 61, 388–95.

Maguire, C.P., Kirby, M., Coen, R., Coakley, D., Lawlor, B.A., and O'Neill, D. (1996). Family members' attitudes toward telling the patient with Alzheimer's disease their diagnosis. Br. Med. J. 313, 529–30.

Martin, J.J., Gheuens, J., Bruyland, M., et al. (1991). Early-onset Alzheimer's disease in 2 large Belgian families. Neurology 41, 62–8.

Masse, I., Bordet, R., Deplanque, D., et al. (2005). Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 76, 1624–9.

Mathurananth, P.S., Nestor, P.J., Berrios, G.E., Rakowicz, W., and Hodges, J.R. (2000). A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia. Neurology 55, 1613–20.

McGeer, P.L., Schulzer, M., and McGeer, E.G. (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47, 425–32.

McKee, A.C., Kosik, K.S., and Kowall, N.W (1991). Neuritic pathology and dementia in Alzheimer's disease. Ann. Neurol. 30, 156–65.

McKeith, I.G., Ballard, C.G., Perry, R.H., et al. (2000). Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 54, 1050–8.

McKhann, G., Drachman, D., Folstein, M., et al. (1984). Clinical diagnosis of Alzheimer's disease. Report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Service Task forces on Alzheimer's disease. Neurology 34, 939–44.

Mehta, N.D., Refolo, L.M., Eckman, C., et al. (1998). Increased Aβ42(43) from cell lines expressing presenilin 1 mutations. Ann. Neurol. 43, 256–8.

(p.224) Mendez, M.F. and Lim, G.T.H. (2003). Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 20, 791–803.

Mendez, M.F. and Zander, B.A. (1991). Dementia presenting with aphasia: clinical characteristics. J. Neurol. Neurosurg. Psychiatry 54, 542–5.

Mendez, M.F., Ghajarania, M., and Perryman, K.M. (2002). Posterior cortical atrophy: clinical characteristics and differences compared to Alzheimer's disease. Dementia Geriatr. Cogn. Dis. 14, 33–40.

Mendiondo, M.S., Ashford, J.W., Kryscio, R.J., and Schmitt, FA. (2000). Modelling Mini Mental State Examination changes in Alzheimer's disease. Statistics Med. 19, 1607–16.

Mesulam, M.M. (2001). Primary progressive aphasia. Ann. Neurol. 49, 425–32.

Mills, C.K. (1900). A case of unilateral ascending paralysis probably presenting a new form of degenerative disease. J. Nerv. Ment. Dis. 27, 195–200.

Mioshi, E., Dawson, K., Mitchell, J., Arnold, R., and Hodges, J.R. (2006). The Addenbrooke's Cognitive Examination Revised (ACER): a brief cognitive test battery for dementia screening. Int. J. Geriatr. Psychiatry 21, 1078–85.

Mirra, S.S., Heyman, A., McKeel, D., et al. (1991). The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41, 479–86.

Morris, J., Heyman, A., Mohs, R., etal. (1989). The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology 39, 1159–65.

Mountjoy, C.Q., Roth, M., Evans, NJ.R., and Evans, H.M. (1983). Cortical neuronal counts in normal elderly controls and demented patients. Neurobiol. Aging 4, 1–11.

MRC CFAS (2001). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study. Lancet 357, 169–75.

Nachev, PC. and Larner, A J. (1996). Zinc and Alzheimer's disease. Trace Elements Electrolytes 13, 55–9.

Näslund, J., Haroutunian, V., Mohs, R., et al. (2000). Correlation between elevated levels of amyloid Ppeptide in the brain and cognitive decline. J. Am. Med. Assoc. 283, 1571–7.

National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease (1997). Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol. Aging 18 (suppl. 14), S1–2.

National Institute for Clinical Excellence (2001). Guidance on the use of donepezil, rivastigmine and galantamine for the treatment of Alzheimer's disease, Technology Appraisal Guidance No. 19. NICE, London.

Natté, R., Maat-Schieman, M.L.C., Haan, J., Bornebroek, M., Roos, R.A.C., and van Duinen, S.G. (2001). Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann. Neurol. 50, 765–72.

