ALZHEIMER''''S DISEASE: ITS DIAGNOSIS AND PATHOGENESIS - PART 3 pptx

ALZHEIMER'S DISEASE 187 Unresolved Issues CAA Insoluble A ~ plaque Microvascular damage ~d flow Disturbances Cell death ,S x, FIG.. Although it is known that neuronal death can o

ALZHEIMER'S DISEASE 187

Unresolved Issues

CAA Insoluble A ~

plaque

Microvascular damage

~d flow Disturbances

Cell death

,S

x,

FIG 4 Many unresolved issues continue to plague our understanding of the pathogene- sis 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 mi- crovascular 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 t h i s n e u r o n a l loss h a s 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 d i f f i c u l t

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 i n 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., 1 9 9 9 )

Depletion o f Pinl may induce n e u r o n death via mitotic arrest and apopto- sis p r i o r to the d e v e l o p m e n t o f NFTs (Lu et al., 1996) T h e neuron-specific activator for cell proteins involved in the mitotic cycle is p35, which is pro- teolytically cleaved to p r o d u c e p25, a f r a g m e n t f o u n d to accumulate in the brains o f patients with AD (Patrick et al., 1999) Application o f Aft 1-42 in- duces the conversion o f p35 to p25 (Lee et al., 2000) p25 links with cell cycle-dependent kinase 5 to h y p e r p h o s p h o r y l a t e tau and p r o m o t e apopto- sis (Lee et al., 2000) Degenerating n e u r o n s in APP V717F Aft-producing transgenic mice show c h r o m a t i n segmentation and condensation, as well as increased T U N E L staining, suggestive o f apoptosis (Nijhawan et aL, 2000) This supports a link between Aft deposition and apoptosis (Fig 4) Increased

T U N E L staining (Druganow et al., 1995; Lassmann et al., 1995; Smale et al., 1995; B a n c h e r et al., 1997), as well as cleaved caspase 3 (Selznick et al., 1999; Stadelmann et al., 1999), an enzymatic m a r k e r o f apoptosis, are f o u n d in vulnerable brain regions in AD APP has b e e n identified as a specific sub- strate 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 f r a g m e n t

f r o m such cleavage has b e e n called C31 (Lu et aL, 2000) C31 is also a p o t e n t

i n d u c e r o f apoptosis and was f o u n d in the brain o f patients with AD (Lu

et al., 2000), whereas caspase deficient mice are resistant to this form o f cell

d e a t h (Nakagawa et al., 2000)

Despite these studies that suggest apoptosis occurs in AD, apoptotic bod- ies and blebbing are n o t features o f AD n e u r o n a l degeneration In addition, the time sequence o f such events remains to be d e t e r m i n e d T h e c h r o n i c nature o f the n e u r o d e g e n e r a t i o n in AD does n o t fit well with the m o r e rapid time course o f apoptosis, which is believed to take only weeks or m o n t h s at most (Stadelmann et al., 1999) O t h e r mechanisms o f n e u r o n a l death, such

as necrosis, were also d e m o n s t r a t e d in AD (Wolozin and Behl, 2000b) In- deed, the same triggers may cause either apoptosis or necrosis, including Aft toxicity, oxidative stress, excitotoxicity, ischemia, and removal o f trophic fac- tors T h e distinction between apoptotic and necrotic mechanisms, however, may be somewhat false given that n e u r o n s may begin with necrosis and then convert to apoptosis or alternatively begin with apoptosis and then u n d e r g o necrosis (Wolozin and Behl, 2000b)

Although Aft plaques are necessary for a diagnosis o f AD, like NFTs, they are poorly related to the d e g r e e o f n e u r o n a l loss However, studies suggest the intracellular accumulation o f Aft may be n e u r o t o x i c (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 c o n c e n t r a t i o n necessary for fibril f o r m a t i o n ( H a r t m a n n , 1999; Wilson et al., 1999) Cell

r u p t u r e would release this intracellular Aft into the s u r r o u n d i n g extracellu- lar milieu, which could stimulate f u r t h e r amyloid deposition Although most

cell types express APE n e u r o n s p r o d u c e the highest a m o u n t and preferen- tially use the intracellular pathways for Aft p r o d u c t i o n ( H a r t m a n n , 1999) It

