Current and future treatments of memory complaints and ... · PDF filedrugs that enhanced cholinergic ... The cost of the 5.3 million Alzheimer’s patients in the USA exceeds US$100

491

Review

ISSN 1475-070810.2217/THY.11.60 © 2011 Future Medicine Ltd Therapy (2011) 8(5), 491–504

PeRsPective

Current and future treatments of memory complaints and Alzheimer’s disease

In the early 1980s, my colleagues and I devel-oped tacrine as the first pragmatic treatment for Alzheimer’s disease (AD) [1]. Tacrine was synthe-sized by Adrian Albert as part of the Australian World War II effort to find an intravenous anti-septic [2]. Use of tacrine to treat AD was unan-ticipated by the scientific community and there was considerable controversy [3–5]. Yet 7 years later, in 1993, tacrine (Cognex®) was the first US FDA-approved treatment for AD.

The theory behind tacrine was the cholin-ergic hypothesis [6]. According to this theory, drugs that enhanced cholinergic neuronal func-tion would improve memory. This might be by cholinesterase inhibition (CI), stimulation of the nicotinic receptor or enhancement of acetylcholine production.

The intent of tacrine was to assist failing cholinergic neurons. Symptomatic treatment. Prevention or reversal of the disease process was never intended with CI therapy. It was under-stood that the deficits of the cholinergic system seen in AD were the result of the disease, not the cause.

Current therapies�� Pharmacotherapies

At present there are three other cholinesterase inhibitors – donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®) [6]. The latter has nicotinic receptor agonist effects. Benefits of CI for each patient results from the

potency and dose of the pharmaceutical agent, and the severity of the cholinergic deficit, and the ability of the cholinergic system to respond to stimuli. In end-stage AD, when the choliner-gic system is largely destroyed, these agents have little value. A defective cholinergic neuron can be stimulated to work more efficiently, but a dead neuron cannot.

Memantine (Namenda) is the first in a novel class of AD medications acting on the gluta-matergic system by reversibly blocking NMDA glutamate receptors [101]. The NMDA receptor (NMDAR), a glutamate receptor, is the predom-inant molecular device for controlling synaptic plasticity and memory function [7]. Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. At normal levels, glu-tamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, triggering the signal for apoptosis, hence killing key brain cells [8]. The common wisdom is that memantine helps Alzheimer’s patients by downmodulation of calcium influx, thus enabling more efficient memory plasticity.

If AD is a progressive disease characterized by the diffuse death of neurons, it seems prob-able that memantine’s benefit may also be due to blocking both caspase-dependent and/or cap-sase-independent apoptosis [9,10]. By preserving AD neurons and permitting repair and recovery, memantine may actually be a disease-modifying

The cost of the 5.3 million Alzheimer’s patients in the USA exceeds US$100 billion per year. This is sufficient motivation to stimulate the pharmaceutical industry to seek a cure. To date, there are four anticholinesterase inhibitors, and an NMDA antagonist. At present 914 clinical trials related to Alzheimer’s disease have been listed, and 157 of these are in Phase III. New drugs that pursue Alzheimer’s prevention and treatment depend upon six different hypotheses as to the cause of Alzheimer’s. These hypotheses are: amyloid hypothesis, tau protein hypothesis, inflammation hypothesis, oxidative stress hypothesis, vascular hypothesis and hibernation hypothesis. These theories and potential therapies are reviewed in this article. The lack of current therapies may be due to the inability of agents to demonstrate efficacy in clinical trials because of flaws in testing instruments and current research designs. Of the theories, a complex antioxidant or combination with CNS inflammatory downmodulation holds the best promise of an effective treatment of Alzheimer’s disease.

KEYWORDS: Alzheimer’s � amyloid � cerebral hypoperfusion � neurodegeneration � neuronal atrophy � oxidative stress � tau protein

William K SummersAlzheimer’s Corporation, 6000 Uptown Blvd, Suite 308, Albuquerque, NM 87110-4148, USA Tel.: +1 505 878 0192 Fax: +1 505 888 6000 [email protected]

PeRsPective SummersPeRsPective Summers

Figure 1. Oxidative stress hypothesis. Numerous brain insults (e.g., head trauma, metabolic) create free radicals, chronic cytokine responses, oxidative injury, foci of inflammation with development of plaques and tangles. After 15–25 years, Alzheimer’s disease results. Death is associated with immune system failure. Reproduced with permission from [16].

Therapy (2011) 8(5)492 future science group

Current & future treatments of memory complaints & Alzheimer’s disease PeRsPective

agent. In what may prove to be flawed work, the first meta-ana lysis of memantine’s value in mild Alzheimer’s did not show promise [11]. The study examined a battery of memory tests over a short period of time, not progression of the illness over years.

�� Available current alternativesMemory calisthenics became quite popular in the early 2000s in both academia and alter-native medicine [12]. This was not an isolated strategy; rather, the proponents of this approach

quickly added the concept of healthy lifestyle. Healthy lifestyle habits include mental stimula-tion, physical exercise, good nutrition, weight control, stress management and adequate sleep, and healthy lifestyles are said to improve brain fitness [13].

Although the healthy lifestyle hypothesis is intuitive, it remains to be proven. Nevertheless, it is hard not to recommend a healthy lifestyle to patients. One caution is that recent data have shown that mild obesity (BMI of 30–39) in the elderly is protective [14].