Nicoll, J.A.R., Roberts, G.W., and Graham, D.I. (1995). Apolipoprotein E epsilon-4 allele is associated with deposition of amyloid beta-protein following head injury. Nature Med. 1, 135–7.

Nicoll, J.A.R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., and Weller, R.O. (2003). Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nature Med. 9, 448–52.

Nolan, K.A., Lino, M.M., Seligmann, A.W., et al. (1998). Absence of vascular dementia in an autopsy series from a dementia clinic. J. Am. Geriatr. Soc. 46, 597–604.

Oken, B.S., Storzbach, D.M., and Kaye, J.A. (1998). The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch. Neurol. 55, 1409–15.

O'Neill, D. (2005). Driving. In Dementia, 3rd edn (ed. A. Burns, J. O'Brien, and D. Ames), pp. 244–51. Hodder Arnold, London.

(p.225) Pantel, J. and Schröder, J. (1996). Posterior cortical atrophy—a new dementia syndrome or a form of Alzheimer's disease? [in German]. Fortschr. Neurol. Psychiat. 64, 492–508.

Perry, E.K., Kilford, L., Lees, A.J., Burn, D., and Perry, R.H. (2003). Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann. Neurol. 54, 235–8.

Petersen, R.C. (ed.) (2003). Mild cognitive impairment. Aging to Alzheimer's disease. Oxford University Press, Oxford.

Petersen, R.C. (2004). Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–94.

Petersen, R.C., Thomas, R.G., Grundman, M., et al. (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–88.

Pogacar, S. and Williams, R.S. (1984). Alzheimer's disease presenting as slowly progressive aphasia. R. I. Med. J. 67, 181–5.

Poirier, J. (1994). Apolipoprotein E in CNS models of CNS injury and in Alzheimer's disease. Trends Neurosci. 17, 525–30.

Polvikoski, T., Sulkava, R., Haltia, M., et al. (1995). Apolipoprotein E., dementia, and cortical deposition of β-amyloid protein. N. Engl. J. Med. 333, 1242–7.

Profenno, L., Tariot, P., Loy, R., and Ismail, S. (2005). Treatments for behavioural and psychological symptoms in Alzheimer's disease and other dementias. In Dementia, 3rd edn (ed. A. Burns, J. O'Brien, and D. Ames), pp. 482–98. Hodder Arnold, London.

Reinwald, S., Westner, I.M., and Niedermaier, N. (2004). Rapidly progressive Alzheimer's disease mimicking Creutzfeldt–Jakob disease. J. Neurol. 251, 1020–2.

Reisberg, B., Doody, R., Stöffler, A., Schmitt, F., Ferris, S., Möbius, H J. for the Memantine Study Group (2003). Memantine in moderate-to-severe Alzheimer's disease. N. Engl. J. Med. 348, 1333–41.

Ritchie, C.W., Bush, A.I., Mackinnon, A., et al. (2003). Metal–protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer's disease: a pilot phase 2 clinical trial. Arch. Neurol. 60, 1685–91.

Ritchie, C.W., Ames, D., Clayton, T., and Lai, R. (2004). Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine and rivastigmine for the treatment of Alzheimer disease. Am. J. Geriatr. Psychiatry 12, 358–69.

Roberts, G.W., Gentlemen, S.M., Lynch, A., and Graham, D.I. (1991). βA4 amyloid protein deposition in brain after head trauma. Lancet 338, 1422–3.

Roberts, G.W., Gentlemen, S.M., Lynch, A., Murray, L., Landon, M., and Graham, D.I. (1994). Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 57, 419–25.

Robertson, B., Blennow, K., Gottfries, C.G., and Wallin, A. (1998). Delirium in dementia. Int. J. Geriatr. Psychiatry 13, 49–56.

Rockwood, K., Cosway, S., Carver, D., et al. (1999). The risk of dementia and death following delirium. Age Ageing 28, 551–6.

Rockwood, K., Kirkland, S., Hogan, D.B., et al. (2002). Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch. Neurol. 59, 223–7.

Rogaev, E.I., Sherrington, R., Rogaeva, E.A., et al. (1995). Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to Alzheimer's disease type 3. Nature 376, 775–8.