is difficult to know how to prove or refute this m o d e l o f AD n e u r o n a l vulnera- bility, although it is o f interest that Aft is n o t deposited within the vulnerable

h i p p o c a m p a l formation or entorhinal cortex (Arnold et al., 1991) and no

n e u r o n a l loss occurs in elderly APP-transgenic mice who show considerable A/3 deposits (Irizarry et al., 1997a, 1997b) Interestingly, a study identified nonpyramidal n e u r o n s containing Aft 1-42 a r o u n d amyloid plaques in AD patients (Mochizuki et al., 2000), suggesting preserved n e u r o n s may con- centrate 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

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

greater influence on vascular changes than n e u r o n a l degeneration

E SUMMARY

Taken together, these studies suggest a multifactorial origin o f n e u r o n a l loss in AD where a n u m b e r of primary and secondary factors may cause

n e u r o n a l death (Fig 4) More work is n e e d e d to link all the potential cellular events that underlie the clinical symptoms o f AD At present, we do not have a good u n d e r s t a n d i n g o f the association between A/3 deposition (required for

a diagnosis o f AD) and the degenerative process T h e link between soluble A/3 and brain atrophy needs to be clarified, and mechanisms o f cell death

o t h e r than N F T formation (and possibly apoptosis) n e e d to be elucidated

It will be i m p o r t a n t to d e t e r m i n e the time sequence o f 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 d e m e n t i a (Writing Committee Lancet C o n f e r e n c e 1996, 1996), and

n u m e r o u s 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 sig- nificantly increased risk o f AD in subjects with a positive family history T h e odds ratios r a n g e d from 2.1 to 9.9 and reflect data obtained from prevalence and incidence studies

A DOMINANT INHERITANCE

It is estimated that between 5% a n d 10% o f AD cases have a d e m o n - strable p a t t e r n o f inheritance These cases, a l t h o u g h rare, provide valuable insights into the p a t h o g e n e s i s o f AD To date, t h r e e genes have b e e n iden- tified T h e s e are APP m u t a t i o n s on c h r o m o s o m e 21, presenilin-1 (PS-1)

m u t a t i o n s on c h r o m o s o m e 14, a n d presenilin-2 (PS-2) m u t a t i o n s on chro-

m o s o m e 1 Each o f these genes have an a u t o s o m a l d o m i n a n t p a t t e r n o f inheritance, a l t h o u g h PS-2 does n o t a p p e a r to have c o m p l e t e p e n e t r a n c e (St George-Hyslop, 2000) T h e s e three identified genes do n o t fully a c c o u n t for all a u t o s o m a l d o m i n a n t cases o f AD, suggesting o t h e r genes are yet to

be identified

T h e APP g e n e e n c o d e s a t r a n s m e m b r a n e p r o t e i n o f 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

o f APP is n o t known, a l t h o u g h it is highly conserved a n d expressed ubiqui- tously In addition to AD, m u t a t i o n s in APP can also result in hereditary cere- bral h a e m o r r h a g e with amyloidosis-Dutch type (HCHWA-D) Mutations in the APP g e n e are mostly located in or a r o u n d the amyloidogenic p o r t i o n o f the molecule, especially n e a r the three secretase sites

Mutations in the PS-1 g e n e are the m o s t c o m m o n o f the early-onset familial AD mutations, a c c o u n t i n g for 30-50% o f all a u t o s o m a l 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 p r o t e i n that is also expressed ubiquitously

a n d has six or eight t r a n s m e m b r a n e d o m a i n s (Checler, 1999) T h e r e is an increasing b o d y o f 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 o f A/3 (Checler, 1999; Ray et al., 1999; Wolfe et al., 1999) a n d thus increase the pro-

d u c t i o n A f l l - 4 2 / 4 3 M o r e t h a n 50 m u t a t i o n s in PS-1 have b e e n identified

T h e majority o f these are missense m u t a t i o n s a n d are scattered t h r o u g h o u t the molecule In addition, a n u m b e r o f splice a c c e p t o r m u t a t i o n s that cause the deletion o f the s e q u e n c e e n c o d e d by e x o n 9 were also described (Kwok

et al., 1997; C r o o k et al., 1998; Smith et al., 2001) A p r o p o r t i o n o f PS-1

m u t a t i o n s with a deletion o f e x o n 9 have AD with spastic paraparesis (SP;