Cardiovascular:myocardial infarction,coronary artery bypass,Binswanger’s disease,cardia arrhythmias,carotid atherosclerosishypertension

Metabolic:diabetes, obesity,atherosclerosis

Autoimmune:lupus erythematosus

Genetics (rare)

Parkinson’s disease

Toxins:iron, copper, mercury, zinc, lead

Virus:HSV1, HSV2, EBV,CMV, VZV

Head trauma:sports, MVA

Brain insults

Free radicals:cytokine response,oxidative injury,chronic microlocalized inflammation

Death

25 years

15

0

Bacteria:chlamydiasyphilis

Plaques andtangles

Immune systemfailure

Pathophysiology of Alzheimer’s disease

Nursing home


www.futuremedicine.com 493future science group


The use of health supplements to improve memory has been investigated. Kamat and col-leagues recently reviewed 20 years of antioxidant use in human and animal studies [15]. They con-cluded that the theory that antioxidants could cause neurological conditions was sound, but that the implementation of antioxidant therapies in humans “must be flawed” [15].

Etiology of ADTo design an effective treatment, understanding of the etiology and pathophysiology is essential. For example, the cholinergic system deficits seen in AD allowed CI therapies to be developed.

There are currently five dominant hypotheses on the etiology of AD and these are: the amyloid hypothesis (AH), the tau hypothesis (tH), the inflammation hypothesis (IH), oxidative stress hypothesis (OSH) and the vascular hypothesis (VH). These theories are not mutually exclusive. For example, the OSH can accommodate both the inflammation hypothesis, the VH, elements of the Ab-AH and tH. There are other theories such as mitochondrial deficits, parasitic infections, bacterial infections, viral infections and post-trau-matic brain injury. These will not be discussed in detail here. Many of these are also subsets of the OSH (Figure 1) [16]. Finally, there is the theory of neuronal hibernation that has been proposed by Swaab and colleagues [17].

�� Amyloid hypothesis Figure 2 displays the AH. This hypothesis was formulated in the 1980s and is the most widely accepted [102]. As Selkoe explains, the hypothesis is based on ten key observations. Some of these are circular logic, such as the tenth observation that alternative hypotheses do not have rigorous evidence to support them. The hypothesis simply stated that genetic events lead to amyloid-b (Ab) accumulation in the form of Ab

42 in the memory

areas of the brain. This Ab accumulation effects synaptic efficiency, is toxic to neurons, creates diffuse plaques, activates inflammatory response and leads to neurofibrillary tangles (NFTs). This becomes a self-perpetrating downward spiral to clinical AD and death.

In recent years the AH has been questioned [18]. Knockout mice lacking Ab demonstrate poorer memory than those with excessive Ab [19]. Summers postulated that Ab is a downstream product of oxidative injury and cellular death [16]. Accumulations of Ab are like tombstones. Tombstones rarely kill people, rather they mark where a body is located. Thus, it may be that an amyloid plaque also marks where functional

neurons were previously located. The purpose of amyloid appears to be protective – the body’s attempt to protect neurons [20]. Furthermore, many cognitively healthy seniors have significant senile plaques but no sign of Alzheimer’s [18]. Finally, CNS amyloid deposition does not corre-late with neuronal, metabolic or synaptic loss [18]. There is also correlation between amyloid deposit density and cognitive deficits [21]. Nevertheless, there are numerous drugs in development based on the Ab-AH at this time.

�� Tau protein hypothesis Figure 3 displays the tH, which states that hyper-phosphorylation of tau protein is the primary caus-ative factor of AD. The tH emerged from studies of the pathology of NFTs as well as from research into the normal biology and functions of tau [22].

Figure 2. Amyloid hypothesis. Genetic abnormalities result in accumulation of the Ab with a cascade of neuronal death and dementia. Ab: Amyloid-b.

Figure 3. Tau protein hypothesis. Abnormal hyperphosphorylation of tau protein results in neurofibrillary tangles, neuronal death and dementia.

Tau protein Normal stabilization of microtubules

Hyper-phosphorylation of tau

Polymerization of tau

Neurofibrillary tangles, microtubule disruption,neuronal dysfunction

Neuron death,plaques

Dementia

Genetic abnormality of APP or Aβ

Gradual accumulation of Aβ

Synaptic dysfunction, diffuse plaques

Activated glia, inflammatory response

Oxidative injury, tangle formation, core plaques

Dementia




Tab

le 1

. Po

ten

tial

th

erap

ies:

am

ylo

id h

ypo

thes

is.

Can

did

ate

Sub

clas

sSp

on

sor

Tria

l p

has

eSu

bje

cts

(n)

Co

mm

ent

Dat

e o

f o

nse

t

AC

C-0

01 (

pare

nter

al)

Ant

i-A

b an

tibo

dies

(pa

rent

eral

)Pfi

zer/

JAN

SSEN

II

76Se

quel

to

infa

mou

s A

N-1

792;

ski

n le

sion

s se

en. N

ine

stud

ies

com

plet

ed o

r in

pro

cess

Mar

ch 2

010

CA

D10

6A

nti-

Ab

antib

odi

es (

pare

nter

al)

Nov

artis

II12

1D

evel

op

ed b

y C

yto

s Bi

otec

hno

log

y; fi

ve

othe

r st

udie

sM

arch

201

0

Bapi

neu

zum

ab (

AA

B0

01)