Rosen, W.G., Mohs, R.C., and Davis, K.L. (1984). A new rating scale for Alzheimer's disease. Am. J. Psychiatry 141, 1356–64.

Roses, A.D. (1996). Apolipoprotein E alleles as risk factors in Alzheimer's disease. Ann. Rev. Med. 47, 387–400.

Rossor, M.N., Tyrrell, P.J., Warrington, E.K., Thompson, P.D., Marsden, CD., and Lantos, P. (1999). Progressive frontal gait disturbance with atypical Alzheimer's disease and corticobasal degeneration. J. Neurol. Neurosurg. Psychiatry 67, 345–52.

(p.226) Royall, D.R. (2000). Executive cognitive impairment: a novel perspective on dementia. Neuroepidemiology 19, 293–9.

Salloway, S., Ferris, S., Kluger, A., et al. (2004). Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 63, 651–7.

Sano, M., Ernesto, C., Thomas, R.G., et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336, 1216–22.

Saunders, A.M. (2001). Apolipoprotein E as a risk factor for Alzheimer's disease. In Neurobiology of Alzheimer's disease, 2nd edn (ed. D. Dawbarn and S.J. Allen), pp. 207–26. Oxford University Press, Oxford.

Saunders, A.M., Strittmatter, W.J., Schmechel, D., et al. (1993). Association of apolipoprotein ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1462–72.

Schenk, D., Barbour, R., Dunn, W., et al. (1999). Immunization with amyloidpi attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–7.

Scheuner, D., Eckman, C., Jensen, M., et al. (1996). Secreted amyloid βprotein similar to that in the amyloid plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864–70.

Sherrington, R., Rogaev, E.I., Liang, Y., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–60.

Shobab, L.A., Hsiung, G-Y.R., and Feldman, H.H. (2005). Cholesterol in Alzheimer's disease. Lancet Neurol. 4, 841–52.

Shulman, K. and Feinstein, A. (2003). Quick cognitive screening for clinicians: mini mental, clock drawing and other brief tests. Martin Dunitz, London.

Shumaker, S.A., Legault, C., Rapp, S.R., et al. (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. J. Am. Med. Assoc. 289, 2651–62.

Silverman, D., Small, G., Chang, C., et al. (2001). Positron emission tomography in evaluation of dementia—regional brain metabolism and long-term outcome. J. Am. Med. Assoc. 286, 2120–7.

Simchowicz, T (1911). Histologische Studien über die Senile Demenz. In Histologische und histopathologis-che Arbeiten über die Grosshirnrinde mit besonderer Beruchsichtigung derpathologischen Anatomie der Geisteskrankheiten (ed. F. Nissl and A. Alzheimer), Vol. 4, pp. 267–444. Fischer, Jena.

Simons, M., Schwärzler, F., Lütjohann, D., et al. (2002). Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–50.

Snowdon, D.A., Kemper, S.J., Mortimer, J.A., Greiner, L.H., Wekstein, D.R., and Markesbery, W.R. (1996). Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. J. Am. Med. Assoc. 275, 528–32.

Snowdon, D.A., Greiner, L.H., Mortimer, J.A., et al. (1997). Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. J. Am. Med. Assoc. 277, 813–17.

Stern, R.G., Mohs, R.C., Davidson, M., et al. (1994). A longitudinal study of Alzheimer's disease: measurement, rate and predictors of cognitive deterioration. Am. J. Psychiatry 151, 390–6.

Stewart, R. (2005). Vascular factors in Alzheimer's disease. In Dementia, 3rd edn (ed. A. Burns, J. O'Brien, and D. Ames), pp. 436–43. Hodder Arnold, London.

Tabira, T., Chui, D.H., Nakayama, H., Kuroda, S., and Shibuya, M. (2002). Alzheimer's disease with spastic paresis and cotton wool type plaques. J. Neurosci. Res. 70, 367–72.

Talbot, PR., Lloyd, J.J., Snowden, J.S., Neary, D., and Testa, H.J. (1998). A clinical role for 99mTc-HMPAO SPECT in the investigation of dementia? J. Neurol. Neurosurg. Psychiatry 64, 306–13.