C r o o k et al., 1998; V e r k k o n i e m i et al., 2000) In AD+SP, there is progressive weakness a n d wasting o f the lower extremities a n d a later age o f onset o f

d e m e n t i a has b e e n described in s o m e o f these families (Smith et al., 2001)

T h e p a t h o l o g y o f e x o n 9 m u t a t i o n s is also interesting in that very large,

n o n c o r e d , a n d faintly neuritic plaques are described (Crook et al., 1998; Smith et al., 2001) T h e s e have b e e n t e r m e d "cotton-wool" plaques because

o f their size a n d u n i f o r m a p p e a r a n c e (Fig 5)

T h e PS-2 g e n e e n c o d e s a t r a n s m e m b r a n e p r o t e i n that is 67% h o m o l - ogous to PS-1 (Checler, 1999) Unlike APP a n d PS-1, PS-2 is expressed

m o r e strongly in p e r i p h e r a l tissues (pancreas, cardiac, a n d skeletal muscle)

ALZHEIMER'S DISEASE 191

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 neu- ritic, 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 , 2 0 0 0 ) 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

T h e mechanism c o m m o n to the known mutations is an increased pro- duction o f Aft 1-42/43 a n d an increased rate o f aggregation o f Aft plaques (see Wolozin and Behl, 2000a, for c o m m e n t a r y ) However, it appears that the PS mutations may also be involved in o t h e r aspects o f the pathology

o f AD by participating in cell d e a t h d u e to apoptosis and in the phos-

phorylation o f tau (see Checler, 1999; Czech et al., 2000) O u r knowledge

o f AD has advanced substantially since the identification o f the mutations responsible for familial forms o f AD and o f the presenilins in particular This rapidly moving field o f research provides valuable insights into the disease processes and has the potential for the d e v e l o p m e n t o f strategies for ther- apeutic intervention However, it is still u n k n o w n w h e t h e r the knowledge gained from studying these cases is generally applicable to the majority o f

AD patients In addition, the knowledge gained has still n o t elucidated the cause(s) o f sporadic AD

B GENETIC RISK FACTORS

Apart from d o m i n a n t inheritance, the clustering o f d e m e n t i a within families must be viewed as evidence for the role o f an individual's genotype in

d e t e r m i n i n g their risk o f AD T h e a p o l i p o p r o t e i n E (ApoE) gene, f o u n d on

c h r o m o s o m e 19, e n c o d e s three isoforms o f e2, e3, and e4, and the presence

o f the e4 allele has b e e n 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 ( C o r d e r et al., 1993) AD It has subsequently b e e n c o n f i r m e d

in many o t h e r studies o f early- a n d late-onset AD and a variety of o t h e r neurological diseases, including o t h e r dementias (e.g., Roses, 1996; Stevens

et al., 1997; H o r s b u r g h et al., 2000) In addition, an allelic dose d e p e n d e n c e

has b e e n shown where subjects who are homozygous for e4 have a greater

risk o f AD at an earlier age than those who are heterozygous ( C o r d e r et al.,

1993) In this study o f families with late-onset AD, subjects with n o e4 h a d a

m e a n age o f onset o f 84.3 years c o m p a r e d with 75.5 years in those with o n e s4 allele and 68.4 years with two alleles

In addition to its effect on age o f onset, ApoE genotype has also b e e n shown to influence, albeit variably, the response to drug treatment A p o o r e r response to the cholinesterase inhibitor tacrine has b e e n shown in patients

with AD who possess the ApoE e4 allele than those who do not (Poirier et al.,

1995), although this effect has n o t b e e n f o u n d in all studies (MacGowan

et al., 1998) In addition, only patients with e4 showed i m p r o v e m e n t in

ALZHEIMER'S DISEASE 193 cognitive p e r f o r m a n c e when treated with a drug that facilitiates n o r a d r e n e r -

gic and vasopressinergic activity in the brain (Richard et al., 1997) Some de-

bate also exists over w h e t h e r ApoE genotype modifies the type or a m o u n t o f

