Alzheimer's disease: Its diagnosis and pathogenesis

ALZHEIMER'S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS

Jillian J. Kril I Centre for Educationand Researchon Ageing, Concord Hospital Department of Medicine, The Universityof Sydney, Concord, New SouthWales, Australia 2139, and Departmentof Pathology,The Universityof Sydney, Sydney, New SouthWales, Australia 2006 Glenda M. Halliday Prince of Wales Medical ResearchInstitute Randwick, New SouthWales, Australia 2031

I. Introduction II. Diagnostic Issues A. A/3 Plaques a n d NFTs for Pathological Diagnosis B. Evaluation of O t h e r Pathologies C. Clinical Correlates of AD Pathology D. Reproducibility of C u r r e n t Clinical Diagnostic Protocols E. S u m m a r y III. Pathogenesis A. Brain Atrophy B. Neuronal Loss C. A/3 Deposition D. NFT Formation E. Mechanisms of Degeneration E Summary IV. Genetic Influences A. D o m i n a n t Inheritance B. Genetic Risk Factors C. S u m m a r y V. Inflammation a n d Anti-inflammatory Drugs VI. Estrogen T h e r a p y VII. Vascular Pathology in AD A. Vascular Risk Factors B. S u m m a r y References

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JILLIANJ. KRILAND GLENDAM. HALLIDAY I. Intr(xludion

In the century since the neuronal inclusions [neurofibrillary tangles (NFTs); Fig. 1] and extracellular protein aggregates (Aft plaques; Fig. 1) that form the pathological hallmarks of Alzheimer's disease (AD) were described, our knowledge of all aspects of AD has grown markedly. AD is uniformly progressive and ultimately results in debilitating cognitive impairment. In the early stages, the impairment may only be apparent on

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l~c,. 1. The major pathologies resulting in dementia are neurofibrillary tangles (NFTs; top left), A¢I plaques (top center), and Lewy bodies (top right, arrow). Diagnosis of AD was previously based on age-corrected densities of A~ plaques; however, the finding that a significant n u m b e r of patients with dementia with Lewy bodies (DLB) also have A¢I plaques questions this practice. Similarly, NFTs can be found in other forms o f dementia and thus are not specific for AD. Newer criteria proposed for the pathological diagnosis of AD use both A/~ plaques and NFTs. This change in the way in which AD is diagnosed pathologically will have a significant impact on the clinical criteria for the identification of AD. These clinical criteria have been validated using A~ plaque-based pathology and now require re-evaluation in light o f the advances in our understanding o f the pathogenesis of the disease.

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neuropsychological testing; however, by end stage, few functions above the automatic remain unaffected (Forstl and Kurz, 1999). The pattern and sequence of functional deficits and the relentlessness of the decline are relatively reproducible, with the course of the disease in one patient similar to that in others. AD remains the most prevalent form of late-life dementia and is the most significant cause of morbidity in the elderly. Yet, we are still unable to, in most instances, accurately predict who will succumb to AD or to effectively treat it in those who do.

II. Diagnostic Issues

T h e definitive diagnosis of AD is made by pathological examination of the brain; however, the accurate and reproducible diagnosis of AD during life is of p a r a m o u n t importance. Not only is it essential to exclude possible treatable causes of dementia, but it is also necessary for the identification of h o m o g e n e o u s groups of patients for evaluation and study, and for the recruitment of patients for drug and other therapeutic trials. Variability in the clinical diagnosis of AD is well recognized and major diagnostic issues continue to be addressed to develop accurate and reproducible criteria for its identification. Yet, similar issues for the neuropathological diagnosis of AD are only beginning to be evaluated in a systematic fashion. In most instances, neuropathology is considered the "gold standard" for the diagnosis of AD, but considerable variation exists between diagnostic protocols. This has the potential to have a significant impact on our understanding of the disease.

A. A/3 PLAQUESAND NFTs FOR PATHOLOGICALDIAGNOSIS

The majority of protocols for the pathological diagnosis of AD use only one of the major pathological lesions first described by Alzheimer. The most commonly used lesion for the diagnosis of AD is the neuritic plaque as Aft deposition is more distinctive for AD than other neurodegenerative diseases. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD; Mirra et al., 1991) developed the most widely used diagnostic protocol. It employs the earlier National Institutes of Health protocol based on age-corrected plaque densities (Khachaturian, 1985) in a semiquantitative fashion to arrive at diagnoses of varying certainties. The CERAD criteria (Mirra et al., 1991; Table I) has gained wide acceptance because of its accuracy and simplicity. In 142 cases with a clinical diagnosis of probable AD

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JILLIAN J. KRIL AND G L E N D A M. HALLIDAY TABLE I CONSORTIUM TO ESTABLISH A REGISTRY FOR ALZHE1MER'S DISEASE ( C E R A D ) CRITERIA FOR NEUROPATHOLOGICAL DIAGNOSIS OF A D a

Plaque Densitiesb <50 Years

50-75 Years

Normal brain

N + No dementia

N + No dementia

Possible AD Probable AD

S, M, or F + No dementia Not defined

Definite AD

S, M, or F + Dementia

S + No dementia S + Dementia, or M + no dementia S, M, o r F + D e m e n t i a

> 75 Years N + No dementia, or S + no dementia S + Dementia M + Dementia F + Dementia

aRegions examined--middle frontal, superior and middle temporal, inferior parietal cortices, hippocampus and entorhinal cortex, midbrain. bN = none, S = sparse, M = moderate, F = frequent plaques. From Mirra et aL (1991).

(the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)-Alzheimer's Disease and Related Disorders Association (ADRDA) most certain clinical category, see Section II.C and Table II), 84% were f o u n d to have definite A D - - 7 % probable and 2% possible (Mirra et al., 1991). In 7% of cases, the age-related plaque score was negligible, suggesting a n o t h e r cause for dementia in these cases. In an i n d e p e n d e n t assessment of the accuracy of the CERAD criteria, subjects with a clinical diagnosis of probable AD had definite AD at autopsy in 27 out of 28 cases (96% Kosunen et al., 1996). Subsequent interlaboratory testing of the CERAD criteria revealed 75% agreement in the rank ordering of 10 cases between 24 neuropathologists at 18 centers (Mirra et al., 1994). The majority of variation was due to staining differences between laboratories, but the data suggest there is considerable variation between pathologists in the CERAD diagnosis of individual cases. In contrast to the plaque-based protocols, Braak and Braak (1991) proposed a staging scheme for the neuritic pathology ofAD (NFTs and neuropil threads). This six-stage scale documents the temporal sequence and topographic spread of AD pathology. Although not proposed as a criteria for the neuropathological diagnosis of AD, dementia is reliably associated with stages V and VI and to a variable degree with stages III and IV (Braak and Braak, 1991; Harding et al., 2000). NFTs first form in the pre-a layer of the transentorhinal cortex (stage 1, Table III), then the pre-a layer of the entorhinal cortex, the hippocampus, and finally the isocortex (Table III). C o m p a r e d with the CERAD criteria, inter-rater reliability for neuritic staging is high (weighted kappa 0.85 to 0.97; Nagy et al., 1997b). However, the

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TABLE II NINCDS-ADRDA CRITERIAFOR CLINICALDIAGNOSISOF A n a Possible AD

Clinical diagnosis of • Dementia syndrome with variation in onset, presentation, or course but in absence of neurological, psychiatric, or systemic disorder sufficient to cause dementia • Dementia in presence of second systemic or brain disorder sufficient to produce dementia, but not considered to be cause of dementia • Single, severe, progressive deficit in single cognitive domain

Probable A D Key features

Inclusion Criteria • Onset between 40 and 90 years • Dementia established on clinical examination and testing • Deficits in two or more areas of cognition • Progressive worsening of functions Exclusion Criteria • No disturbance of consciousness • Absence of systemic or brain disease, which may account for progressive deficits in memory and cognition

Probable AD Supportive features

• Progressive deterioration in specific cognitive function, such as language, motor skills, and perception • Impaired activities of daily living and altered behavior pattern • Family history of similar disorder • Normal CSF • Normal or nonspecific changes on EEG • Progressive cerebral atrophy on CT scan

Probable AD Suggestive features

After exclusion of other causes • Plateaus in course of progression • Associated symptoms of depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic verbal, emotional or physical outbursts, sexual disorders, weight loss • Neurological abnormalities, especially in advanced patients--motor signs (increased muscle tone, myoclonus, or gait disorder), epilepsy • CT scan noixnal for age

Probable AD Features not consistent with AD

• Sudden apoplectic onset • Focal neurological signs---hemiparesis, sensory loss, visual field deficit, incoordination early in disease • Seizures or gait disturbance at onset or early in disease

Definite AD

• Clinical criteria for probable AD • Histopathologic evidence from biopsy or autopsy

aDiagnostic certainty is ranked as possible, probable, or definite based on the features present. From McKhann et al. (1984).