Ant

i-A

b an

tibo

dies

(pa

rent

eral

)Pfi

zer/

JAN

SSEN

II8

00

Con

tinua

tion

of

othe

r st

udie

s; 1

3 ot

her

stud

ies

com

plet

ed o

r in

pro

cess

es. T

his

is

iden

tica

l to

the

natu

ral a

ntib

od

y tr

igg

ered

by

AN

-179

2

May

20

08

PF0

436

0365

Ant

i-A

b an

tibo

dies

(pa

rent

eral

)Pfi

zer

II17

5Pa

ssiv

e an

ti-A

b an

tibo

dies

July

20

08

LY45

0139

(se

mag

aces

tat)

g- a

nd b

-sec

reta

se in

hibi

tor

Eli L

illy

and

Co

III11

00

This

is m

ixed

(an

d b-

secr

etas

e in

hibi

tor;

five

ot

her

stud

ies

com

plet

ed o

r in

pro

cess

Sept

emb

er 2

00

8

BM

S-70

8163

g-se

cret

ase

inhi

bito

rBr

isto

l–M

yers

Sq

uib

bII

270

12 o

ther

stu

dies

com

plet

ed o

r in

pro

cess

(g

-sec

reta

se in

hibi

tors

cau

se c

ance

r)M

ay 2

00

9

CH

F 5

074

g-se

cret

ase

mo

dula

tor

Chi

esi P

harm

a-

ceut

ical

s In

c.

II9

6Th

ree

othe

r st

udie

s co

mpl

eted

or

in p

roce

ssM

arch

201

1

Posi

phen

b-se

cret

ase

mo

dula

tor

QR

Phar

ma

Inc.

I3

0D

ual a

ctio

n g-

secr

etas

e in

hibi

tion

an

d A

CH

EiFe

brua

ry 2

010

E26

09

b-se

cret

ase

inhi

bito

rEi

sai I

nc.

I4

8O

ral b

-sec

reta

se in

hibi

tor

Dec

emb

er 2

010

Mem

oryX

L™M

ixed

sec

reta

se, A

b in

hibi

tor

U M

assa

chus

etts

, W

orce

ster

II3

00

Six-

com

pon

ent

nutr

iceu

tica

l sai

d to

hav

e b

oth

g- a

nd b

-sec

reta

se in

hibi

tion

and

re

duce

Ab

pro

duct

ion

Mar

ch 2

011

AZD

103

ELN

D0

05

(scy

llo-i

nosi

tol)

Prev

ents

fibr

iliza

tion

of

Ab

Elan

Pha

rmac

euti

cals

II15

0H

ighe

r d

ose

10

00

and

200

0 m

g p.

o. b

.i.d

asso

ciat

ed w

ith

exce

ssiv

e d

eath

s Ju

ne

200

9

MA

BT51

02A

Ant

i-A

b an

tibo

dies

, pas

sive

(p

aren

tera

l)G

enen

tech

II

372

Pass

ive

mon

ocl

onal

Ab

antib

od

yA

pril

2011

Sola

nez

umab

(LY

2062

430

) A

nti-

Ab

antib

od

y (p

aren

tera

l)El

i Lill

y an

d C

oIII

1275

Bind

s sp

ecifi

cally

to

solu

ble

amyl

oid

-b. F

ive

stud

ies

liste

d, e

arlie

r st

udie

s p

osi

tive

D

ecem

ber

201

0

Gan

ten

erum

abA

nti-

Ab

antib

od

y (p

aren

tera

l)H

offm

ann

–La

Roch

e II

36

0Po

siti

ve P

hase

I st

udy

Nov

emb

er 2

010

AFF

ITO

PE A

D03

(M

imoV

ax)

Ant

i-A

b an

tibo

dy

(par

ente

ral)

Affi

ris A

GII

420

Nin

e st

udie

s in

tot

al. I

s th

ough

t to

be

a m

ore

sele

ctiv

e va

ccin

eSe

ptem

ber

201

0

Ab:

Am

ylo

id-b

; AC

HEi

: Ace

tylc

holin

este

rase

inhi

bit

or;

b.i.

d.: T

wic

e da

ily; p

.o. P

er o

rem

.




Tau protein has more than 40 known phosphory-lation sites and misfolding of tau protein is seen in several neurodegenerative diseases [23,24].

There is criticism of the tH. Su et al. have shown that oxidative stress precedes and causes tau phosphorylation via intracellular signaling of JNK and p38 activation [25]. Thus, NFT is part of the cascade seen in AD and not the cause. Furthermore, NFTs may not be involved in neuronal death, and neurons with NFTs can survive for decades in AD patients [26,27]. Nevertheless, there are potential drugs based on tH in development at this time.

�� Inflammation hypothesis The IH is actually as old as the dominant AH [28]. In 1989 Griffin et al. demonstrated microglia associated with amyloid plaques in Alzheimer brains, which expressed one of the most potent inflammatory cytokines – IL-1 [29]. In 1994, Breitner et al. observed that patients taking non-steroidal anti-inflammatory drugs (NSAIDs) were less likely to develop AD [30]. Over the next decade other inflammatory cytokines were found in high concentrations such as IL-6, IL-2, IL-3, IFN-a and TGF-b1. At the time it was thought that these cytokines migrated into the CNS. Microglia and astrocytes in the early 1990s were thought by most scientists to simply be “packing or styrofoam peanuts” cushioning the important cells – the neurons [16]. But circulating antibodies are too large to cross the blood–brain barrier. The brain and spinal cord are ‘immune privileged’ organs separated by the blood–brain barrier.

The word ‘glia’ is derived from the Greek for ‘glue’. Microglia, which initially are created in bone marrow, migrate to the CNS to recognize foreign bodies, sample them, and act as anti-gen-presenting cells activating T-cells. When activated, microglia become cytokine facto-ries. The astrocyte is the most numerous of the macroglia. Recently, it is understood that they regulate neurons, precipitate apoptosis, secure the blood–brain barrier and also actively secrete cytokines and neurotransmitters [16,31].