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; L a n d e n et al., 1996), have f o u n d an increase in the density of neu-

rofibrillary tangles and senile plaques in AD Moreover, the correlation with brain pathology is f u r t h e r complicated by the finding that normal subjects

in their forties and older who possess an e4 allele have smaller right hip-

pocampi than those without e4 (Tohgi et al., 1997) It is unclear w h e t h e r

this finding represents a lifelong trait or is an indicator o f "preclinical" AD Longitudinal studies on such groups o f 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 b e e n f o u n d in individuals with e4 (Wahlund et al., 1999) However, this association has n o t

b e e n f o u n d in all studies (Barber et al., 1999)

T h e mechanism of action o f ApoE is not fully elucidated ApoE is in- volved in the regulation o f the transport o f cholesterol and phospholipid and has an i m p o r t a n t role in the distribution o f these molecules during peri- ods of m e m b r a n e remodeling, such as synaptic plasticity and m e m b r a n e re- pair In addition, ApoE-lipid complexes are believed to assist in the removal

of Aft via the low-density lipoprotein-related r e c e p t o r (Wolozin and Behl, 2000a) Isoform differences in the behavior o f ApoE have b e e n 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, o t h e r modifying influences have

b e e n identified (e.g., HLA, butyrylcholinesterase K, ~ 1 antichymotrypsin) ; however, the exact nature o f the relationship between genotype and disease susceptibility remains obscure Although there is strong evidence for an as- sociation between ApoE e4 and AD, the presence o f 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 o f Medical Genetics/American Society o f H u m a n Genetics Working G r o u p on ApoE and Alzhemer's Disease, 1995) Similar results are likely for o t h e r genetic risk factors Nevertheless, such genotypes are i m p o r t a n t variables to be considered in research studies examining aspects o f the pathogenesis

and progression o f AD, especially as reports o f monozygotic twins that are discordant for AD (Creasey et al., 1989) suggest that inheritability is n o t solely responsible for one's risk o f AD Few studies are integrating the multi- ple genotype analyses r e q u i r e d to u n d e r s t a n d genetic versus e n v i r o n m e n t a l influences

V Inflammation and Anti-inflammatory Drugs

N u m e r o u s lines o f evidence suggest a link between brain inflammation and AD (see Gahtan and Overmier, 1999; Halliday et al., 2000a) Initial ev- idence f r o m clinical studies for a role o f anti-inflammatory drugs in the prevention o f AD came from case control studies that e x a m i n e d arthritis

as a risk factor and f o u n d a r e d u c e d risk o f d e m e n t i a in patients who con-

a n u m b e r o f similar studies were unable to identify a significant reduction in risk (e.g., H e y m a n et al., 1984) This inconsistency may reflect the relatively small samples e x a m i n e d in each study individually because a meta-analysis

o f 17 studies showed a r e d u c e d risk o f AD d e m e n t i a in patients taking both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs; McGeer et al., 1996) It should be noted, however, that the majority o f these studies were

o f cross-sectional design where significant biases exist in selection of cases for study and the r e p o r t i n g of drug use (Stewart et al., 1997)

Antigens o f the major histocompatibility c o m p l e x are intimately associ- ated with inflammation and polymorphisms o f the genes e n c o d i n g these proteins have b e e n associated with an increased risk o f disease In partic- ular, CNS and peripheral diseases with an inflammatory basis o c c u r m o r e

c o m m o n l y in subjects who have a particular HLA genotype; notable a m o n g these is the association between r h e u m a t o i d arthritis and HLA-DR4 (Khan

et al., 1983; Stastny et al., 1988) A n u m b e r of different associations were de- scribed between AD a n d HLA alleles In late-onset patients who do not have ApoE e4 alleles, an increased risk o f AD was f o u n d in patients with HLA- DR1, 2, or 3, and a r e d u c e d risk was f o u n d in patients with HLA-DR4 or 6