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JILLIANJ. KRIL AND GLENDA M. HALLIDAY TABLE III BRAAK STAGING SCHEME OF NFT FORMATION DURING AGING AND A D

Stage

I II III 1V V VI

Neurofibrillary tanglesa NFTs in pre-a layer of the transentorhinal cortex Isolated NFTs in pre-a layer of entorhinal cortex proper Numerous NFTs in transentorhinal cortex Sparse NFTs in CA1 sector of hippocampal formation Severe involvement of transentorhinal cortex, including eNFTs Modest involvement of CA1 NFTs in subiculum Numerous NFTs in CA1, some in CA4 Mild involvement of isocortices, sparing of primary cortices All sectors of hippocampus involved Moderate involvement of subcortical nuclei Isocortex moderately involved Severe involvement of isocortices Severe involvement of subcortical nuclei Mild involvement of primary cortices

aNFT = neurofibrillary tangle, eNFT = extracellular or "ghost" neurofibrillary tangle. From Braak and Braak (1991 ). strict h i e r a r c h i c a l o r d e r o f N F T f o r m a t i o n is n o t o b s e r v e d in all cases. I n a s t u d y o f 42 b r a i n s , G e r t z a n d c o l l e a g u e s (1998) f o u n d t h a t o n l y six cases fully fitted t h e e x p e c t e d p a t t e r n o f N F T d i s t r i b u t i o n . M o s t o f t h e s e v i o l a t i o n s o f s t a g i n g o r d e r w e r e in t h e early stages, s u g g e s t i n g t h e y w o u l d n o t a l t e r t h e effectiveness o f t h e p r o t o c o l f o r i d e n t i f y i n g AD. The NINCDS and ADRDA working group proposed a number of criteria f o r t h e n e u r o p a t h o l o g i c a l d i a g n o s i s o f A D , w h i c h e v a l u a t e d b o t h Aft p l a q u e s a n d N F T a n d e x c l u d e d c e r e b r o v a s c u l a r d i s e a s e ( T i e r n e y et al., 1988). However, t h e p r o t o c o l s have n o t b e e n widely a d o p t e d , in p a r t , b e c a u s e o f t h e i r c o m p l e x i t y a n d m o d e s t sensitivity. C o m p a r i s o n b e t w e e n N I N C D S - A D R D A clinical a n d p a t h o l o g i c a l c r i t e r i a s h o w e d a g r e e m e n t in 8 o f 9 n o n d e m e n t e d c o n t r o l s , 18 o f 38 cases with p o s s i b l e AD, a n d 18 o f 19 cases with p r o b a b l e AD (Nagy et al., 1998). A n e v a l u a t i o n o f t h e K h a c h a t u r i a n , CERAD, N I N C D S - A D R D A , a n d B r a a k m e t h o d s f o r assessing A D in a g r o u p o f 60 eld e r l y subjects with k n o w n M i n i - M e n t a l State (MMS) score, r e v e a l e d t h a t all c r i t e r i a a c c u r a t e l y i d e n t i f i e d i n d i v i d u a l s with severe d e m e n t i a (MMS 0-10; J e l l i n g e r et al., 1995). However, in m o d e r a t e l y d e m e n t e d i n d i v i d u a l s (MMS 11-23) r e l i a n c e o n p l a q u e - b a s e d c r i t e r i a r e s u l t e d in s i g n i f i c a n t u n d e r d i a g nosis o f AD. T h e m a j o r i t y o f t h e s e subjects also h a d l i m b i c NFTs (Braak stages III a n d IV). I n a d d i t i o n , t h e use o f p l a q u e d e n s i t i e s w i t h o u t assessing clinical state r e s u l t e d in 5 o f 9 n o n d e m e n t e d subjects b e i n g classified as AD,

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indicating the presence of plaques is a poor indicator of the presence of dementia, at least in the very old. Because o f these difficulties, the neuritic staging scheme of Braak has been combined with the CERAD protocol for assessment of plaques into the National Institute on Aging (NIA)-Reagan Institute criteria for the diagnosis of AD (Hyman and Trojanowski, 1997; National Institute on Aging and Reagan Institute Working Group, 1997; Newell et al., 1999). Topographical assessment of NFT type (intra- or extracellular) and A/3 plaque density is used to classify cases into high, intermediate, or low likelihood of AD. These criteria are the currently accepted "gold standard" for the diagnosis of AD, even though their reliability, reproducibility, and overall accuracy are yet to be determined.

B. EVALUATION OF OTHER PATHOLOGIES Further problems with assessing the accuracy of neuropathological diagnoses exist. In most studies, diagnostic validity is assessed by reporting cases that meet criteria for AD, regardless of whether other pathologies are present. In some instances, coexisting pathologies may contribute to the dementia process and thus be of importance in the assessment of the clinical criteria. In one study addressing this issue, diagnostic accuracy was 81% for AD (using CERAD criteria) including coexisting disease, but only 44% for pure cases (Bowler et al., 1998). The presence of infarction was the primary reason for the differences encountered. Furthermore, the identification of a n u m b e r of previously unrecognized dementing disorders, with clinical a n d / o r pathological overlap with AD (e.g., dementia with Lewy bodies (DLB) ; Kosaka et al., 1984; McKeith et al., 1996, 1999; Fig. 1; and small vessel disease dementia (Pantoni et al., 1996)), calls into question the usefulness of many of the existing criteria for the diagnosis of AD. Because the majority of cases with DLB also have plaques (McKeith et al., 1996), the CERAD criteria cannot differentiate these disorders and the evaluation of intracellular pathology is required. In addition, the overlap between cerebrovascular disease and AD is well known (see Di Iorio et al., 1999; Breteler, 2000; de la Torre, 2000). However, the demonstration that small vessel disease alone can cause a clinical syndrome indistinguishable from AD (Pantoni et al., 1996) suggests that reevaluation of the role of this pathology is also necessary. Few studies have addressed these issues. The NIA-Reagan Institute criteria for the diagnosis of AD (Hyman and Trojanowski, 1997; National Institute on Aging and Reagan Institute Working Group, 1997) states that all pathologies should be evaluated, but does not suggest how overlapping diagnoses can be arrived at or how they

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should be incorporated into the diagnostic criteria. This represents a significant weakness in the current neuropathological criteria for the diagnosis of AD and must be addressed before the effectiveness of any criteria can be adequately evaluated.

C. CLINICAL CORRELATES OF A D PATHOLOGY

Reevaluation of the clinical diagnosis of AD in light of the changing concepts of the pathology of the disease is necessary. It is no longer adequate that clinical criteria for AD alone are developed. Better diagnostic criteria for patients with similar core clinical features that differentiate the signs and symptoms of other pathologies are required. The most widely used clinical criteria are those established by the NINCDS-ADRDA (McKhann et al., 1984). Diagnoses of probable and possible AD (Table II) can be made using these criteria. Possible AD is considered when dementia is apparent in the presence of other systemic or brain disorders that, may themselves, result in dementia. A diagnosis of probable AD is considered when the patient is free from complicating diseases and when deficits in two or m o r e areas of cognition are present. The CERAD group (Morris et al., 1989) proposed a battery of clinical and neuropsychological tests to aid in the classification of cases into the NINCDS-ADRDA possible and probable AD groups. A multicenter study of the NINCDS-ADRDA criteria, which evaluated 60 cases (40 with AD), showed an initial sensitivity of 0.81 and specificity of 0.73 (Blacker et al., 1994). These values were improved to 0.83 and 0.84, respectively, after consensus rating (Blacker et al., 1994). Validity studies that tested the NINCDS-ADRDA criteria against pathologically confirmed cases show variable results d e p e n d i n g on the cases included in the study. In "typical" cases, the agreement between probable and definite AD has been shown to be 100% (Martin et al., 1987; Morris et al., 1988). However, in unselected cases, accuracies of 68-76% and 88% for probable AD (Burns et al., 1990; Risse et al., 1990) and 78% for possible AD (Burns et al., 1990) were found. Thus, the NINCDS-ADRDA protocol for the diagnosis of AD has been well-validated within and across centers as correlating with the CERAD plaque-based pathological criteria. However, because these studies would have included cases with DLB and possibly other pathologies, reevaluation of the accuracy of these criteria is required. In addition to the NINCDS-ADRDA criteria for the clinical diagnosis of AD, a n u m b e r of other diagnostic protocols for use in clinical and population settings have been developed. The Diagnostic and Statistical M a n u a l of Mental Disorders, Fourth Edition (DSM-IV) of the American Psychiatric Association (APA; World Health Organization, 1992) criteria require a

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deficit in memory, as well as one other cognitive domain of gradual onset and progressive decline. These criteria result in similar classification of patients to the NINCDS-ADRDA criteria (see above). In addition, the Clinical Dementia Rating (CDR; McCulla et al., 1989; Morris, 1993) and Mini-Mental State Examination (MMSE; Folstein et al., 1975) are used to determine the severity of dementia. These protocols are useful for screening for cognitive impairment as they are easy to administer and have been validated across a variety of social and ethnic populations. However, they lack specificity for AD. Pathological validation of these protocols has been performed, but as with other criteria, reevaluation is necessary in light of the changing nature of dementia diagnosis. It would be of interest for those centers with large clinical and pathological databases to reevaluate the clinical diagnosis of AD and similar dementia syndromes using the currently r e c o m m e n d e d neuropathological criteria for AD. This may help define better diagnostic tools that can then be evaluated longitudinally.

D. REPRODUCIBILITYOF CURRENT CLINICALDIAGNOSTICPROTOCOLS Several studies to test the reliability of the clinical criteria for AD have been performed. Both Lopez and colleagues (1990) and Kukall and colleagues (1990) used four raters to evaluate the NINCDS-ADRDA criteria. Using cases with dementia (AD and non-AD) and n o n d e m e n t e d controls, percentage agreement ranged from 55% to 75% for pairs of raters (kappa coefficients were 0.36-0.65) with the most experienced clinicians achieving the greatest agreement (Lopez et al., 1990). Interestingly, many of the disagreements in diagnosis were found between possible and probable AD categories. Although there is little disagreement on whether patients have dementia, the underlying causes of the dementia syndrome are less reliably agreed u p o n between clinicians. The inclusion of cases with multiple pathologies using the current criteria probably contributes to this variability.

E. SUMMARY Considerably more research is required on the diagnosis and definition of AD. The current r e c o m m e n d e d "gold standard" has yet to be widely validated, and protocols for overlapping pathologies n e e d to be incorporated. This will, of course, have an impact on the clinical diagnosis of AD. At present, clinical criteria for AD cannot differentiate patients with different underlying disease mechanisms (e.g., DLB versus AD). In addition, it will be important to determine the clinical profile of cases that have both

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NFTs and Aft. Difficulties with the definition of the disease have important implications for any study o f AD. From the point of view of researching the pathogenesis of AD, pure groups are desired to eliminate potential confounding causes. T h e continual modification and improvement of criteria for the diagnosis of AD is therefore necessary until we understand, and either prevent or cure, this illness.