The IH is well explained by Mrak [31] and can be seen in the middle portion of Figure 1. Ab plaques are an evolutionary process of four stages with increasing amounts of insoluble Ab. But in all stages, activated microglia are pres-ent and inflammatory cytokines are elevated. Likewise NTFs go through stages to mature NFTs which are said to be toxic. But again the activated microglia are present and inflamma-tory cytokines are elevated in the earliest stages of NFT formation.

The IH states that glia, especially microglia, form a chronic persistent pathologic inflamma-tion similar to rheumatoid arthritis and ulcer-ative colitis. What activates the glia? Aging and head trauma are the only two items offered by Mrak. Numerous other potential activating agents are listed at the top of Figure 1.

Proponents of the IH discuss matters upstream from the AH and the tH. However, they do not point to events that precipitate the pathologic ini-tiation of glia. In the OSH of Figure 1, the inflam-matory process is incorporated in the middle stages of the chart, while associated causes that precipitate chronic inflammation are listed at the top. This includes infectious agents such as herpes viruses [32] or bacteria such as Chlamydia pneumonia [33].

Trials with NSAIDs have been inconclusive to date [34–36]. Use of corticosteroids appears more promising, but both steroids and NSAIDs have serious side effects when chronically used [37].

�� Oxidative stress hypothesisThe OSH was proposed following the observa-tion in 1997 that AD is associated with aging, not genetics [38]. It became apparent that AD was associated with and the result of aging plus an initial brain insult. The initial brain injury could be metabolic, anoxic, vascular, infectious or trau-matic (Figure 1). The insult precipitates necrosis and localized inflammation may become chronic [16].

Halliwell and Gutteridge brilliantly noted that the brain is uniquely vulnerable to oxida-tive injury [39]. First, oxygen is highly utilized

Table 2. Potential therapies: tau hypothesis.

Candidate Subclass Sponsor Trial phase Subjects (n)

Comment Date of onset

Lithium Tau aggregation inhibitor

University of Sao Paulo II 80 Poor commercial viability March 2007

Davuetide (AL108)

Tau aggregation inhibitor

Allon Therapeutics II and III 300 Previous positive Alzheimer’s disease study

October 2010

Tideglusib (NP-12 or NP031112)

Tau aggregation inhibitor

Noscira SA II 280 Three studies. Application in supranuclear palsy. Blocks glycogen synthase kinase-3

April 2011


1

23

4

5

6

7814

15

9

1310

1112

Figure 4. Neuronal compartments. (1) Neucleolus, (2) nucleus, (3) ribosome, (4) vesicle, (5) rough endoplasmic reticulum, (6) Golgi apparatus, (7) cytoskeleton, (8) smooth endoplasmic reticulum, (9) mitochondria, (10) vacuole, (11) cytosol, (12) lysosome, (13) centriole, (14) receptor, (15) capillaries/blood–brain barrier.



by neurons. As such the brain receives 20% of cardiac output, but is only 1% of a person’s body by weight. Second, neurons have a large cell surface because of the long axons. This means energy production via ATP metabolism in mito-chondria occurs at a high level. This metabolic pathway is a principle generator of free radicals that create oxidative injury to cells. A normal brain (1011–1012 neurons) requires 4 × 1021 mol-ecules of ATP per moment. This is a massive energy requirement and produces large quan-tities of free radical byproducts. Third, the principle substrate of brain is glucose (glycoly-sis and Krebs cycle). Because glycogen is not stored in neurons, any interruption in glucose metabolism creates huge quantities of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Fourth, high calcium ion traffic across neuronal membranes causes potentially high intracellular free calcium. This leads to the production of ROS and RNS. Fifth, com-mon catecholamine neurotransmitters (dopa, dopamine, serotonin and noradrenaline) cre-ate ROS and RNS when metabolized [39]. Interactions between catecholamines gener-ate the superoxide radical. Metabolism of the amine moiety (R-CH

2-NH

2) by monoamine

oxidases results in reactive hydrogen peroxide

(H2O

2) and reactive ammonia (NH

3). Sixth,

some neurotransmitters are by nature excito-toxic. Glutamate, aspartate and nitric oxide are such neurotransmitters. Excess concentrations of excitotoxins result in intracellular signaling, which leads to apoptosis [39]. Seventh, metal-loproteins are essential components in cyto-chromes, ferritin tyrosine hydroxylase, tryp-tophane hydroxylase and others. In traumatic, anoxic and other brain injuries, these metallo-proteins are released into the intracellular space [39–41]. The release of the iron, copper and zinc, often from the mitochondria, reacts with lipids, free hydroxyl radicals and hydrogen peroxide. Although Ab is an efficient antioxidant of iron, copper and zinc, it is membrane-bound and when overwhelmed can promote neuron death [42–44]. The result is lipid peroxidation, further free radical production, mitochondrial dysfunc-tion, and neuronal apoptosis, inactivation or necrosis [16,45].

Figure 4 accentuates the importance of where oxidative injury occurs. Physically oxidative injury occurs in compartmentalized locations: blood–brain barrier, intercellular spaces, cell lipid membranes, cell receptors, cytosol, nucleus, mitochondria lipid membranes, endoplasmic reticulum, Golgi apparatus and other organelles.




In general, oxidative injury occurs at four chemical levels:

�� Lipid membranes – lipid peroxidation: cell membrane, mitochondrial membrane, nuclear membrane, endoplasmic reticulum and Golgi apparatus;

�� Nucleic acids – nucleic oxidation: DNA, mRNA, mcRNA, tmRNA, rRNA, RNAi, siRNA and mitochondrial DNA;

�� Protein oxidation – protein peroxides: pep-tides, enzymes, structural, cell signaling, membrane or receptor proteins;

�� Alkaline earth and transition metals – metal dysregulation: calcium, iron and copper.