(Middleton et al., 1999b), or only partly replicated (Neill et al., 1999), and the converse relationship (HLA-DR3 is protective) was f o u n d in a study o f autopsy-confirmed cases o f A D (Culpin et al., 1999) In addition, an earlier age o f onset by 3 years has b e e n r e p o r t e d in subjects with HLA-A2 com-

p a r e d with o t h e r 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

ApoE e4 a p p e a r e d to be additive (Payami et al., 1997) A similar additive effect of HLA-A2 and ApoE e4 has b e e n f o u n d in early-onset familial AD (Ballerini et al., 1999) O t h e r associations with HLA alleles were r e p o r t e d (Small et al., 1991; Middleton et al., 1999a), but these studies are yet to

be replicated It is therefore unclear w h e t h e r the initial studies implicat- ing 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 b e e n only three longitudinal studies analyzing the question of drug protection in AD Two o f these studies (Stewart et al.,

1997; Prince et aL, 1998) f o u n d a beneficial effect o f NSMDs T h e Baltimore Longitudinal Study o f Aging f o u n d a r e d u c e d risk o f AD a m o n g users o f 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 o f cognitive function in NSMD users, although the benefit was

r e d u c e d in older subjects In contrast, a study of Australians ages 70 years or older (mean age of 80) f o u n d that NSMDs or aspirin provided no protection against cognitive decline or incidence o f d e m e n t i a over a 3- to 4-year period ( H e n d e r s o n et al., 1997) Taken together, these studies suggest that some protection is c o n f e r r e d at ages when susceptibility is relatively low It may be that sufficient protection occurs only with long-term drug usage

It is t h e r e f o r e n o t surprising that clinical trials aimed at assessing the role

o f NSMDs in preventing AD p r o d u c e d conflicting results Rogers and col- leagues (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 f o u n d

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 f o u n d no difference between groups in measures o f cognitive p e r f o r m a n c e Drop-out rates in b o t h studies were considerable (up to 50%) and follow-up times short ( a r o u n d 6 months), so

n e i t h e r study can be considered conclusive Nevertheless, on cross-sectional analysis cognitive p e r f o r m a n c e is improved in AD patients taking NSMDs and aspirin (Broe et al., 2000) c o m p a r e d with their n o n t r e a t e d counter- parts 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 t h r o u g h reducing inflammation but t h r o u g h some other, possibly

Neuropathological studies d e m o n s t r a t e d 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 e x p e c t e d to occur secondary to the d e g e n e r a t i o n in AD, evidence suggests the inflammatory response itself may contribute to the

pathology o f AD Many o f the proteins o f 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 o f inflammation-related substances that have b e e n shown to be n e u r o t o x i c in rats (Weldon et al., 1998), and it has

b e e n suggested that microglia might facilitate Aft deposition (see Gahtan

a n d 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 b e e n f o u n d

brain's reaction to the increased AD-type pathology in aging or, alternatively, indicate changes to the i m m u n e status o f 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

process itself stimulates an i m m u n e response W h e t h e r 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 u n d e r s t o o d (Fig 4) Although some epidemiological and clin- ical evidence suggests a beneficial effect o f t r e a t m e n t with NSAIDs, o t h e r research suggests any such benefit is mediated t h r o u g h a n o n i n f l a m m a t o r y mechanism (Broe et al., 2000; Halliday et al., 2000b) A clearer picture o f the sequence o f the early and subsequent cellular events in patients with AD would help clarify any direct role o f 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 o f treatment, Aft peptide immunization (Schenk et al., 2000)

I m m u n i z a t i o n trials are a b o u t to c o m m e n c e following the dramatic find- ings that transgenic mice that o v e r p r o d u c e APP and deposit Aft can recover

were i m m u n i z e d at a y o u n g age, they developed little if any Aft depositions with advancing age Moreover, the progression o f b o t h neuritic dystrophy and astrogliosis were significantly r e d u c e d in the treated animals, suggest- ing the immunization h a d benefits b e y o n d simply reducing Aft deposition

W h e n immunization was b e g u n at later ages when the mice exhibit Aft de- position, f u r t h e r 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 o f the activity o f these cells by anti-inflammatory medica- tions would be o f benefit in AD These studies support the c o n c e p t that the

i m m u n e system may be harnessed into an appropriately targeted therapy for AD If the trials o f Aft immunization are effective in AD, it will provide compelling evidence for its causative role in AD