IIh Pathogenesis To understand the pathogenesis of AD, it is necessary to determine the sequence of events that occurs over the life of a patient. Because it is not possible to p e r f o r m longitudinal cellular analyses in humans, most of our understanding of the pathogenesis of AD is inferred from patients sampled cross-sectionally at different time points in the disease process. Information concerning the initial events is the most patchy as it is extremely difficult to determine, with accuracy, when the disease first begins. T h e single greatest risk factor for the development o f AD is age (Jorm, 1990). However, we do not yet fully understand the normal aging process; thus, it is difficult to distinguish the pathological process (es) underlying AD. We do know that dementia in old age isfar from a universal p h e n o m e n o n and that other factors must play a role in determining susceptibility to disease. These factors include genetic, environmental, and lifestyle factors, as well as coexisting disease. Although a decline in brain function with age is accepted as normal by many authors, increasing evidence suggests cognitive decline is not an inevitable consequence of aging (Rubin et al., 1998; Morris, 1999; Unger et al., 1999) but rather a manifestation of underlying disease processes. Longitudinal studies of community-dwelling elderly subjects do not find a decrease in cognitive p e r f o r m a n c e with advancing age (Rubin et al., 1998; Morris, 1999). Interestingly, those who do develop dementia may have a long preclinical period with stable deficits (usually memory), which precedes a precipitous decrease in function (Rubin et al., 1998; Small et al., 2000). Such studies call into question the idea of an age-related decline in brain function and more likely represent cohort differences in health, education, and other factors. Nevertheless, many o f these studies are p e r f o r m e d on highly selected groups of elderly subjects who are free from neurological and systemic diseases, and although adequately addressing the question of age-associated cognitive decline, do not represent the majority of elderly subjects. Cognitive deficits may be present in a proportion of elderly subjects, although these would be expected to have greater brain pathology. Numerous studies have shown an increased risk o f AD in subjects with low education levels (primary school level or a r o u n d 6 or less years of schooling)

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as c o m p a r e d with subjects with higher education levels. T h e level of increased risk varies between studies (Katzman, 1993; The Canadian Study of Health and Aging Study Center, 1994; Stern et al., 1994; L e t e n n e u r et al., 1999; Hall et al., 2000) but is generally found to be between 1.5 and 2 times that of the higher-educated reference groups. Nevertheless, the finding of an association between education and AD is by no means universal because a n u m b e r of studies have found no relationship (Beard et al., 1992; Cobb et al., 1995). In particular, no association between autopsy-confirmed AD and either education or occupation was found in a study of 115 patients with AD, although the authors suggest this may reflect different attitudes to consent to autopsy among groups with different education levels (Munoz et al., 2000). The mechanism that links low educational attainment and AD is unclear. Some authors suggested education provides increased functional capacity or "brain reserve," which requires the brain to undergo a greater period of degeneration before the critical threshold for dementia is reached. Conversely, low education may reflect other factors such as lower socioeconomic status, increased likelihood of exposure to adverse events, or childhood deprivation (Hall et al., 2000). This latter hypothesis, referred to as "brain battering," proposes that subjects with higher education have higher socioeconomic status and enjoy healthier lives with fewer coexisting brain diseases (Del Ser et al., 1999). This hypothesis is supported by the work of Del Ser and colleagues (1999), who, in an autopsy study, found patients with low education had more cerebrovascular disease than those with a high level of education. Gaining a better understanding of this association between low education and AD is of great importance because education is a modifiable factor and, unlike increasing age or genotype, amenable to intervention and possible correction.

A. BRAINATROPHY It is well established that the brains of older individuals are, o n average, smaller than their younger counterparts (Dekaban, 1978). Although this may be interpreted as a loss of brain tissue with age, it may also represent cohort differences in body size as a result of improvements in nutrition and health standards (Miller and Corsellis, 1977). Cross-sectional in viva studies have demonstrated atrophy of all brain compartments (Murphy et al., 1996; Yue et aL, 1997), prefrontal grey matter (Raz et al., 1997), and hippocampus (Convit et aL, 1995). In several in vivo studies, age-associated atrophy was found to be greater in men than in women (Matsumae et al., 1996; Murphy et al., 1996; Yue et al., 1997; Coffey et al., 1998). However, postmortem analysis of normal subjects ages 46 to 92 years find no decrease in cortical volume,

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but significant white matter atrophy (Double et al., 1996), suggesting that marked loss of cortical neurons is not a feature of normal aging. This is supported by studies in older primates (Peters et al., 1996) and by longitudinal MRI studies (Mueller et al., 1998; Fox et al., 2000). Because brain atrophy occurs in a number of conditions other than neurodegenerative disease (Kril and Halliday, 1999) and factors such as hypertension, smoking, and high alcohol consumption contribute to atrophy (Akiyama et al., 1997), rigorous exclusion criteria are necessary in cross-sectional samples investigating true age-related changes. A loss of cerebral white matter may underlie the slowing of mental processing identified in many elderly subjects (Howieson et al., 1993; Ylikoski et al., 1993). Overall, the data are consistent with the clinical finding that, at least in a proportion of the elderly, there is no substantial deficit over time. In contrast to normal aging, cross-sectional studies show that there is marked cortical atrophy in AD (Fig. 2) and that the degree of atrophy correlates with the severity of dementia (Double et al., 1996; Mouton et al., 1998; Regeur, 2000). Atrophy in AD is most severe in the temporal lobe, particularly in the medial temporal lobe (Double et al., 1996; Convit et al., 1997; Detoledo-Morrell et al., 1997; Jack et al., 1998; Frisoni et al., 1999; Visser et al., 1999). More important, longitudinal analyses of brain volume confirmed that marked temporal lobe atrophy distinguishes AD (Fox et al., 1996, 2000; Smith and Jobst, 1996; Kaye et al., 1997; Yamada et al., 1998) from the relatively constant brain volumes during healthy aging (Shear et al., 1995; Mueller et al., 1998). The greatly accelerated atrophy of the temporal neocortex, not the hippocampus, in AD patients is associated with the symptomatic onset of dementia (Fox et al., 1996, 2000; Smith andJobst, 1996; Convit et al., 1997, 2000; Detoledo-Morrell et al., 1997; Kaye et al., 1997; Juottonen et al., 1998a, 1998b; Yamada et al., 1998), whereas atrophy of the hippocampus occurs 1 to 2 years before dementia onset (Fox et al., 1996; Convit et al., 1997). These data show that significant cortical atrophy occurs in AD and distinguishes it from normal aging. The degeneration begins in the hippocampus and spreads to involve first the temporal lobe and then other cortical association areas (Fig. 2).

B. NEURONALLOSS Controversy exists over whether neuronal loss is a normal consequence of aging or is only related to disease processes. Many earlier studies using measures of neuronal density found widespread degeneration in older subjects (Brody, 1955; Henderson et al., 1980; Anderson et al., 1983; Terry et al., 1987), although this finding was not universal (Haug and Eggers, 1991).

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Hippocampal atro )hy

AD diagnosis

~.-

Hippocampal and temporal atrophy

,l

Global atrophy (end-stage)

~t /

i

FIG. 2. At autopsy, AD is characterized macroscopically by generalized atrophy of the cerebral hemispheres (left panel), which results in widening of the sucli (upper), ventricular dilatation (V, lower), and atrophy of the hippocampal formation, causing dilatation of the temporal horn (TH, lower) of the lateral ventricles. Atrophy of the hippocampal formation can be detected in susceptible patients prior to the diagnosis of dementia (right upper). The atrophy progresses to involve the adjacent temporal lobe (right center) and then, uhimately, spreads to involve most regions of the brain (right lower).

T h e i n t r o d u c t i o n o f u n b i a s e d q u a n t i t a t i v e t e c h n i q u e s has r e v o l u t i o n i z e d q u a n t i t a t i v e n e u r o p a t h o l o g y ; however, in m a n y instances, t h e r e is still u n c e r t a i n t y as to w h e t h e r n e u r o n a l loss with a g i n g occurs. P a k k e n b e r g a n d G u n d e r s e n (1997) f o u n d a 10% d e c l i n e in total e s t i m a t e d n e u r o n n u m b e r b e t w e e n 20 a n d 90 years o f age. T h i s study was p e r f o r m e d o n s a m p l e s f r o m the entire neocortex, regardless of anatomical or functional location, but has yet to b e c o n f i r m e d by others. Interestingly, t h e y also d e m o n s t r a t e d a large (16%) d i f f e r e n c e in n e u r o n n u m b e r with g e n d e r , w h i c h is n o t as a r e s u l t o f d i f f e r e n c e s in b o d y h e i g h t . S t u d i e s in w h i c h specific f u n c t i o n a l r e g i o n s o f t h e b r a i n have b e e n e x a m i n e d u s i n g u n b i a s e d t e c h n i q u e s have r e p o r t e d v a r i a b l e results with r e g a r d

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to a n a g e - a s s o c i a t e d loss o f n e u r o n s . N o loss o f n e u r o n s was f o u n d in t h e sup e r i o r t e m p o r a l ( G o m e z - I s l a et al., 1997) o r e n t o r h i n a l c o r t i c e s ( G o m e z - I s l a et al., 1996) o f n o n d e m e n t e d c o n t r o l s b e t w e e n t h e sixth a n d n i n t h d e c a d e s , o r f r o m t h e l o c u s c o e r u l e u s ( O h m et al., 1997). I n t h e h i p p o c a m p a l form a t i o n , a loss o f CA1 (West a n d G u n d e r s e n , 1990; Simic et al., 1997), CA4 (West et al., 1994), a n d s u b i c u l a r (West, 1993; West et al., 1994) n e u r o n s was r e p o r t e d . However, this is in c o n t r a s t to t h e f i n d i n g t h a t t h e a p p a r e n t r e d u c t i o n in CA1 n e u r o n n u m b e r with a g e c a n b e a c c o u n t e d f o r by d i f f e r e n c e s in c e r e b r u m v o l u m e b e t w e e n y o u n g e r a n d o l d e r a d u l t s ( H a r d i n g et al., 1998). T h i s r e l a t i o n s h i p b e t w e e n p r e m o r b i d b r a i n size a n d h i p p o c a m p a l n e u r o n n u m b e r h i g h l i g h t s s o m e o f t h e difficulties with cross-sectional c o h o r t studies a n d suggests m u l t i p l e factors n e e d to b e a n a l y z e d to d e t e r m i n e p o t e n t i a l c a u s e a n d effect. T h e m o s t c o n s i s t e n t f i n d i n g in AD is s u b s t a n t i a l n e u r o n a l loss f r o m t h e e n t o r h i n a l c o r t e x a n d h i p p o c a m p u s (Fig. 3). T h i s reflects t h e p a t t e r n o f n e u r o f i b r i l l a r y p a t h o l o g y , w h i c h is a c a r d i n a l f e a t u r e o f A D a n d app e a r s to o c c u r very early in t h e disease p r o c e s s ( B r a a k a n d Braak, 1997). A 32% loss o f n e u r o n s f r o m t h e e n t o r h i n a l c o r t e x was f o u n d in AD p a t i e n t s

Control

AD

CA1

Ch4

FIG. 3. Marked neuronal loss and NFT formation is seen in AD (right panels) compared with controls (left panels) in both the CA1 region of the hippocampus (upper panels) and cholinergic basal forebrain (Ch4, lower panels). Eventually, neuronal loss exceeds NFT formation in the hippocampus but is equivalent in the basal forebrain. Nickel peroxidase with cresyl violet counterstain.