Tariot, P.N., Farlow, M.R., Grossberg, G.T., et al. (2004). Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. J. Am. Med. Assoc. 291, 317–24.

(p.227) Terry, R.D. (1963). The fine structure of neurofibrillary tangles in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 22, 629–41.

Terry, R.D., Masliah, E., Salmon, D.P., et al. (1991). Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–80.

Tschampa, H.J., Neumann, M., Zerr, I., et al. (2001). Patients with Alzheimer's disease and dementia with Lewy bodies mistaken for Creutzfeldt–Jakob disease. J. Neurol. Neurosurg. Psychiatry 71, 33–9.

Tzourio, C., Anderson, C., Cahpman, N., et al. for the PROGRESS Collaborative Group (2003). Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch. Intern. Med. 163, 1069–75.

Van Broeckhoven, C., Backhoven, H., Cruts, M., et al. (1994). ApoE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neurosci. Lett. 169, 179–80.

van Gool, W.A., Aisen, P.S., and Eikelenboom, P. (2003). Antiinflammatory therapy in Alzheimer's disease: is hope still alive? J. Neurol. 250, 788–92.

Verghese, J., Lipton, R.B., Katz, M.J., et al. (2003). Leisure activities and risk of dementia in the elderly. N. Engl. J. Med. 348, 2508–16.

Volicer, L., Harper, D.G., Manning, B.C., Goldstein, R., and Satlin, A. (2001). Sundowning and circadian rhythms in Alzheimer's disease. Am. J. Psychiatry 158, 704–11.

Waegemans, T., Wilsher, C.R., Danniau, A., Ferris, S.H., Kurz, A., and Winblad, B. (2002). Clinical efficacy of piracetam in cognitive impairment: a meta-analysis. Dementia Geriatr. Cogn. Dis. 13, 217–24.

Waldemar, G., Dubois, B., Emre, M., Scheltens, P., Tanska, P., and Rossor, M. (2000). Diagnosis and management of Alzheimer's disease and other disorders associated with dementia. The role of neurologists in Europe. European Federation of Neurological Societies. Eur. J. Neurol. 7, 133–44.

Warren, J.D., Schott, J.M., Fox, N.C., et al. (2005). Brain biopsy in dementia. Brain 128, 2016–25.

Whitehouse, P.J., Price, D.L., Struble, R.G., Clark, A.W., Coyle, J.T., and Delon, M.R. (1982). Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–9.

Wilcock, G.K. (2003). Memantine for the treatment of dementia. Lancet Neurol. 2, 503–5.

Wilcock, G., Birks, J., Whitehead, A., and Evans, J.G. (2002). The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials. Int. J. Geriatr. Psychiatry 17, 175–83.

Wilcock, G., Howe, I., Coles, H., et al. (2003). A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease. Drugs Aging 20, 777–89.

Wilson, R.S., Mendes de Leon, C.F., Barnes, L.L., et al. (2002). Participation in cognitively stimulating activities and risk of incident Alzheimer disease. J. Am. Med. Assoc. 287, 742–8.

Winblad, B. and Poritis, N. (1999). Memantine in severe dementia: results of the 9M-Best Study. Benefit and efficacy in severely demented patients during treatment with memantine. Int. J. Geriatr. Psychiatry 14, 135–46.

Wischik, CM., Novak, M., Thogersen, H.C., et al. (1988). Isolation of a fragment of tau from the core of the paired helical filament of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 85, 4506–10.

Wisniewski, H.M., Wegiel, J., and Kotula, L. (1996). Some neuropathological aspects of Alzheimer's disease and its relevance to other disciplines. Neuropathol. Appl. Neurobiol. 22, 3–11.

Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G.G., and Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–43.

Zandi, P.P., Carlson, M.C., Plassman, B.L., et al. (2002). Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. J. Am. Med. Assoc. 288, 2123–9.

Zandi, P.P., Anthony, J.C., Khachaturian, A.S., et al. (2004). Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch. Neurol. 61, 82–8.

Zandi, P.P., Sparks, D.L., Khachaturian, A.S., et al. (2005). Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch. Gen. Psychiatry 62, 217–24. (p.228)