ALZHEIMER''''S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS - PART 1 doc

ALZHEIMER'S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS Jillian J.. Kril I Centre for Education and Research on Ageing, Concord Hospital Department of Medicine, The University of Sydney, Co

ALZHEIMER'S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS

Jillian J Kril I Centre for Education and Research on Ageing, Concord Hospital

Department of Medicine, The University of Sydney, Concord, New South Wales, Australia 2139, and Department of Pathology, The University of Sydney, Sydney,

New South Wales, Australia 2006

Glenda M Halliday Prince of Wales Medical Research Institute Randwick, New South Wales, Australia 2031

I I n t r o d u c t i o n

II Diagnostic Issues

A A/3 Plaques a n d NFTs for Pathological Diagnosis

B Evaluation o f O t h e r Pathologies

C Clinical Correlates o f AD Pathology

D Reproducibility o f C u r r e n t Clinical Diagnostic Protocols

E S u m m a r y

III Pathogenesis

A Brain Atrophy

B N e u r o n a l Loss

C A/3 Deposition

D NFT F o r m a t i o n

E M e c h a n i s m s of D e g e n e r a t i o n

E S u m m a r y

IV Genetic I n f l u e n c e s

A D o m i n a n t I n h e r i t a n c e

B Genetic Risk Factors

C S u m m a r y

V I n f l a m m a t i o n 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

l A u t h o r to w h o m c o r r e s p o n d e n c e s h o u l d be addressed

NEUROBIOLOGY, VOL 48 All rights of reproduction in any form reserved

168 JILLIAN J KRIL AND GLENDA M 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 de- scribed, our knowledge of all aspects of AD has grown markedly AD is uniformly progressive and ultimately results in debilitating cognitive im- pairment In the early stages, the impairment may only be apparent on

Lesion type

" j A I ~ plaques

0 e ; O 0 e ; • ; o • "

m ° °

t ? other dementi~

• ' ' Q I ° l~c, 1 T h e major pathologies resulting in d e m e n t i a are neurofibrillary tangles (NFTs; top left), A¢I plaques (top center), a n d Lewy bodies (top right, arrow) Diagnosis o f AD was pre- viously based on age-corrected densities o f A~ plaques; however, the finding that a significant

n u m b e r o f patients with d e m e n t i a with Lewy bodies (DLB) also have A¢I plaques questions this practice Similarly, NFTs can be found in o t h e r forms o f d e m e n t i a a n d thus are n o t specific for AD Newer criteria p r o p o s e d for the pathological diagnosis o f 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 o f AD These clinical criteria have b e e n val- idated using A~ plaque-based pathology a n d now require re-evaluation in light o f the advances

in o u r u n d e r s t a n d i n g o f the pathogenesis o f the disease

ALZHEIMER'S DISEASE 169 neuropsychological testing; however, by e n d stage, few functions above the automatic remain unaffected (Forstl and Kurz, 1999) T h e pattern and se-

q u e n c e o f functional deficits and the relentlessness o f the decline are rel- atively reproducible, with the course o f the disease in o n e patient similar

to that in others AD remains the most prevalent form o f late-life d e m e n t i a and is the most significant cause o f 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 o f the brain; however, the accurate and reproducible diagnosis o f AD during life is o f p a r a m o u n t importance Not only is it essential to exclude possible treatable causes o f dementia, but it is also necessary for the identification

o f h o m o g e n e o u s groups o f patients for evaluation and study, and for the

r e c r u i t m e n t o f patients for drug and o t h e r therapeutic trials Variability in the clinical diagnosis o f AD is well recognized and major diagnostic issues

c o n t i n u e 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 in- stances, n e u r o p a t h o l o g y is considered the "gold standard" for the diagnosis

o f AD, b u t considerable variation exists between diagnostic protocols This has the potential to have a significant impact on o u r u n d e r s t a n d i n g o f the disease

A A/3 PLAQUES AND N F T s FOR PATHOLOGICAL DIAGNOSIS

T h e majority o f protocols for the pathological diagnosis of AD use only

o n e o f the major pathological lesions first described by Alzheimer T h e most

c o m m o n l y used lesion for the diagnosis o f AD is the neuritic plaque as Aft deposition is m o r e distinctive for AD than o t h e r n e u r o d e g e n e r a t i v e diseases T h e Consortium to Establish a Registry for Alzheimer's Disease (CERAD; Mirra et al., 1991) developed the most widely used diagnostic pro- tocol It employs the earlier National Institutes o f Health protocol based on age-corrected plaque densities (Khachaturian, 1985) in a semiquantitative fashion to arrive at diagnoses of varying certainties T h e CERAD criteria (Mirra et al., 1991; Table I) has gained wide acceptance because o f its ac- curacy and simplicity In 142 cases with a clinical diagnosis o f probable AD