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with a CDR score of 0.5, whereas a 48% loss was found in all AD patients (Gomez-Isla et al., 1996). When specific laminae were examined, the loss was more dramatic with a 60% loss of layer II neurons in mild AD and a 90% loss in severe AD (CDR = 3; Gomez-Isla et al., 1996). Marked neuronal loss from the hippocampus has also been described. Simic and colleagues (1997) found a 23% loss of neurons from the dentate gyrus and subiculum, whereas West and colleagues (1994) found a 25% loss from the CA4, 47% from the subiculum, and 68% from the CA1. The dramatic loss of neurons from the CA1 and subiculum has been confirmed in other studies (Bobinski et al., 1995) and has been found to occur early in the disease process. Thus, the early atrophy noted clinically in medial temporal lobe structures (see above) is a result of marked neuronal loss in this region (Bobinski et al., 2000). O t h e r consistently affected regions in AD are the cholinergic nucleus basalis (Vogels et al., 1990; Cullen et al., 1997; Fig. 3), the serotoninergic raphe nuclei (Aletrino et al., 1992; Halliday et al., 1992), and the noradrenergic locus coeruleus (Busch et al., 1997). These subcortical nuclei innervate cortical pyramidal neurons, capillaries, and arterioles, and play an important role in cortical synaptic neurotransmission and the neurogenic control of blood flow through the capillary bed. The early loss of cortical cholinergic transmission is believed to lead to hyperactivity of acetylcholinesterase and a loss of cholinergic neurogenic control, thus significantly contributing to the cognitive deterioration seen in AD (Bartus et al., 1982; Francis et al., 1999; Tong and Hamel, 1999). Hyperactivity of acetylcholinesterase underlies the currently r e c o m m e n d e d treatments for AD, which use cholinesterase inhibitors such as tacrine, donepezil, or rivastigmine (Francis et al., 1999; Ladner and Lee, 1998). Despite mixed success with such treatments, there is a great deal of evidence supporting the cholinergic hypothesis of AD. Choline acetyltransferase levels were found to correlate with cognitive impairment in AD (Baskin et al., 1999), whereas degeneration in cholinergic basal forebrain neurons correlates with MMSE score (Iraizoz et al., 1999), cortical atrophy (Cullen et al., 1997), the stage of cortical pathology (Cullen and Halliday, 1998; Iraizoz et al., 1999; Beach et al., 2000), and the earliest depositions of A/~ (Beach et al., 2000). A/3 potently inhibits various cholinergic neurotransmitter functions (Auld et al., 1998) by killing cortically projecting cholinergic neurons (Harkany et al., 2000). Furthermore, cortical cholinergic denervation elicits vascular Aft deposition (Roher et al., 2000), suggesting a link between Aft deposition, small vessel disease, and cholinergic cell loss in AD. In addition, it has been shown that the action o f tacrine is through improving cerebral blood flow rather than due its effects on neuronal cholinergic neurotransmission (Peruzzi et al., 2000). Although cortical atrophy is a consistent feature of AD (see above), whether this atrophy represents neuronal loss is not universally agreed upon.

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Earlier studies of neuron density found a widespread and marked loss of neurons in AD (Colon, 1973; Shefer, 1973; Ball, 1977). However, using unbiased techniques, Reguer and colleagues (1994) found no overall loss of cortical neurons in AD. This study, which was conducted on entire lobes of the brain, generated much debate (see commentaries in Neurobiology of Aging (1994) 15(3) :353-380), the consensus of which was that regional and population differences do exist in AD and that they were masked by the quantitative technique used. Using unbiased techniques, total neuron number was found to decrease by 53% in the superior temporal gyrus (Gomez-Isla et al., 1997) and 30% in visual areas 17 and 18 (Leuba and Kraftsik, 1994). In addition, a study described the loss of microcolumnar ensemble organization in AD (Buldyrev et al., 2000), although the relationship between neuronal patterning and cell loss remains to be determined. A considerable amount of research is still required to evaluate the specificity of the disease process for cortical regions and neuron type, and to correlate these findings with atrophy, clinical indices, and the temporal sequence of events. As long as research remains concentrated on individual brain regions affected by AD, the entire disease process will not be fully understood.

C..Aft DEPOSITION Aft is a hydrophobic peptide, 39-43 residues long, which tends to form insoluble aggregates. There has been considerable debate about the toxicity of this peptide, with its neurotoxic activity believed to depend on its ability to form fibrils (Haas, 1996; Neve and Robakis, 1998; Storey and Cappai, 1999; Wilson et al., 1999; Coughlan and Breen, 2000; Gandy and Petanceska, 2000). The peptide is derived by the proteolytic processing of its high molecular weight precursor, the amyloid precursor protein (APP). APP is a transmembrane protein with a small C-terminal cytoplasmic domain, one transmembrane domain, and a large N-terminal extracellular domain (Haas, 1996; Neve and Robakis, 1998; Storey and Cappai, 1999; Wilson et al., 1999; Coughlan and Breen, 2000; Gandy and Petanceska, 2000). The Aft domain is partially embedded within the phospholipid bilayer. APP is cleaved via two proteolytic pathways, with only one pathway generating Aft peptide (Haas, 1996; Neve and Robakis, 1998; Storey and Cappai, 1999; Wilson et al., 1999; Coughlan and Breen, 2000; Gandy and Petanceska, 2000). During transport to the cell surface, APP is cleaved at the membrane by an unknown protease called 0t-secretase into its soluble extracellular domain (sAPP) and a membrane-bound 10-kD C-terminal fragment. The membrane-bound fragment is further processed by, the as yet unidentified, y-secretase at the C-terminal end of the Aft domain into a small rapidly

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released peptide called p3. This pathway is the major processing pathway for APP and does not involve the production of Aft. p3 is found in abundance in the plaques associated with aging (Dickson, 1997). Uncleaved APP that is reinternalized is processed in the endosome/lysosome system by two hypothetical enzymes called/3- and y-secretases./3-secretase cleaves APP at the N-terminus of the A/3 domain, creating a 12-kD intermediate peptide, which recycles back to the cell surface, y-Secretase (s) cleave this intermediate peptide at the C-terminal end of the A/3 domain, releasing A/3 into the extracellular space. y-Secretase cleavage occurs at one of two main sites producing mainly A/31-39/40 or sometimes A/31-42/43 (Haas, 1996; Neve and Robakis, 1998; Storey and Cappai, 1999; Wilson et al., 1999; Coughlan and Breen, 2000; Gandy and Petanceska, 2000). These peptides concentrate in the plaques found in AD (Iwatsubo et al., 1996; Dickson, 1997), although there is a general age-related increase in A/3 generation by neural cells (Turner et al., 1996), with the longer A/3 peptide being more amyloidogenic. The development of specific antisera for A/31-40 and A/31-42/43 has enabled the evolution and composition of plaques to be systematically studied (Iwatsubo et al., 1996; Dickson, 1997). The results suggest that A/31-42/43 initially forms the nucleus of a plaque, enabling the subsequent deposition of the more soluble Afll-40 and other protein fragments. This is consistent with the identification of mainly A/31-42/43 in plaque cores of both demented and nondemented individuals (Fukumoto et al., 1996). Evidence suggests that protofibrils of A/3 may also be toxic and that fibril formation is concentration dependent (Hartley et al., 1999), with A/3 peptides changing from soluble forms in control brain to insoluble forms in AD brain (Wang et al., 1999). Although we know a lot about the production of A/3, we know much less about its clearance from brain tissue. Evidence suggests that A/3 deposition is regulated by a specific protease that degrades extracellular A/3 (Iwata et al., 2000). Infusions of the protease inhibitor thiorphan into rat brain cause extracellular deposits of endogenous A/3 as diffuse plaques. The enzyme responsible for the clearance of Aft peptides is neutral endoprotease or neprilysin (enkephalinase; Iwata et al., 2000). Cross-sectional analysis of cases at different stages of AD suggests the A/3 plaque deposition occurs only early in AD with resorption surpassing deposition at end-stage disease (Thal et al., 1998). This suggests that A/3 clearance mechanisms are largely intact throughout the disease process and that the disease starts with early excessive A/3 production and deposition. Cross-sectional studies suggest the progressive deposition of A/3 in the brain and microvasculature appears to precede the onset of dementia by many years. Examination of a large unselected autopsy series shows a small

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proportion of people in their 40s begin to deposit Aft plaques in the basal cortex (Braak and Braak, 1997). Few people at these ages have dementia, and the low frequency of pathology is believed to represent very early "preclinical" disease. By the age of 74, 50 % of the population will have Aft plaque deposits (Duyckaerts and Hauw, 1997), although few people will have overt dementia at this age (Jorm, 1990). At these and older ages, a subset of cognitively intact individuals have extensive neocortical Aft plaque deposition (Price and Morris, 1999), reinforcing the concept of "preclinical" disease. Furthermore, an accumulation of AD-type pathology was shown to negatively correlate with the change in MMSE score in nondemented subjects, indicating that burden of pathology does reflect functional performance (Morris et al., 1996; Green et al., 2000) and thus may represent "preclinical" AD. However, the concept that normal aging is synonymous with preclinical AD, which then proceeds to clinical AD, requires close scrutiny prior to being universally accepted. Several sets of data are difficult to reconcile with this model ofa contiuum between aging and AD. NFTs are present in all autopsy samples from people ages 91-95 years, whereas approximately 20% of these subjects are free from plaques (Braak and Braak, 1997). This suggests that Aft plaque accumulation may not be an inevitable component of aging. Alternatively, as discussed above, plaque-dominant AD has been proposed as a developmental stage of the disease only (Berg et al., 1998; Thal et al., 1998), with longitudinal data of cerebrospinal fluid showing changes in Aft levels are greatest within the first 2 years of diagnosis (Tapiola et al., 2000). Although much research has concentrated on determining the cellular biology of Aft production, there is only limited information on the relationship between Aft deposition and measures of degeneration. Large cross-sectional studies incorporating volumetric, neuronal, Aft deposition, and functional indices are necessary to determine the time sequence and relationship between these measures, particularly the role that Aft may play in the neurodegeneration of AD.

