ALZHEIMER''''S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS - PART 4 pps

The topographical and neuroanatomical distrubution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease.. Neurofibrillary tangles b

Vh Esltogen Therapy

A n u m b e r of studies examining g e n d e r as a risk factor for AD find an increased risk in women, especially older women, even after controlling for education level and o t h e r factors, such as differential survival rates This led to the hypothesis that h o r m o n a l factors may play a role in determin- ing susceptibility to AD This suggestion is supported by the finding that postmenopausal w o m e n receiving h o r m o n e r e p l a c e m e n t therapy have a re-

d u c e d risk of AD (Paganini-Hill and H e n d e r s o n , 1994, 1996) A r e d u c e d risk

of AD was also identified in the Baltimore Longitudinal Study o f Aging, a prospective study o f the effect of estrogen r e p l a c e m e n t therapy on incident

AD (Kawas et al., 1997)

T h e mechanism by which estrogen protects from AD is unclear It was suggested the m o d e o f action is t h r o u g h estrogen-sensitive n e u r o n s in the

h i p p o c a m p u s and cortex (Maki and Resnick, 2000), although evidence from transgenic mice showed that estrogen treatment increased the a m o u n t o f the neuroprotective sAPP fragment, but did not r e d u c e the p r o d u c t i o n o f Aft (Vincent and Smith, 2000) Estrogen has also b e e n shown to have antiox- idant activity (Niki and Nakano, 1990) that may contribute to its protective role

T r e a t m e n t of w o m e n with mild to m o d e r a t e AD with estrogen for 1 year has n o t b e e n f o u n d to improve cognitive function or slow the progression

o f 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 p e r f o r m a n c e and in- creased regional CBF than n o n t r e a t e d subjects (Maki and Resnick, 2000) This, together with the epidemiological evidence of r e d u c e d risk of AD in subjects treated with estrogen, suggests the benefits o f estrogen are lost after the onset o f AD This is not surprising as the regions f o u n d to be sensitive

to estrogen (i.e., hippocampus, parahippocampus, and temporal cortex; Maki and Resnick, 2000) are the areas o f the brain that are d a m a g e d ear- liest and to the greatest degree in AD (Braak and Braak, 1991; Gomez-Isla

et al., 1996)

Vlh Vascular Pathology in AD

T h e r e is m o u n t i n g evidence for an etiological link between AD and vas- cular pathology Although both AD and cerebrovascular disease are com-

m o n in the elderly and their importance as i n d e p e n d e n t causes o f brain pathology is acknowledged (Kokmen et al., 1996; Snowdon et al., 1997;

Shi et al., 2000), it is their possible synergy that provides exciting o p p o r - tunities for the investigation o f the pathogenesis o f AD Evidence exists to suggest that cerebrovascular disease may c o n t r i b u t e to AD p a t h o l o g y by

p r o m o t i n g n o n - N F T 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) a n d

e x a c e r b a t i n g Aft plaque f o r m a t i o n (Lin et al., 1999; B e n n e t t et al., 2000)

T h e relationship between AD a n d vascular disease is far f r o m clear; how- ever, we know that b o t h infarction a n d microvascular p a t h o l o g y can be in- volved (Fig 4) Abnormalities in cerebral white m a t t e r have b e e n identified

at autopsy in m o r e t h a n half the patients with AD (Englund, 1998) T h e s e include r e d u c e d vessel density, white m a t t e r pallor (rarefaction), a n d glio- sis a n d thickening o f the vessel wall Such changes are believed to be the pathological correlate o f the leukoaraiosis, which is frequently seen on neu-

r o i m a g i n g in elderly subjects with a n d 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 o f the cerebral microvasculature including a t r o p h i c vessels, g l o m e r u l a r loops, a n d tortu- osities in AD (Ravens, 1978; Kalaria a n d H e d e r a , 1995; Buee et al., 1999)

T h e s e were also shown to o c c u r in n o r m a l aging, a l t h o u g h they are m o r e frequently e n c o u n t e r e d in AD

O n e o f the m a i n theories for how a b n o r m a l arterioles a n d capillaries can affect brain function is the disturbance o f the n o r m a l l a m i n a r flow that exists in b l o o d vessels (de la Torre, 1997; Fig 4) Briefly, in situations o f

n o r m a l flow, red b l o o d cells travel in the c e n t e r o f a vessel where flow is greatest At the periphery, t h e r e is a cell-free zone with virtually n o flow, which allows for the transfer o f nutrients a n d o t h e r molecules across the vessel wall Alterations in vessel architecture result in t u r b u l e n c e with im- paired flow and, ultimately, i m p a i r e d delivery o f nutrients Such t u r b u l e n c e would result in ischemic n e u r o n a l loss as a c o n s e q u e n c e of the failure o f de- livery o f sustaining nutrients a n d may differentially affect those areas o f the brain with h i g h e r m e t a b o l i c d e m a n d , such as the h i p p o c a m p u s 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 a n d microvas- cular 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 d e a t h w h e n cocultured with pri-

m a r y 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

w h e n n e u r o n s were cultured with m e d i a c o n d i t i o n e d 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 n a t u r e o f the soluble toxin is n o t known at present, b u t a n u m b e r o f candidates such as nitric oxide, reactive oxygen species, a n d 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 a n d the p r e s e n c e o f brain infarction (Nagy et al., 1997a; Snowdon et al.,