170 J I L L I A N J KRIL AND G L E N D A M H A L L I D A Y

T A B L E I CONSORTIUM TO ESTABLISH A REGISTRY FOR ALZHE1MER'S DISEASE ( C E R A D ) CRITERIA

FOR NEUROPATHOLOGICAL DIAGNOSIS OF A D a

Plaque Densities b

S + no dementia

S, M, or F + Dementia

N o r m a l b r a i n

P o s s i b l e A D S + N o d e m e n t i a

P r o b a b l e A D S + D e m e n t i a , o r

M + n o d e m e n t i a

D e f i n i t e A D S, M, o r F + D e m e n t i a F + D e m e n t i a

aRegions examined middle frontal, superior and middle temporal, inferior parietal cor- tices, hippocampus and entorhinal cortex, midbrain

From Mirra et aL (1991)

(the National Institute o f Neurological a n d Communicative Disorders a n d Stroke (NINCDS)-Alzheimer's Disease a n d Related Disorders Association (ADRDA) most certain clinical category, see Section II.C a n d Table II), 84%

were f o u n d to have definite A D - - 7 % probable a n d 2% possible (Mirra et al.,

1991) In 7% o f cases, the age-related plaque score was negligible, suggesting

a n o t h e r cause for d e m e n t i a in these cases In an i n d e p e n d e n t assessment o f the accuracy o f the CERAD criteria, subjects with a clinical diagnosis o f prob-

able AD h a d definite AD at autopsy in 27 o u t o f 28 cases (96% Kosunen et al.,

1996) Subsequent interlaboratory testing o f the CERAD criteria revealed 75% a g r e e m e n t in the rank o r d e r i n g o f 10 cases between 24 n e u r o p a t h o l -

ogists at 18 centers (Mirra et al., 1994) T h e majority o f variation was due

to staining differences between laboratories, b u t the data suggest there is considerable variation between pathologists in the CERAD diagnosis o f in- dividual cases

In contrast to the plaque-based protocols, Braak a n d Braak (1991) pro- posed a staging scheme for the neuritic pathology o f A D (NFTs a n d neuropil threads) This six-stage scale d o c u m e n t s the temporal sequence a n d topo- graphic spread o f AD pathology A l t h o u g h n o t p r o p o s e d as a criteria for the n e u r o p a t h o l o g i c a l diagnosis o f AD, d e m e n t i a is reliably associated with stages V a n d VI a n d to a variable degree with stages III a n d IV (Braak a n d

Braak, 1991; H a r d i n g et al., 2000) NFTs first form in the pre-a layer o f

the transentorhinal cortex (stage 1, Table III), then the pre-a layer o f the entorhinal cortex, the h i p p o c a m p u s , a n d finally the isocortex (Table III)

C o m p a r e d with the CERAD criteria, inter-rater reliability for neuritic stag-

ing is high (weighted kappa 0.85 to 0.97; Nagy et al., 1997b) However, the

ALZHEIMER'S DISEASE 171

TABLE II NINCDS-ADRDA CRITERIA FOR CLINICAL DIAGNOSIS OF A n a

Possible A D

P r o b a b l e A D

Key features

Probable A D

Supportive features

P r o b a b l e A D

Suggestive features

P r o b a b l e A D

Features not

consistent with AD

Definite A D

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 Inclusion Criteria

• Onset between 40 and 90 years

• Dementia established on clinical examination and testing

• Deficits in two or m o r e 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 m e m o r y and cognition

• Progressive deterioration in specific cognitive function, such as language, m o t o r 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 After exclusion of o t h e r 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

p a t i e n t s - - m o t o r signs (increased muscle tone, myoclonus,

or gait disorder), epilepsy

• CT scan noixnal for age

• 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

• 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

172 JILLIAN J KRIL AND GLENDA M HALLIDAY

TABLE III

BRAAK STAGING SCHEME OF NFT FORMATION DURING AGING AND A D

I

II

III

1V

V

VI

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" neurofib- rillary 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 i n 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

f i t t e d 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 e a r l y 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

e f f e c t i v e n e s s 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

T h e N I N C D S a n d A D R D A w o r k i n g g r o u p p r o p o s e d a n u m b e r o f c r i t e r i a

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) How-

ever, t h e p r o t o c o l s h a v e n o t b e e n w i d e l y 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

c l i n i c a l 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 w i t h p o s s i b l e AD, a n d 18 o f 19 cases w i t h p r o b -

a b l e A D ( N a g y 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 el-

d e r l y s u b j e c t s w i t h k n o w n M i n i - M e n t a l S t a t e (MMS) s c o r e , 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 w i t h s e v e r e d e m e n t i a ( M M S 0 - 1 0 ;