D. NYI" FORMATION NFTs were first identified by Alzheimer in 1907. They consist of paired helical filaments of the microtubule-associated protein tau. In the normal brain, tau is bound to axonal microtubules where it stabilizes the microtubles, promotes their assembly, and allows fast axonal transport to occur (Goedert et al., 1991). In AD, tau becomes hyperphosphorylated and no longer binds to the microtubules, impairing their stability, and consequently impairing much of the normal function of the neuron. The hyperphosphorylated tau aggregates into paired helical filaments and ultimately NFTs. The

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gene for tau is on c h r o m o s o m e 17 and contains 15 exons. Mternative splicing of these leads to six isoforms of tau, ranging f r o m 352 to 441 a m i n o acids and with either three or four t a n d e m repeats at the C-terminus e n d (Goedert et aL, 1991; Tolnay and Probst, 1999). In normal brain, three and four repeat tau is expressed in approximately equal amounts, and these same isoforms are present, in a hyperphosphorylated form, in AD (Tolnay and Probst, 1999). NFTs progressively accumulate in the cell body and processes of neurons until the cell dies (Bancher et al., 1989; Braak et al., 1994). T h e earliest feature of N F T formation is the accumulation of hyperphosphorylated tau, which aggregates into insoluble granules (Bancher et al., 1989). This is called the "pretangle" stage and precedes the formation of the classical fibrillar NFTs ("mature tangles"). Once the n e u r o n dies, the largely insoluble NET remains in the neuropil as a "ghost" or "tombstone" tangle (Bondareff et al., 1994). T h e time taken for an N F T to form and mature is unknown. Several estimates have b e e n m a d e based on extrapolation from relationships with disease duration. Bobinski and colleagues (1998) calculated it takes 3.4 years in the CA1 and 5.4 years in the subiculum for a mature NFT to b e c o m e a ghost tangle. This, together with the finding of Morsch and colleagues (1999) that CA1 neurons with NFTs can survive for 15-25 years, suggests that NFTs are slow to develop and that the onset of pathology is many decades before the onset of clinical disease. This hypothesis is supported by the findings that the calculated time taken to progress f r o m NFT stage I to 1V is nearly 50 years ( O h m et al., 1995) and that lower scores on neuropsychological testing can be f o u n d as m u c h as 10 years prior to onset of d e m e n t i a (Elias et al., 2000; Small et al., 2OOO). NFTs and other abnormalities of tau are not unique to AD. Several other neurodegenerative diseases--such as Down syndrome, progressive supranuclear palsy, corticobasal degeneration, and p a r k i n s o n i s m - d e m e n t i a complex of G u a m and Pick disease--also have tau-positive inclusions (Tolnay and Probst, 1999). This has led to the collective n a m e of tauopathies, and m u c h effort has b e e n e x p e n d e d to understand the commonality of these disorders. To date, a n u m b e r of differences were f o u n d in the cellular populations affected and the tau isoforms expressed (Brion, 1998). However, similarities in types of tau deposited and clinical expression of the diseases were also described. Cross-sectional studies suggest that progressive NFT formation in the brain precedes the onset of d e m e n t i a by m a n y years. Examination of a large unselected autopsy series shows that a small p r o p o r t i o n of people in their 20s begin to f o r m NFT in the entorhinal cortex (Braak and Braak, 1997). Few people at these ages have d e m e n t i a and the low frequency of pathology

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is not believed to affect cognitive function. By the age o f 47, 50% of the population will have NFTs (Duyckaerts and Hauw, 1997), although few people will have overt dementia at this age (Jorm, 1990). As m e n t i o n e d above, all subjects ages 91-95 years have NFT formation (Braak and Braak, 1997), and although dementia is more prevalent at these ages, it is not inevitable (Jorm, 1990). By 86 years of age, 50% of the population have sufficient accumulation of NFTs to suspect a pathological diagnosis of AD, particularly in the presence of Aft plaques (Duyckaerts and Hauw, 1997). At the age of 86 and older, approximately 20% of people meet NFT criteria for AD (Braak and Braak, 1997). This is consistent with the prevalence of clinical AD at these ages (Jorm, 1990). In contrast to the Aft deposits, NFTs accumulate in regions of n e u r o n loss (Braak and Braak, 1997; Cullen and Halliday, 1998; Duyckaerts et al., 1998; Iraizoz et al., 1999), and their accumulation correlates with measures of functional decline (McKee et al., 1991; Arriagada et al., 1992; Bancher et al., 1993; Grober et al., 1999) and the degree of hippocampal atrophy (Bobinski et al., 1995; Nagy et al., 1996, 1999; Smith andJobst, 1996). However, as described above, NFTs take many years to evolve and, therefore, the temporal relationship between the formation of NFTs and the rapid neuronal loss and brain atrophy in AD is difficult to reconcile. In addition, as dementia is present only when NFTs occur in the n e o c o r t e x and the extent of neocortical n e u r o n loss is unclear in AD (see above), the association between this cortical degeneration and NFT and Aft deposition needs to be further examined.

E. MECHANISMS OF DEGENERATION Studying the mechanism(s) o f neuronal death in AD is difficult because of the e x t e n d e d interval between the onset of symptoms and associated cell death, and investigation at autopsy. NFT formation is considered to be the major cause of n e u r o n death in AD (Fig. 4), and cells dying as a result of NFT formation can be identified by the presence of ghost NFTs. However, reports show NFTs are not responsible for all the n e u r o n loss seen in AD. Studies on the temporal (Gomez-Isla et al., 1997) and occipital (Leuba and Kraftsik, 1994) cortices, and hippocampus (Kril et al., 2000) have shown that neuronal loss exceeds the degree of NFT formation. This is in contrast to studies of the cholinergic basal forebrain in AD (Cullen and Halliday, 1998) and the parkinsonism-dementia complex of Guam (Schwab et al., 1998, 1999), where NFT formation does account for all the n e u r o n loss. In the CA1 region of the hippocampus, NFTs were f o u n d to account for less than 20% of the n e u r o n loss (Kril et al., 2000) suggesting that a n o t h e r

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Unresolved Issues

CAA

Insoluble A ~ plaque Soluble AI3 4

Microvascular damage

X~ ~d flow Disturbances

Cell death

,S

NFT

x, Inflammation '

FIG. 4. Many unresolved issues continue to plague our understanding of the pathogenesis of AD. Although it is known that neuronal death can occur due to NFT formation and cerebrovascular disease, such as cerebral amyloid angiopathy (CAA), altered perfusion, or microvascular pathology (pale arrows), the exact role of AB and inflammation are unknown (dark arrows). A/3 deposition and inflammation are both universal findings in the brain of AD, and the former is necessary for a pathological diagnosis of AD. However, whether either results in neuronal death, and if so by what mechanism, is yet to be determined.

m a j o r m e c h a n i s m o f n e u r o n a l d e g e n e r a t i o n o c c u r s in A D . U n f o r t u n a t e l y , t h e l a c k o f a r e a d i l y i d e n t i f i a b l e m a r k e r f o r this n e u r o n a l loss has m a d e t h e i d e n t i f i c a t i o n o f its c a u s e e x t r e m e l y difficult. A s t u d y h a s s h o w n t h a t t h e p r o l y l i s o m e r a s e , P i n l , is s e q u e s t e r e d i n t o t h e N F T a n d d e p l e t e d in t h e b r a i n s o f A D p a t i e n t s ( L u et al., 1999).

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Depletion o f Pinl may induce n e u r o n death via mitotic arrest and apoptosis prior to the development of NFTs (Lu et al., 1996). The neuron-specific activator for cell proteins involved in the mitotic cycle is p35, which is proteolytically cleaved to produce p25, a fragment f o u n d to accumulate in the brains of patients with AD (Patrick et al., 1999). Application of Aft 1-42 induces the conversion of p35 to p25 (Lee et al., 2000). p25 links with cell cycle-dependent kinase 5 to hyperphosphorylate tau and p r o m o t e apoptosis (Lee et al., 2000). Degenerating neurons in APP V717F Aft-producing transgenic mice show chromatin segmentation and condensation, as well as increased TUNEL staining, suggestive of apoptosis (Nijhawan et aL, 2000). This supports a link between Aft deposition and apoptosis (Fig. 4). Increased TUNEL staining (Druganow et al., 1995; Lassmann et al., 1995; Smale et al., 1995; Bancher et al., 1997), as well as cleaved caspase 3 (Selznick et al., 1999; Stadelmann et al., 1999), an enzymatic marker of apoptosis, are found in vulnerable brain regions in AD. APP has been identified as a specific substrate for caspase 3 with the resultant peptides (including Aft), inducing apoptosis (Gervais et al., 1999). O t h e r apoptotic-specific caspases can also cleave APP (Pellegrini et al., 1999), and the resultant C-terminal fragment from such cleavage has been called C31 (Lu et aL, 2000). C31 is also a potent inducer of apoptosis and was f o u n d in the brain of patients with AD (Lu et al., 2000), whereas caspase deficient mice are resistant to this form of cell death (Nakagawa et al., 2000). Despite these studies that suggest apoptosis occurs in AD, apoptotic bodies and blebbing are not features of AD neuronal degeneration. In addition, the time sequence of such events remains to be determined. The chronic nature of the n e u r o d e g e n e r a t i o n in AD does not fit well with the more rapid time course of apoptosis, which is believed to take only weeks or months at most (Stadelmann et al., 1999). O t h e r mechanisms of neuronal death, such as necrosis, were also demonstrated in AD (Wolozin and Behl, 2000b). Indeed, the same triggers may cause either apoptosis or necrosis, including Aft toxicity, oxidative stress, excitotoxicity, ischemia, and removal of trophic factors. The distinction between apoptotic and necrotic mechanisms, however, may be somewhat false given that neurons may begin with necrosis and then convert to apoptosis or alternatively begin with apoptosis and then undergo necrosis (Wolozin and Behl, 2000b). Although Aft plaques are necessary for a diagnosis of AD, like NFTs, they are poorly related to the degree o f neuronal loss. However, studies suggest the intracellular accumulation of Aft may be neurotoxic (Fig. 4). T h e r e is an additional site o f APP cleavage within the endoplasmic reticulum that gives rise to intracellular Aft 1-42/43, which over time reaches the concentration necessary for fibril formation (Hartmann, 1999; Wilson et al., 1999). Cell rupture would release this intracellular Aft into the surrounding extracellular milieu, which could stimulate further amyloid deposition. Although most