Research agents previously used in OSH therapies are vitamin E (only the d-a tocoph-erol form), vitamin C and CoQ

10. However,

vitamin E comes in eight natural forms. Vitamin E is lipophilic and a potent scavenger of peroxyl radicals in the intracellular space and intracellularly at the mitochondria [39]. It cooperates with vitamin C, which regener-ates a-tocopherol from a-tocopheryl radicals within membranes and lipoproteins. However, vitamin C is water soluble and largely isolated to vascular, intracellular and cytosol compart-ments. Its principle activity in the body as a whole is regeneration of reduced uric acid (urate radical). Uric acid accounts for over half of the free radical scavenging in the blood and intracellular space [46]. Use of vitamin E plus vitamin C would likely still not fully address free radical damage in the nucleus, endoplas-mic reticulum, Golgi apparatus, misfolded proteins, peroxidation of cellular membranes or transition metal ions released by cellular death. The transition metal ions frequently released by mitochondrial dysfunction or cel-lular death are iron, copper, zinc and in cer-tain cases mercury [44]. Ab is the principal host defense that complexes transition metals, as well as some post-transition metals (alumi-num and lead). Within the mitochondria itself, vitamin CoQ

10 is effective at attenuating dys-

function [47]. CoQ10

is a lipophilic electron car-rier in the electron transport chain of oxidative phosphorylation that is embedded in the inner mitochondrial membrane.

It is apparent that single, simple antioxidants should not work. An effective agent would be complex, working in multiple locations in both aqueous and lipid environments. Kamat et al. extensively reviewed the use of antioxidants in CNS diseases [15]. In animal models of AD

Kamat et al. concluded that antioxidants were promising. He also noted that the massive doses required were not practical in humans. In human studies results are mixed at best.

Although results to date are disappointing, the OSH is growing in favor. It is inclusive of most of the AH, the tH and the IH. To some extent the VH may fall under the umbrella of the OSH. It should be noted that the previous agents explored were of poor design [48].

�� Vascular hypothesisThe VH, proposed in 1993, is not necessarily about stoke and acute hypoxia [49]. Rather it is about chronic hypoxia by means of endo-thelial cell dysfunction due to aging [18,50]. Endothelial cells are part of a neurovascular unit, which consists of neurons, glial cells and endothelial cells. Endothelial dysfunction pre-cipitates Ab, and Ab causes endothelial toxic-ity. Further signaling between glia, neurons and endothelial cells promotes neuroinflam-mation and incompetence of the blood–brain barrier. AD then follows.

Experimental VH follows the sequence seen in Figure 5 [51]. Note that chronic brain hypo-perfusion is a central feature of the VH and the beginning of the final common pathway to AD.

Aging, apoE4 genotype, cardiovascular disease and diabetes

Chronic brain hypoperfusion

Neuronal dysfunction and astrocytosis

Oxidative stress and protein abnormalities

Spatial memory loss

Brain atrophy & death

Endothelial cell damage, vascular nitric oxide dysfunction

Aβ1–42 upregulation and overexpression of G protein receptor kinase2

Figure 5. Vascular hypothesis. Chronic brain hypoperfusion results in brain atrophy and death.




Diagnosis of AD is by carotid artery ultra-sound and echocardiogram. Treatment is vigor-ous treatment of discovered cardiovascular prob-lems, presumably to increase cerebral vascular flow. Experimental treatments would focus on neoangiogenesis and vasculogenesis [18].

The VH is intriguing, but open to criticism. Doubtless there is evidence of endothelial dys-function in AD [50,51]. As yet treatment modalities have not been tested in animal or human studies. Further, it excludes direct parenchymal pathol-ogy as causal. It follows that viral- or bacterial-induced dementias must initially affect cerebral blood flow. Head trauma, per this theory, must initially induce chronic cerebral hypoperfusion before the dementia progresses. Oxidative stress occurs late in the sequence of the VH. Memory loss occurs before Ab

1–41 upregulation and depo-

sition [51]. This sequence does not seem to match the human pathological sequence.

�� Hibernation hypothesisSwaab et al. proposed the hypothesis that neurons do not die due to AD, but rather the neurons undergo atrophy and possibly hiber-nate [17]. Swaab demonstrated that the number of neurons in key locations is the same for AD and age-matched controls, and suggested that the ‘missing neurons’ are merely atrophied. Swaab also reviewed the evidence that the atro-phic neurons are dramatically hypometabolic using Golgi apparatus markers, nucleolus size and NGF receptors (p75). The well-recognized 50–70% reduction in CNS glucose metabo-lism may be due to atrophic hibernating neu-rons. The question is how to wake hibernating atrophic neurons.

Future therapiesThere are currently 914 clinical trials related to AD listed on the US government clinical trials website and 157 of these have an FDA

Phase III status [103]. Alzheimer’s drug develop-ment appears to be stalled. Since the introduc-tion of tacrine in 1993 and Namenda in 2003, there have been no approved new medications for AD. In part this is due to the insensitive testing instruments used to test outcomes [48,52]. Most cognitive testing instruments in popular use were developed before it was suspected that memory problems could be reversed. The origi-nal intent of the test was to diagnose a condi-tion, not to measure improvement, for example, the Longitudinal Aging Study Amsterdam used the Mini-Mental State Exam (MMSE) to measure cognitive decline [53]. Yet, the MMSE suffers from both floor and ceiling effects, making it a crude unreliable tool [52]. Some studies use a battery of ‘cognitive tests’ to mea-sure change [54]. These tests often take hours, and the data may be affected by the subject’s response to fatigue. For example, the Boston Naming Test was developed for assessment of aphasia, has a 135 page instruction book and requires 90 min to complete [104].