J e l l i n g e r et al., 1995) H o w e v e r , 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 -

n o s i s o f AD T h e m a j o r i t y o f t h e s e s u b j e c t s also h a d l i m b i c N F T s ( B r a a k stages I I I 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

c l i n i c a l 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 s u b j e c t s b e i n g c l a s s i f i e d as AD,

ALZHEIMER'S DISEASE 1 7 3 indicating the presence o f plaques is a p o o r indicator o f the presence o f dementia, at least in the very old

Because o f these difficulties, the neuritic staging scheme o f Braak has

b e e n c o m b i n e d with the CERAD protocol for assessment of plaques into the National Institute on Aging (NIA)-Reagan Institute criteria for the diagnosis

o f AD (Hyman and Trojanowski, 1997; National Institute on Aging and Reagan Institute Working Group, 1997; Newell et al., 1999) Topographical assessment o f N F T type (intra- or extracellular) and A/3 plaque density is used to classify cases into high, intermediate, or low likelihood o f AD These criteria are the currently accepted "gold standard" for the diagnosis o f AD, even t h o u g h their reliability, reproducibility, and overall accuracy are yet to

be determined

B EVALUATION OF OTHER PATHOLOGIES

Further problems with assessing the accuracy o f neuropathological di- agnoses exist In most studies, diagnostic validity is assessed by r e p o r t i n g cases that m e e t criteria for AD, regardless of w h e t h e r o t h e r pathologies are present In some instances, coexisting pathologies may contribute to the de- mentia process and thus be o f i m p o r t a n c e in the assessment o f the clinical criteria In o n e 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) T h e presence o f infarction was the primary reason for the differences e n c o u n t e r e d F u r t h e r m o r e , the identification

of a n u m b e r of previously u n r e c o g n i z e d d e m e n t i n g disorders, with clini- cal a n d / o r pathological overlap with AD (e.g., d e m e n t i a with Lewy bodies (DLB) ; Kosaka et al., 1984; McKeith et al., 1996, 1999; Fig 1; and small vessel disease d e m e n t i a (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 cri- teria c a n n o t 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

T h e 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 n o t suggest how overlapping diagnoses can be arrived at or how they

174 JILLIAN J KRIL AND GLENDA M HALLIDAY

should be i n c o r p o r a t e d into the diagnostic criteria This represents a signif- icant weakness in the c u r r e n t neuropathological criteria for the diagnosis

o f AD and must be addressed before the effectiveness o f any criteria can be adequately evaluated

C CLINICAL CORRELATES OF A D PATHOLOGY

Reevaluation o f the clinical diagnosis o f AD in light o f the changing con- cepts o f the pathology o f the disease is necessary It is n o longer adequate that clinical criteria for AD alone are developed Better diagnostic crite- ria for patients with similar core clinical features that differentiate the signs and symptoms o f o t h e r pathologies are required T h e most widely used clin-

ical criteria are those established by the NINCDS-ADRDA (McKhann et al.,

1984) Diagnoses o f probable and possible AD (Table II) can be m a d e using these criteria Possible AD is considered when d e m e n t i a is a p p a r e n t in the presence o f o t h e r systemic or brain disorders that, may themselves, result in dementia A diagnosis o f probable AD is considered when the patient is free from complicating diseases and when deficits in two or m o r e areas o f cogni-

tion are present T h e CERAD g r o u p (Morris et al., 1989) p r o p o s e d a battery

o f clinical and neuropsychological tests to aid in the classification o f cases into the NINCDS-ADRDA possible and probable AD groups A multicenter study o f the NINCDS-ADRDA criteria, which evaluated 60 cases (40 with AD), showed an initial sensitivity o f 0.81 and specificity o f 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 patho- logically c o n f i r m e d cases show variable results d e p e n d i n g o n the cases in- cluded in the study In "typical" cases, the a g r e e m e n t between probable and

definite AD has b e e n 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) a n d 78% for possible

AD (Burns et al., 1990) were found Thus, the NINCDS-ADRDA protocol

for the diagnosis o f AD has b e e n 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 o t h e r pathologies, reevaluation o f the accuracy of these criteria is required

In addition to the NINCDS-ADRDA criteria for the clinical diagnosis o f

AD, a n u m b e r o f o t h e r diagnostic protocols for use in clinical and popu-

lation settings have b e e n developed T h e Diagnostic a n d Statistical M a n u a l

of M e n t a l Disorders, Fourth Edition ( D S M - I V ) o f the American Psychiatric Association (APA; World Health Organization, 1992) criteria require a

ALZHEIMER'S DISEASE 175 deficit in memory, as well as o n e o t h e r cognitive d o m a i n of gradual onset and progressive decline These criteria result in similar classification of pa- tients to the NINCDS-ADRDA criteria (see above) In addition, the Clinical