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cell types express APE neurons produce the highest a m o u n t and preferentially use the intracellular pathways for Aft production (Hartmann, 1999). It is difficult to know how to prove or refute this model of AD neuronal vulnerability, although it is of interest that Aft is not deposited within the vulnerable hippocampal formation or entorhinal cortex (Arnold et al., 1991) and no neuronal loss occurs in elderly APP-transgenic mice who show considerable A/3 deposits (Irizarry et al., 1997a, 1997b). Interestingly, a study identified nonpyramidal neurons containing Aft 1-42 around amyloid plaques in AD patients (Mochizuki et al., 2000), suggesting preserved neurons may concentrate these peptides intracellularly. In contrast, a n u m b e r of studies suggest that soluble A/3, and particularly Aft 1-40, is synaptotoxic without causing plaque formation or overt cell death (Mucke et al., 2000). Reductions in soluble A/31--40 concentrations correlate with synaptic loss in patients with AD (Lue et al., 1999). Interestingly, in the same patients, soluble A/31-40 levels correlate with cerebrovascular amyloid angiopathy and ApoEe4 allele frequency (Lue et al., 1999), suggesting a greater influence on vascular changes than neuronal degeneration.

E SUMMARY Taken together, these studies suggest a multifactorial origin of neuronal loss in AD where a n u m b e r of primary and secondary factors may cause neuronal death (Fig. 4). More work is n e e d e d to link all the potential cellular events that underlie the clinical symptoms of AD. At present, we do not have a good understanding of the association between A/3 deposition (required for a diagnosis of AD) and the degenerative process. The link between soluble A/3 and brain atrophy needs to be clarified, and mechanisms of cell death other than NFT formation (and possibly apoptosis) need to be elucidated. It will be important to determine the time sequence of these events to target appropriate therapeutic measures.

IV. Genetic Influences

As many as 50% of patients with AD have at least one first-degree relative with dementia (Writing Committee Lancet Conference 1996, 1996), and numerous studies have investigated family history as a risk factor for AD. Nine of the 14 case control studies reviewed b y J o r m (1990) showed a significantly increased risk of AD in subjects with a positive family history. The odds ratios ranged from 2.1 to 9.9 and reflect data obtained from prevalence and incidence studies.

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A. DOMINANT INHERITANCE It is estimated that between 5% and 10% of AD cases have a d e m o n strable pattern of inheritance. These cases, although rare, provide valuable insights into the pathogenesis of AD. To date, three genes have b e e n identified. These are APP mutations on c h r o m o s o m e 21, presenilin-1 (PS-1) mutations on c h r o m o s o m e 14, and presenilin-2 (PS-2) mutations on chrom o s o m e 1. Each of these genes have an autosomal d o m i n a n t pattern of inheritance, although PS-2 does not a p p e a r to have complete p e n e t r a n c e (St. George-Hyslop, 2000). These three identified genes do not fully account for all autosomal d o m i n a n t cases of AD, suggesting o t h e r genes are yet to be identified. T h e APP gene encodes a t r a n s m e m b r a n e protein of 770 a m i n o acids f r o m which Aft is derived (see section III.C above). T h e n o r m a l function of APP is not known, although it is highly conserved and expressed ubiquitously. In addition to AD, mutations in APP can also result in hereditary cerebral h a e m o r r h a g e with amyloidosis-Dutch type (HCHWA-D). Mutations in the APP gene are mostly located in or a r o u n d the amyloidogenic portion of the molecule, especially n e a r the three secretase sites. Mutations in the PS-1 gene are the most c o m m o n o f the early-onset familial AD mutations, accounting for 30-50% of all autosomal d o m i n a n t cases. PS-1 is a t r a n s m e m b r a n e protein that is also expressed ubiquitously and has six or eight t r a n s m e m b r a n e domains (Checler, 1999). T h e r e is an increasing body of evidence that suggests the presenilins function as the y-secretase, or in close association with y-secretase, in the p r o d u c t i o n of A/3 (Checler, 1999; Ray et al., 1999; Wolfe et al., 1999) and thus increase the production A f l l - 4 2 / 4 3 . More than 50 mutations in PS-1 have b e e n identified. T h e majority of these are missense mutations and are scattered t h r o u g h o u t the molecule. In addition, a n u m b e r of splice acceptor mutations that cause the deletion of the sequence e n c o d e d by exon 9 were also described (Kwok et al., 1997; Crook et al., 1998; Smith et al., 2001). A p r o p o r t i o n of PS-1 mutations with a deletion of exon 9 have AD with spastic paraparesis (SP; Crook et al., 1998; Verkkoniemi et al., 2000). In AD+SP, there is progressive weakness and wasting of the lower extremities and a later age of onset of d e m e n t i a has b e e n described in some of these families (Smith et al., 2001). T h e pathology of exon 9 mutations is also interesting in that very large, n o n c o r e d , and faintly neuritic plaques are described (Crook et al., 1998; Smith et al., 2001). These have b e e n t e r m e d "cotton-wool" plaques because of their size and uniform a p p e a r a n c e (Fig. 5). T h e PS-2 gene encodes a t r a n s m e m b r a n e protein that is 67% homologous to PS-1 (Checler, 1999). Unlike APP and PS-1, PS-2 is expressed m o r e strongly in peripheral tissues (pancreas, cardiac, and skeletal muscle)

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FIG. 5. Photomicrographs of the temporal neocortex of a patient with a presenilin-1 (PS-1) mutation. In the upper panel, both neuritic (arrows) and diffuse plaques can be seen. The diffuse plaques (inset) in these patients are unusual because they are large, only faintly neuritic, and lack cores. They have been termed "cotton wool" plaques and are tound exclusively in patients with PS-I mutations. t h a n in t h e b r a i n (St. G e o r g e - H y s l o p , 2000). A s m a l l n u m b e r o f f a m i l i e s w i t h m i s s e n s e m u t a t i o n s in PS-2 h a v e b e e n i d e n t i f i e d , i n d i c a t i n g t h e y a r e m u c h r a r e r t h a n PS-1 m u t a t i o n s . T h e e x a c t m e c h a n i s m by w h i c h PS-2 m u t a t i o n s c a u s e A D is u n c l e a r , a l t h o u g h b e c a u s e o f its s e q u e n c e h o m o l o g y w i t h PS-1, it is b e l i e v e to h a v e a s i m i l a r f u n c t i o n .

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T h e mechanism c o m m o n to the known mutations is an increased production of Aft 1-42/43 and an increased rate of aggregation of Aft plaques (see Wolozin and Behl, 2000a, for commentary). However, it appears that the PS mutations may also be involved in other aspects of the pathology o f AD by participating in cell death due to apoptosis and in the phosphorylation of tau (see Checler, 1999; Czech et al., 2000). Our knowledge of AD has advanced substantially since the identification o f the mutations responsible for familial forms of AD and of the presenilins in particular. This rapidly moving field of research provides valuable insights into the disease processes and has the potential for the development of strategies for therapeutic intervention. However, it is still unknown whether the knowledge gained from studying these cases is generally applicable to the majority of AD patients. In addition, the knowledge gained has still not elucidated the cause(s) of sporadic AD.