Another possible cause of poor outcomes is the ‘Epic Research Project’. Here, blue panel academicians conduct a multicenter, multi-million dollar, multiyear research study; thou-sands of people (subjects and research assistants) are employed. The findings are reported and often such epic projects find no benefit from, for example, the use of vitamin/health supplements in humans [55–58].

The problem of the epic study is the method-ology. Adherence to rigorous protocols is very difficult in these colossal projects. Thus, pla-cebo and active treatment data merge into a nonstatistical gray zone.

Finally, if the OSH is correct (Figure 1) there are multiple opportunities to interrupt the chain of events, but shutting down the path-way limits the bodies ability to respond to oxidative insults such as infections or trauma.

Table 3. Potential therapies: inflammation hypothesis.

Candidate Subclass Sponsor Trial phase Subjects (n) Comment Date of onset

CERE-110 Cytokine modulation

Ceregene I 50 NGF gene delivered by adenovirus with induction of NGF

September 2009

Bryostatin 1 Intracellular signaling modulation

Blanchette Rockefeller Neuroscience Institute

II 9 Protein kinase C modulation. Myalgia side effect. Parenteral

April 2008

Etanercept (Enbrel®)

Cytokine modulation

University of Southampton

II 40 TNF-a inhibitor used in autoimmune diseases

January 2011

Lornoxicam (Xefo®)

COX-1 and -2 inhibition

JSW Lifesciences II 220 One study. Cox-1 and -2 inhibitor September 2009

Thalidomide TNF-a inhibitor Bannor Health II and III 20 Vague outcome measurements March 2010




As noted above, the location of injury is quite variable. Thus, the safest and possibly most effective approach would be complex synergis-tic modulations of the free radicals and chronic inflammatory response.

The pipeline of therapeutic agents should be reviewed per the order of the hypothesis of AD etiology [103].

�� Therapies via the AHTable 1 lists 16 drugs related to manipulation of Ab [103]. Three approaches are under investiga-tion. Anti-aggregation agents include metal che-lation therapies (e.g., EDTA, desferrioxamine, and clinoquinol) that are available in alternative health clinics. There is no funding for stud-ies to bring these treatments through the FDA process. Melatonin, an antioxidant, also has anti-Ab properties. AZD103 (Scyllo-inositol) is a stereoisomer of inositol. In December 2009 a study using 1000 and 2000 mg of AZD103 twice daily was withdrawn due to safety issues [105]. The current study uses AZD103 orally 250 mg twice a day.

There are eight anti-Ab immune modula-tors under investigation by large pharmaceu-tical concerns. The drug companies and FDA label these anti-Ab antibodies. These paren-teral treatments are inspired by AN-1792 (Elan Pharmaceuticals), which was found unaccept-able due to a high rate of meningoencephalitis. ACC-001 is actually a derivative of AN-1792. Bapineuzumab (AAB001) from Pfizer/Janssen is identical to the natural antibody triggered by AN-1792. The other anti-Ab antibodies are said to be ‘passive’ or more selective.

Tramiprosate (3APS), another anti-Ab aggregation therapy, was in Phase III studies, but failed to show significant findings and is no longer under study. Results is this group have been disappointing to date with no improve-ment in cognitive performance tests, except in the post-hoc analyses [59,60].

Production of Ab is dependent on two enzymes – g- and b-secretase. The pharmaceu-tical companies have five candidates inhibiting these secretases (Table 1). Of the five, semagace-stat from Eli Lilly has had the most publicity and expectation. Like other attempts to inter-fere with Ab physiology, this drug failed its end points. It actually appears to have worsened the condition of the subjects taking the drug [106]. The long-term toxicity of these agents is a seri-ous concern. g-secretases have been implicated in tumorigenesis via proteolytic release of Notch intracellular domain [61].

Posiphen® inhibits amyloid precursor pro-tein synthesis by inhibition of b-secretase, and reduces Ab [103,107]. It is a small molecule, the pos-itive isomer of phenserine, is orally available and has a high brain:plasma ratio (7:1). It also has a slow-onset acetylcholinesterase inhibitory action. Posiphen is distinct from the AD drugs currently available or in development, because it has a dual mechanism of action: it is disease modifying by reducing plaques through inhibition of amyloid precursor protein synthesis and it provides some symptomatic relief through acetylcholinesterase inhibition [108].

There is a new mixed secretase inhibitor under study by the University of Massachusetts (MA, USA) that is a complex nutraceutical (MemoryXL). It contains folic acid (400 µg), vitamin B12 (6 µg), vitamin E (as a-tocoph-erol 30 IU), S-adenosylmethionine (400 mg), N-acetyl cysteine (600 mg) and acetyl-l-carnitine (500 mg). Results of any testing are not available.

To summarize, the clinical trials of Ab mod-ulators have been disappointing. Furthermore, these trials fail to prove the AH.

�� Therapies via tHTable 2 lists the active trials of therapies address-ing the tH [103]. Lithium is one therapy that is thought to produce its therapeutic effects via the tH. However, it has been shown to have poor commercial viability. Davunetide (AL-108; Allon Therapeutics) is an eight amino acid peptide that was granted orphan status by the FDA. The current active study by Allon is based on prior positive results in early AD. Tideglusib (NP-12 or NP031112) blocks glycogen synthase kinase-3. Glycogen synthase kinase-3 is one of the main factors that causes the tau protein to become ‘sticky’, forming the neurofibrillary tangles. Tideglusib also has an orphan medicinal status.

To summarize, the clinical trials of drugs that target the tH are uncertain.