D e m e n t i a Rating (CDR; McCulla et al., 1989; Morris, 1993) and Mini-Mental State Examination (MMSE; Folstein et al., 1975) are used to d e t e r m i n e the severity of dementia These protocols are useful for screening for cognitive

i m p a i r m e n t as they are easy to administer and have b e e n validated across

a variety of social and ethnic populations However, they lack specificity for

AD Pathological validation o f these protocols has b e e n p e r f o r m e d , but as with o t h e r criteria, reevaluation is necessary in light o f the changing na- ture o f d e m e n t i a diagnosis It would be of interest for those centers with large clinical and pathological databases to reevaluate the clinical diagnosis

of AD and similar d e m e n t i a 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 REPRODUCIBILITY OF CURRENT CLINICAL DIAGNOSTIC PROTOCOLS

Several studies to test the reliability o f the clinical criteria for AD have been p e r f o r m e d Both Lopez and colleagues (1990) and Kukall and col- leagues (1990) used four raters to evaluate the NINCDS-ADRDA criteria Using cases with d e m e n t i a (AD and non-AD) and n o n d e m e n t e d controls,

p e r c e n t a g e a g r e e m e n t ranged from 55% to 75% for pairs of raters (kappa coefficients were 0.36-0.65) with the most e x p e r i e n c e d clinicians achiev- ing the greatest a g r e e m e n t (Lopez et al., 1990) Interestingly, many o f the disagreements in diagnosis were f o u n d between possible and probable AD categories Although there is little disagreement on w h e t h e r patients have dementia, the underlying causes of the d e m e n t i a syndrome are less reli- ably agreed u p o n between clinicians T h e inclusion of cases with multiple pathologies using the c u r r e n t criteria probably contributes to this variability

E SUMMARY

Considerably m o r e research is required on the diagnosis and definition

of AD T h e c u r r e n t 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 incorpor- ated This will, o f course, have an impact on the clinical diagnosis o f AD

At present, clinical criteria for AD c a n n o t differentiate patients with differ- ent underlying disease mechanisms (e.g., DLB versus AD) In addition, it will be i m p o r t a n t to d e t e r m i n e the clinical profile o f cases that have both

176 JILLIAN J KRIL AND GLENDA M HALLIDAY

NFTs and Aft Difficulties with the definition o f the disease have i m p o r t a n t implications for any study o f AD From the p o i n t o f view o f researching the pathogenesis o f AD, p u r e groups are desired t o eliminate potential con-

f o u n d i n g causes T h e continual modification and i m p r o v e m e n t o f criteria for the diagnosis o f AD is t h e r e f o r e necessary until we understand, and either p r e v e n t or cure, this illness

IIh Pathogenesis

To u n d e r s t a n d the pathogenesis o f AD, it is necessary to d e t e r m i n e the sequence o f events that occurs over the life o f a patient Because it is not possible to p e r f o r m longitudinal cellular analyses in humans, most o f o u r

u n d e r s t a n d i n g o f the pathogenesis o f AD is i n f e r r e d from patients sampled cross-sectionally at different time points in the disease process I n f o r m a t i o n

c o n c e r n i n g the initial events is the most patchy as it is extremely difficult to

d e t e r m i n e , with accuracy, when the disease first begins T h e single greatest risk factor for the d e v e l o p m e n t o f AD is age (Jorm, 1990) However, we do

n o t yet fully u n d e r s t a n d the n o r m a l aging process; thus, it is difficult to distin- guish the pathological process (es) underlying AD We do know that d e m e n - tia in old age isfar from a universal p h e n o m e n o n and that o t h e r factors must play a role in d e t e r m i n i n g susceptibility to disease These factors include ge- netic, environmental, and lifestyle factors, as well as coexisting disease Although a decline in brain function with age is accepted as n o r m a l by many authors, increasing evidence suggests cognitive decline is n o t an in- evitable c o n s e q u e n c e o f aging (Rubin et al., 1998; Morris, 1999; U n g e r et al.,

1999) b u t r a t h e r a manifestation o f underlying disease processes Longitudi- nal studies o f community-dwelling elderly subjects do n o t 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 d o develop d e m e n t i a may have a long preclinical period with stable deficits (usually m e m o r y ) , which precedes a precipitous decrease in function (Rubin et al., 1998; Small et al., 2000) Such studies call into question the idea o f an age-related decline in brain function and m o r e likely r e p r e s e n t c o h o r t differences in health, education, and o t h e r factors Nevertheless, many o f these studies are p e r f o r m e d on highly selected groups

o f elderly subjects who are free f r o m neurological and systemic diseases, and although adequately addressing the question o f age-associated cognitive de- cline, do not r e p r e s e n t the majority o f elderly subjects Cognitive deficits may be p r e s e n t in a p r o p o r t i o n o f elderly subjects, although these would be

e x p e c t e d to have greater brain pathology

N u m e r o u s 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 o f schooling)