B. GENETICRISKFACTORS Apart from d o m i n a n t inheritance, the clustering of dementia within families must be viewed as evidence for the role of an individual's genotype in determining their risk of AD. T h e apolipoprotein E (ApoE) gene, f o u n d on c h r o m o s o m e 19, encodes three isoforms of e2, e3, and e4, and the presence of the e4 allele has been f o u n d to increase the risk o f A D (Katzman, 1994; Strittmatter and Roses, 1995). ApoE is involved in lipid transport and is present in the serum (Uterman, 1994). An association between ApoE e4 and AD was first described in 1993 in both sporadic (Saunders et al., 1993) and familial (Corder et al., 1993) AD. It has subsequently been confirmed in many other studies of early- and late-onset AD and a variety of other neurological diseases, including o t h e r dementias (e.g., Roses, 1996; Stevens et al., 1997; Horsburgh et al., 2000). In addition, an allelic dose d e p e n d e n c e has been shown where subjects who are homozygous for e4 have a greater risk of AD at an earlier age than those who are heterozygous (Corder et al., 1993). In this study of families with late-onset AD, subjects with no e4 had a mean age of onset of 84.3 years c o m p a r e d with 75.5 years in those with one s4 allele and 68.4 years with two alleles. In addition to its effect on age of onset, ApoE genotype has also been shown to influence, albeit variably, the response to drug treatment. A p o o r e r response to the cholinesterase inhibitor tacrine has been shown in patients with AD who possess the ApoE e4 allele than those who do not (Poirier et al., 1995), although this effect has not been found in all studies (MacGowan et al., 1998). In addition, only patients with e4 showed improvement in

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cognitive performance when treated with a drug that facilitiates noradrenergic and vasopressinergic activity in the brain (Richard et al., 1997). Some debate also exists over whether ApoE genotype modifies the type or a m o u n t of AD pathology in individuals carrying the e4 allele. Several studies (Schmechel et al., 1993; Nagy et al., 1995; Overmyer et al., 1999), but not all (Morris et al., 1995; Landen et al., 1996), have found an increase in the density of neurofibrillary tangles and senile plaques in AD. Moreover, the correlation with brain pathology is further complicated by the finding that normal subjects in their forties and older who possess an e4 allele have smaller right hippocampi than those without e4 (Tohgi et al., 1997). It is unclear whether this finding represents a lifelong trait or is an indicator of "preclinical" AD. Longitudinal studies on such groups of subjects are necessary to clarify this issue. In patients with AD, greater brain atrophy (Lehtovirta et al., 1995; J u o t t o n e n et al., 1998b) and an increased rate of atrophy has been found in individuals with e4 (Wahlund et al., 1999). However, this association has not been found in all studies (Barber et al., 1999). The mechanism of action of ApoE is not fully elucidated. ApoE is involved in the regulation of the transport of cholesterol and phospholipid and has an important role in the distribution of these molecules during periods of m e m b r a n e remodeling, such as synaptic plasticity and m e m b r a n e repair. In addition, ApoE-lipid complexes are believed to assist in the removal of Aft via the low-density lipoprotein-related receptor (Wolozin and Behl, 2000a). Isoform differences in the behavior of ApoE have been identified (e.g., Strittmatter et al., 1993; Nathan et al., 1994), and these are believed to underlie the susceptibility to AD in individuals with the e4 allele (Horsburgh et al., 2000; Wolozin and Behl, 2000a).

C. SUMMARY

In addition to these genetic factors, other modifying influences have been identified (e.g., HLA, butyrylcholinesterase K, ~ 1 antichymotrypsin) ; however, the exact nature of the relationship between genotype and disease susceptibility remains obscure. Although there is strong evidence for an association between ApoE e4 and AD, the presence of e4 is not causative or is it necessary to develop AD. For these reasons, it is r e c o m m e n d e d that ApoE not be used for predictive testing (American College of Medical Genetics/American Society of H u m a n Genetics Working Group on ApoE and Alzhemer's Disease, 1995). Similar results are likely for other genetic risk factors. Nevertheless, such genotypes are important variables to be considered in research studies examining aspects of the pathogenesis

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and progression of AD, especially as reports of monozygotic twins that are discordant for AD (Creasey et al., 1989) suggest that inheritability is not solely responsible for one's risk of AD. Few studies are integrating the multiple genotype analyses required to understand genetic versus environmental influences.

V. Inflammation and Anti-inflammatory Drugs Numerous lines of evidence suggest a link between brain inflammation and AD (see Gahtan and Overmier, 1999; Halliday et al., 2000a). Initial evidence from clinical studies for a role of anti-inflammatory drugs in the prevention of AD came from case control studies that examined arthritis as a risk factor and f o u n d a r e d u c e d risk of dementia in patients who consumed anti-inflammatory drugs (Broe et al., 1990; Breitner, 1996). However, a n u m b e r of similar studies were unable to identify a significant reduction in risk (e.g., Heyman et al., 1984). This inconsistency may reflect the relatively small samples examined in each study individually because a meta-analysis of 17 studies showed a reduced risk of AD dementia in patients taking both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs; McGeer et al., 1996). It should be noted, however, that the majority of these studies were of cross-sectional design where significant biases exist in selection of cases for study and the reporting of drug use (Stewart et al., 1997). Antigens of the major histocompatibility complex are intimately associated with inflammation and polymorphisms of the genes encoding these proteins have been associated with an increased risk of disease. In particular, CNS and peripheral diseases with an inflammatory basis occur more commonly in subjects who have a particular HLA genotype; notable among these is the association between rheumatoid arthritis and HLA-DR4 (Khan et al., 1983; Stastny et al., 1988). A n u m b e r of different associations were described between AD and HLA alleles. In late-onset patients who do not have ApoE e4 alleles, an increased risk of AD was f o u n d in patients with HLADR1, 2, or 3, and a reduced risk was f o u n d in patients with HLA-DR4 or 6 (Curran et al., 1997). However, these findings were not replicated by others (Middleton et al., 1999b), or only partly replicated (Neill et al., 1999), and the converse relationship (HLA-DR3 is protective) was found in a study of autopsy-confirmed cases o f A D (Culpin et al., 1999). In addition, an earlier age of onset by 3 years has been reported in subjects with HLA-A2 compared with other alleles (Payami et al., 1997; Combarros et al., 1998), and when the patient's ApoE status was examined, the effect o f HLA-A2 and

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ApoE e4 appeared to be additive (Payami et al., 1997). A similar additive effect of HLA-A2 and ApoE e4 has been found in early-onset familial AD (Ballerini et al., 1999). O t h e r associations with HLA alleles were reported (Small et al., 1991; Middleton et al., 1999a), but these studies are yet to be replicated. It is therefore unclear whether the initial studies implicating anti-inflammatory medications as protective for AD are due to a direct effect on brain inflammation or are associated with genotype and disease susceptibility. To date, there have been only three longitudinal studies analyzing the question of drug protection in AD. Two of these studies (Stewart et al., 1997; Prince et aL, 1998) found a beneficial effect of NSMDs. The Baltimore Longitudinal Study of Aging found a reduced risk of AD among users of NSMDs and aspirin, which was increased the longer the drugs were used (Stewart et al., 1997). Prince and colleagues (1998) showed less decline in some tests of cognitive function in NSMD users, although the benefit was reduced in older subjects. In contrast, a study of Australians ages 70 years or older (mean age of 80) found that NSMDs or aspirin provided no protection against cognitive decline or incidence of dementia over a 3- to 4-year period (Henderson et al., 1997). Taken together, these studies suggest that some protection is conferred at ages when susceptibility is relatively low. It may be that sufficient protection occurs only with long-term drug usage. It is therefore not surprising that clinical trials aimed at assessing the role of NSMDs in preventing AD produced conflicting results. Rogers and colleagues (1993) p e r f o r m e d a study o f i n d o m e t h a c i n in 28 patients and found a small but significant slowing of cognitive decline in the treated patients. Conversely, Scharf and colleagues (1999) used an NSMD in combination with a gastroprotective agent and found no difference between groups in measures of cognitive performance. Drop-out rates in both studies were considerable (up to 50%) and follow-up times short (around 6 months), so neither study can be considered conclusive. Nevertheless, on cross-sectional analysis cognitive performance is improved in AD patients taking NSMDs and aspirin (Broe et al., 2000) compared with their nontreated counterparts. Interestingly, this effect was present at low doses of aspirin, which are not considered to be anti-inflammatory suggesting the effect of these drug is not through reducing inflammation but through some other, possibly peripheral mechanism (Broe et al., 2000). Neuropathological studies demonstrated a close relationship between Aft plaques and both reactive astrocytes and microglia (Rozemuller et al., 1992; McGeer and McGeer, 1995; Halliday et al., 2000b). M t h o u g h a glial response might be expected to occur secondary to the degeneration in AD, evidence suggests the inflammatory response itself may contribute to the

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pathology of AD. Many o f the proteins of the c o m p l e m e n t pathway, together with acute phase proteins, are f o u n d in Aft plaques (see Walker, 1998) and are believed to be synthesized by microglia. In addition, activated microglia synthesize and excrete a n u m b e r of inflammation-related substances that have been shown to be neurotoxic in rats (Weldon et al., 1998), and it has been suggested that microglia might facilitate Aft deposition (see Gahtan and Overmier, 1999). Overall, the data show that patients with AD have an active i m m u n e response in the brain. An age-related increase in inflammatory microglia has also been f o u n d (Mattiace et al., 1990; Mackenzie and Munoz, 1998) which may reflect the brain's reaction to the increased AD-type pathology in aging or, alternatively, indicate changes to the i m m u n e status of the elderly brain. Interestingly, this age-associated increase in activated microglia is ameliorated by NSAID use (Mackenzie and Munoz, 1998), unlike AD patients where NSAID use does not decrease inflammation (Halliday et al., 2000b). This suggests the disease process itself stimulates an i m m u n e response. Whether inflammation is a primary cause for the n e u r o d e g e n e r a t i o n in AD or a secondary event to aid in its clearance is still unclear because the sequence o f these events is still poorly understood (Fig. 4). Although some epidemiological and clinical evidence suggests a beneficial effect of treatment with NSAIDs, other research suggests any such benefit is mediated through a noninflammatory mechanism (Broe et al., 2000; Halliday et al., 2000b). A clearer picture of the sequence of the early and subsequent cellular events in patients with AD would help clarify any direct role of inflammation in the disease process. T h e e n h a n c e d i m m u n e response in AD patients is now being used for a new type of treatment, Aft peptide immunization (Schenk et al., 2000). Immunization trials are about to c o m m e n c e following the dramatic findings that transgenic mice that overproduce APP and deposit Aft can recover following immunization (Schenk et al., 2000). Specifically, when the mice were immunized at a young age, they developed little if any Aft depositions with advancing age. Moreover, the progression of both neuritic dystrophy and astrogliosis were significantly reduced in the treated animals, suggesting the immunization had benefits beyond simply reducing Aft deposition. When immunization was begun at later ages when the mice exhibit Aft deposition, further Aft deposition was blocked and somewhat reversed, as was the neuritic dystrophy and astrogliosis. In addition, remaining Aft deposits were often actively metabolized by microglia cells, questioning the premise that reduction of the activity of these cells by anti-inflammatory medications would be of benefit in AD. These studies support the concept that the i m m u n e system may be harnessed into an appropriately targeted therapy for AD. If the trials of Aft immunization are effective in AD, it will provide compelling evidence for its causative role in AD.