�� Therapies via the IHThere are five candidates that could be classified as therapies based on the IH (Table 3). CERE-110 uses a virus (an adenovirus) to transfer a gene that makes NGF, a protein that may make nerve cells in the brain healthier and protect them from dying. CERE-110 has been studied in laboratory animals and is in the early stages of being tested in humans [62].

Bryostatin 1 is part of a group of 20 macrolide lactones first isolated in the 1960s by George Pettit from extracts of a species of bryozoan, Bugula neritina. The structure of bryostatin 1




Table 4. Potential therapies: oxidative stress hypothesis.

Candidate Subclass Sponsor Trial phase Subjects (n) Comment Date of onset

Exdendin-4 (exenatide)

Neuroprotection, hormonal

NIH clinical center II 230 Neuroprotective via glucagon-like peptide-1

November 2010

Tamibarotene (OAM80)

Single antioxidant Osaka City University II 50 Synthetic retinoid April 2010

Sunphenon EGCg

Neuroprotection, herbal

Charite University, Berlin, Germany

II and III 50 Modified single herbal (green tea) which affects intracellular signaling

August 2009

Acitretin (Soriatane)

Single antioxidant Johannes Gutenberg University Mainz

II 76 Second generation retinoid March 2010

Curcumin Single antioxidant UCLA III 132 Three other studies by other institutions, often with a second antioxidant Results have been poor

July 2011

DCB-AD1 (Fo Ti)

Single antioxidant National Taiwan University

II 80 Derivative of Fo-ti September 2005

Melatonin Single antioxidant Neurim Pharmaceuticals Ltd

II 50 Only study for memory October 2007

was determined in 1982. Bryostatins are potent modulators of protein kinase C. Bryostatin 1, which is also under investigation for cancer therapy, has been shown to improve memory in marine slug (Hermissenda crassicornis) and rats. The current small study is primarily for human safety [63–65].

Etanercept (Enbrel®), is a Pfizer/Amgen product principally marketed for psoria-sis and rheumatoid arthritis. Etanercept is a fusion protein produced through expression of recombinant DNA. Etanercept acts by interfering with TNF, an inflammatory cyto-kine that is secreted by activated astrocytes. A study being conducted by the University of Southampton (UK) is principally looking at safety of etanercept in mild-to-moderate AD.

Lornoxicam (Xefo®) is a NSAID of the oxi-cam class. Lornoxicam inhibits both isoforms, cyclooxygenase-1 and -2, equally. The object of lornoxicam is to downmodulate CNS pros-taglandins. Prostaglandins are paracrine secre-tions (local hormones) that are released from astrocytes and cause changes in neighboring neurons and glia that carry specif ic mem-brane prostaglandin receptors. Prostaglandins essentially function as proinflammatory cyto-kines [16]. NSAIDs have been used in prior studies with mixed results [34–37].

Thalidomide is the drug that allowed the FDA to press legislation that stated that drugs needed to be “safe and effective” rather than just safe [66]. Currently, thalidomide is an immunomodulatory agent used primarily, combined with dexamethasone, to treat mul-tiple myeloma. Thalidomide may reduce the

levels of TNF-a, which is a pro inflammatory cytokine produced by astrocytes [16]. The downmodulation of TNF-a in the CNS may slow progression of AD, but the metrics stated by Bannor Health may not be able to measure this.

�� Therapies via OSH Table 4 lists potential antioxidant therapies for AD. Currently eight studies are underway investigating these therapies. Most therapies are being developed by universities, which makes commercialization difficult. The targets of the current OSH candidates are quite diffuse, rang-ing from hormonal (exdendin-4) to a single lipid antioxidant (secoisolariciresinol). The current investigational OSH agents have simple com-pounds with single foci of intervention (Figure 4) and use insensitive testing instruments. Thus, the current OSH agents are unlikely to be used to treat AD.

Dimebon™ (latrepirdine), which was in Phase III trials, was dropped from development in March 2010. This Russian over-the-counter small molecule (3,6-dimethyl-9-[2-methyl- pyridyl-5]-ethyl-1,2,3,4-tetrahydro-g-carboline dihydrochloride) has a broad and pleiotropic spectrum of pharmacological properties. It is an antihistamine that has been available in Russia for 23 years. Latrepirdine blocks the mitochon-drial permeability transition pore (MPTP) that stabilizes the mitochondria. It is also an L-type calcium channel antagonist. As such, latrepird-ine inhibits neuronal death, potentially by mito-chondrial-mediated inhibition of apoptosis. The drug is also thought to have activity as a CI and




NMDAR. In vitro, latrepirdine protected pri-mary neuron cultures against Ab toxicity, and it was suggested that it worked at multiple levels.

The first clinical trial of latrepirdine (by Medivation, conducted in Russia) on 183 sub-jects demonstrated efficacy in five independent measures of cognitive improvement [67]. The statistical significance between latrepirdine and placebo was astonishing, with p < 0.0001 in many cases. Another study of latrepirdine in 600 subjects failed to demonstrate any statistical response using the ADAS-cog and CIBIC-plus scales [108].

One recent human study involving OSH therapies should be highlighted [48]. A potent 34-component antioxidant blend (Memory reVITALIZER®) or placebo was given using a double-blind protocol to 113 normal subjects age 50–75 years. Memory reVITALIZER has multiple representatives of each of the five basic antioxidant classes. The memory metrics were sensitive to change. The 16 week duration of the study would allow change in CNS by oxidative repair. The design of the study was simple (three subject visits of 30 min) and only at one center with minimal personnel involvement. The results showed significant improvement in working memory (20 word recall task) and declarative memory (50 part paired association task) [68–70].