1997) In the N u n study, patients with AD a n d infarcts showed p o o r e r cogni- tive p e r f o r m a n c e t h a n AD patients without infarction (Snowdon et al., 1997)

Similarly, for an equivalent level of cognitive impairment, the density o f plaques is less in AD patients with cerebrovascular disease than those with- out such disease (Nagy et al., 1997a) In addition, lacunar infarction with

or without l e u k o e n c e p h a l o p a t h y was f o u n d in 20 o f 25 cases with clinically probable AD and the majority o f these had a lower Braak neuritic stage than

d e m e n t e d patients without cerebrovascular disease (Goulding et al., 1999)

F u r t h e r m o r e , it was d e m o n s t r a t e d that impaired circulation can result in in- creased Aft deposition In experimental animals, chronic hypoperfusion can trigger the cleavage of APP and the formation o f Aft (Bennett et al., 2000), whereas in humans, soluble A/31-42/43 levels are similar in patients with multi-infarct d e m e n t i a and AD (Kalaria, 2000) Overall, these studies show that AD pathology may be less severe when there is coexisting cerebrovas- cular disease and that cerebrovascular disease may contribute to AD-type pathology

T h e association between vascular disease and AD is f u r t h e r s u p p o r t e d by the finding that subjects dying of cardiovascular disease show m o r e AD-type pathology than those dying o f noncardiac causes (Sparks et al., 1990; Sparks, 1997) In n o n d e m e n t e d individuals dying o f cardiac causes, the density of senile plaques is half that seen in AD (Sparks et al., 1990) T h e effect o f ApoE e4 in this population was not e x a m i n e d 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 f u r t h e r strengthens the link between vascular disease and AD

A VASCULAR RISK FACTORS

Epidemiological evidence links cardio- and cerebrovascular factors with

AD In a longitudinal study, subjects who developed d e m e n t i a had h i g h e r systolic b l o o d 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 o f diagnosis o f

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 n e u r o d e g e n e r a t i v e diseases Diabetes mellitus, which is known to be associated with an increased risk o f stroke, was also shown to be associated with an increased risk o f AD (Kuusisto et al., 1997; Ott et al., 1999) A relative risk of 1.9 was f o u n d for both AD and d e m e n t i a of any type (Ott et al., 1999) T h e risk is h i g h e r

(RR 4.3, CI 1.7-10.5) in those treated with insulin, suggesting there is an in- creasing risk with increasing severity o f diabetes Patients with diabetes mel- litus have a high incidence o f vascular complications (West, 1978), and the

r e p o r t e d association with AD may reflect increased cerebrovascular disease

in these patients A p o s t m o r t e m study c o m p a r i n g cerebrovascular pathology

in diabetic and nondiabetic AD patients has n o t b e e n p e r f o r m e d However, AD-type pathology was studied in diabetic subjects and is n o t increased ( H e i t n e r and Dickson, 1997) T h e associated risk is t h e r e f o r e 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, polymor- phisms o f the angiotensin-converting enzyme (ACE) have b e e n associated with an increased risk o f AD ( H u 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 c o m p l e x relationship between vascular disease and its risk factors and an increased risk o f AD

B SUMMARY

A hypothesis has b e e n p r e s e n t e d that links many o f the identified and pu- tative risk factors f o r A D and suggests a mechanism for their action Crawford (1996, 1998) proposes an association between AD and cerebral b l o o d flow (CBF) by citing evidence that many o f the factors that are linked with an increased risk o f AD also decrease CBF (e.g., old age, depression, under- activity, h e a d trauma) Similarly, it is suggested factors that increase CBF are associated with a decreased risk o f AD (e.g., education, exercise, smok- ing, NSAIDs) Although the authors acknowledge that r e d u c e d CBF is n o t sufficient to cause AD, the r e p o r t e d positive and negative associations pro- vide tantalizing evidence for a c o m m o n m o d e o f action for many o f the equivocal risk factors r e p o r t e d to date This hypothesis is also consistent with o t h e r data that links microvascular damage and impaired b l o o d flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999)

Gaining a better u n d e r s t a n d i n g o f the interaction between AD and vas- cular disease is o f great importance Not only will it provide insights into the pathogenesis o f AD, but it may also provide us with a rare o p p o r t u n i t y for the t r e a t m e n t and possible p r e v e n t i o n ofAD A great many risk factors for vascular disease have b e e n identified and intervention programs have suc- cessfully r e d u c e d the incidence o f h e a r t disease and stroke T h e potential exists to provide the same level o f success with AD

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 help- ful 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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