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Vh EsltogenTherapy

A n u m b e r of studies examining gender as a risk factor for AD find an increased risk in women, especially older women, even after controlling for education level and other factors, such as differential survival rates. This led to the hypothesis that hormonal factors may play a role in determining susceptibility to AD. This suggestion is supported by the finding that postmenopausal women receiving h o r m o n e replacement therapy have a reduced risk of AD (Paganini-Hill and Henderson, 1994, 1996). A reduced risk of AD was also identified in the Baltimore Longitudinal Study of Aging, a prospective study of the effect of estrogen replacement therapy on incident AD (Kawas et al., 1997). The mechanism by which estrogen protects from AD is unclear. It was suggested the mode of action is through estrogen-sensitive neurons in the hippocampus and cortex (Maki and Resnick, 2000), although evidence from transgenic mice showed that estrogen treatment increased the a m o u n t of the neuroprotective sAPP fragment, but did not reduce the production of Aft (Vincent and Smith, 2000). Estrogen has also been shown to have antioxidant activity (Niki and Nakano, 1990) that may contribute to its protective role. Treatment of women with mild to moderate AD with estrogen for 1 year has not been found to improve cognitive function or slow the progression of the disease (Mulnard et al., 2000). Interestingly, however, n o n d e m e n t e d subjects treated with estrogen have better cognitive performance and increased regional CBF than nontreated subjects (Maki and Resnick, 2000). This, together with the epidemiological evidence of reduced risk of AD in subjects treated with estrogen, suggests the benefits of estrogen are lost after the onset of AD. This is not surprising as the regions found to be sensitive to estrogen (i.e., hippocampus, parahippocampus, and temporal cortex; Maki and Resnick, 2000) are the areas of the brain that are damaged earliest and to the greatest degree in AD (Braak and Braak, 1991; Gomez-Isla et al., 1996).

Vlh Vascular Pathologyin AD

T h e r e is mounting evidence for an etiological link between AD and vascular pathology. Although both AD and cerebrovascular disease are comm o n in the elderly and their importance as i n d e p e n d e n t causes of brain pathology is acknowledged (Kokmen et al., 1996; Snowdon et al., 1997;

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Shi et al., 2000), it is their possible synergy that provides exciting opportunities for the investigation of the pathogenesis of AD. Evidence exists to suggest that cerebrovascular disease may contribute to AD pathology by p r o m o t i n g non-NFT m e d i a t e d n e u r o n a l loss ( G r a m m a s et al., 1999) and exacerbating Aft plaque formation (Lin et al., 1999; Bennett et al., 2000). T h e relationship between AD and vascular disease is far f r o m clear; however, we know that b o t h infarction and microvascular pathology can be involved (Fig. 4). Abnormalities in cerebral white matter have b e e n identified at autopsy in m o r e than half the patients with AD (Englund, 1998). These include r e d u c e d vessel density, white matter pallor (rarefaction), and gliosis and thickening of the vessel wall. Such changes are believed to be the pathological correlate of the leukoaraiosis, which is frequently seen on neuroimaging in elderly subjects with and without d e m e n t i a (Smith et al., 2000). In addition, n u m e r o u s studies showed altered architecture of the cerebral microvasculature including atrophic vessels, g l o m e r u l a r loops, a n d tortuosities in AD (Ravens, 1978; Kalaria and Hedera, 1995; Buee et al., 1999). These were also shown to occur in n o r m a l aging, although they are m o r e frequently e n c o u n t e r e d in AD. O n e of the main theories for how a b n o r m a l arterioles and capillaries can affect brain function is the disturbance of the n o r m a l laminar flow that exists in blood vessels (de la Torre, 1997; Fig. 4). Briefly, in situations of n o r m a l flow, red blood cells travel in the center of a vessel where flow is greatest. At the periphery, there is a cell-free zone with virtually no flow, which allows for the transfer of nutrients and o t h e r molecules across the vessel wall. Alterations in vessel architecture result in turbulence with impaired flow and, ultimately, impaired delivery of nutrients. Such turbulence would result in ischemic n e u r o n a l loss as a consequence of the failure of delivery of sustaining nutrients and may differentially affect those areas of the brain with higher metabolic d e m a n d , such as the hippocampus. Alternative m e c h a n i s m s were also p r o p o s e d for the link between AD and microvascular pathology. It has b e e n d e m o n s t r a t e d that microvessels isolated f r o m patients with AD can result in n e u r o n a l death when cocultured with primary rat n e u r o n s ( G r a m m a s et al., 1999). T h e effect was also d e m o n s t r a t e d when n e u r o n s were cultured with m e d i a conditioned by AD microvessels, suggesting a soluble substance is responsible for the n e u r o d e g e n e r a t i o n . T h e nature of the soluble toxin is not known at present, but a n u m b e r of candidates such as nitric oxide, reactive oxygen species, and cytokines were suggested ( G r a m m a s et al., 1999). Several studies have r e p o r t e d an association between cognitive function in AD and the presence of brain infarction (Nagy et al., 1997a; Snowdon et al., 1997). In the N u n study, patients with AD and infarcts showed p o o r e r cognitive p e r f o r m a n c e than AD patients without infarction (Snowdon et al., 1997).

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Similarly, for an equivalent level of cognitive impairment, the density of plaques is less in AD patients with cerebrovascular disease than those without such disease (Nagy et al., 1997a). In addition, lacunar infarction with or without leukoencephalopathy was found in 20 of 25 cases with clinically probable AD and the majority of these had a lower Braak neuritic stage than d e m e n t e d patients without cerebrovascular disease (Goulding et al., 1999). Furthermore, it was demonstrated that impaired circulation can result in increased Aft deposition. In experimental animals, chronic hypoperfusion can trigger the cleavage of APP and the formation of Aft (Bennett et al., 2000), whereas in humans, soluble A/31-42/43 levels are similar in patients with multi-infarct dementia and AD (Kalaria, 2000). Overall, these studies show that AD pathology may be less severe when there is coexisting cerebrovascular disease and that cerebrovascular disease may contribute to AD-type pathology. The association between vascular disease and AD is further supported by the finding that subjects dying of cardiovascular disease show more AD-type pathology than those dying of noncardiac causes (Sparks et al., 1990; Sparks, 1997). In n o n d e m e n t e d individuals dying of cardiac causes, the density of senile plaques is half that seen in AD (Sparks et al., 1990). The effect of ApoE e4 in this population was not examined and a study by Irina and colleagues (1999), which was unable to confirm the finding, suggested the association is due to ApoE e4 and not cardiovascular disease per se. In addition to AD, an association between cardiovascular disease and ApoE genotype is well established (see Katzman, 1994), which further strengthens the link between vascular disease and AD.

A. VASCULARRISK FACTORS Epidemiological evidence links cardio- and cerebrovascular factors with AD. In a longitudinal study, subjects who developed dementia had higher systolic blood pressure measured 15 years earlier than their n o n d e m e n t e d counterparts (Skoog et al., 1996). Interestingly, at the time of diagnosis of AD, these same subjects had blood pressure similar to or lower than the n o n d e m e n t e d subjects. This latter point may underlie the cross-sectional association described between higher blood pressure and better cognitive function in later life (Farmer et al., 1987). These studies suggest early and midlife events significantly affect late-life neurodegenerative diseases. Diabetes mellitus, which is known to be associated with an increased risk of stroke, was also shown to be associated with an increased risk of AD (Kuusisto et al., 1997; Ott et al., 1999). A relative risk of 1.9 was found for both AD and dementia of any type (Ott et al., 1999). The risk is higher

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(RR 4.3, CI 1.7-10.5) in those treated with insulin, suggesting there is an increasing risk with increasing severity of diabetes. Patients with diabetes mellitus have a high incidence of vascular complications (West, 1978), and the reported association with AD may reflect increased cerebrovascular disease in these patients. A postmortem study comparing cerebrovascular pathology in diabetic and nondiabetic AD patients has not been performed. However, AD-type pathology was studied in diabetic subjects and is not increased (Heitner and Dickson, 1997). The associated risk is therefore likely to be due to non-AD pathology, most likely, vascular disease. Genetic predisposition may also play a role in the relationship between vascular disease and AD. In addition to the association with ApoE, polymorphisms o f the angiotensin-converting enzyme (ACE) have been associated with an increased risk of AD (Hu et al., 1999; Kehoe et al., 1999). Despite associations between ACE and cardiovascular risk factors, the association is i n d e p e n d e n t o f A p o E (Hu et al., 1999). Thus, it appears there is a complex relationship between vascular disease and its risk factors and an increased risk of AD.

B. SUMMARY

A hypothesis has been presented that links many of the identified and putative risk factors forAD and suggests a mechanism for their action. Crawford (1996, 1998) proposes an association between AD and cerebral blood flow (CBF) by citing evidence that many of the factors that are linked with an increased risk of AD also decrease CBF (e.g., old age, depression, underactivity, head trauma). Similarly, it is suggested factors that increase CBF are associated with a decreased risk of AD (e.g., education, exercise, smoking, NSAIDs). Although the authors acknowledge that reduced CBF is not sufficient to cause AD, the r e p o r t e d positive and negative associations provide tantalizing evidence for a c o m m o n m o d e of action for many of the equivocal risk factors r e p o r t e d to date. This hypothesis is also consistent with other data that links microvascular damage and impaired blood flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999). Gaining a better understanding of the interaction between AD and vascular disease is o f great importance. Not only will it provide insights into the pathogenesis of AD, but it may also provide us with a rare opportunity for the treatment and possible prevention ofAD. A great many risk factors for vascular disease have been identified and intervention programs have successfully reduced the incidence of heart disease and stroke. T h e potential exists to provide the same level of success with AD.

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Acknowledgments The authors are grateful to Heidi Cartwright for the preparation of the illustrations, Francoise Png and Smita Patel for bibliographic assistance, and Dr. Claire Shepherd for helpful discussions. Studies described in this article were conducted with financial assistance from the Medical Foundation of The University of Sydney and the National Health and Medical Research Council (NHMRC) of Australia.J.J.K. is a Medical Foundation Fellow and G.M.H. is a Principal Research Fellow of the NHMRC.

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