Perhaps if some of these principles were incor-porated into OSH therapy research, the results of human studies would become more positive.

�� Therapies via the VH There are five clinical trials that address the VH of AD listed on the Clinical Trials website [103]. The principal proponent of the VH seems to advocate more aggressive screening for presence of cardiovascular disease [71]. Four candidates are currently marketed medications that are being studied by universities (Table 5). One candidate (AC-1204) is novel, and approaches the problem of hypofunction with a lipid metabolic enhancer.

�� Therapies via the hibernation hypothesisThe Clinical Trials website lists 19 studies cur-rently recruiting for therapies based on the hibernation hypothesis [103]. These therapies include ‘light therapy’, deep brain stimulation, magnetic stimulation, melatonin, cognitive train-ing, aerobic exercises and other brain stimulation approaches. Earlier studies of structured exercise and peripheral nerve stimulation with transcu-taneous electrical nerve stimulations improved memory of early AD cases [72]. Light therapy and exercise have been found to be effective in early AD [73,74].

Future perspectiveDespite the fact that there are 914 clinical trials related to AD are listed, and 157 of these in are in Phase III trials, there appears to little likelihood of an effective new treatment in the near future [103]. Therapies based on the popular Ab-AH or the tH are failing the safety and efficacy end points. Such failures reinforce the position that Ab and NFTs are the host’s attempt to establish homeostasis [20]. The OSH and VH candidates do not receive such large pharmaceutical industry support.

The OSH is inclusive of the other hypothetical causes of AD. The OSH does offer hope as there have been positive animal models and one study in elderly subjects without AD [15,48]. However, researchers in the field are handicapped by the view that a massive single agent intervention is appropriate. Synergistic polypharmacy of com-plex formulations studied over a long period is alien to this construct.

The field of Alzheimer’s research has further been handicapped by the crudeness of the tools used. Studies in the field use antiquated psycho-metrics not developed for rapid administration and to measure improvement of dementia sub-jects. More sensitive instruments might demon-strate the benefit of treatments based on the hibernation hypothesis.

Table 5. Potential therapies: vascular hypothesis.

Candidate Subclass Sponsor Trial phase Subjects (n)

Comment Date of onset

Carvedilol (Coreg)

Antihypertensive Johns Hopkins University IV 50 Nonselective b/a-1 adrenergic blocker

May 2011

Prazosin (Minipress®)

Antihypertensive The Seattle Institute for Biomedical and Clinical Research

III 120 a-adrenergic blockers May 2011

AC-1204 (Ketasyn®)

Metabolic enhancer Accera, Inc. II and III 400 Oral lipid that metabolizes in the CNS to energy enhancing ketone bodies

October 2011

Ramipril (Altace®)

Antihypertensive University of Wisconsin IV 20 ACE inhibitor April 2009




Financial & competing interests disclosureWK Summers is the developer and patent holder of Tacrine, the first drug to treat Alzheimer’s disease. The patent is now expired, and Warner Lambert who owned the license have been bought by Pfizer. WK Summers is also the developer and patent holder for Memory reVITALIZER®, as well as the President and CEO for Alzheimer’s Corporation, which

conducted a study cited in this work. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials dis-cussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Executive summary

The current state of therapy for Alzheimer’s disease � Symptomatic relief can be achieved via cholinesterase inhibitors. � Symptomatic relief and possible disease modification can be achieved via memantine. � No new therapies for Alzheimer’s disease (AD) have been approved since 2003.

Current research therapies for AD should modify the course of the illness � There are six theories on the cause of AD. � There are 914 clinical trials on the treatment of AD listed and 157 are in Phase III. � Analysis of these on the basis of the six theories of AD do not demonstrate viable therapeutic candidates likely to be marketed within

the near future.

Future therapies for AD � The amyloid, tau, vascular and inflammation theories appear to be downstream from the etiology of AD. � More sensitive means measuring change in early-to-moderate AD needs to be addressed. � Synergistic combinations of antioxidants or anti-inflammatory agents appear to have promise. � Clinical trial designs should be simplified and more efficient. � The possibility of awakening hibernating neurons is intriguing.

Bibliography1 Summers WK, Majovski LJ, Marsh GM et al.

Use of oral THA in long-term treatment of senile dementia, Alzheimer’s type. N. Engl. J. Med. 315, 1241–1245 (1986).

2 Albert A. Improved synthesis of amino acridines. J. Soc. Chem. Ind. (Chem). 65, 169–175 (1945).

3 Summers WK, Majovski LV, Marsh GM et al. Oral tetrahydroamino acridine in the treatment of senile dementia Alzheimer’s type, Response to six letters to the Editor. N. Engl. J. Med. 316, 1603–1605(1987).

4 Waldholtz M. “A Psychiatrist’s Work Leads to a U.S. Study of Alzheimer’s Drug. But Dr. Summers Shuns test, seeks to widen his own; Is memory really aided? The Fee-for-Research Furor. Wall St. J. 4th August (1987).

5 Editorial Staff. “Dr. Summers’s Victory”. Wall St. J. 25th May (1989).

6 Summers WK. Tacrine and Alzheimer’s treatment, chapter in Alzheimer’s disease 100 year anniversary. J. Alzheimer’s Dis. 9, 439–445 (2006).

7 Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 33(8), 1351–1365 (2011).

8 Olney JW, Sharpe LG, Feigin RD. Glutamate-induced brain damage in infant primates. Exp. Neurol. 31(3), 464–488 (1972).

9 Yu SP, Yeh C-H, Strasser U et al. NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science 284(5412), 336–339 (1999).

10 Liu J, Chang L, Roselli F et al. Amyloid-b induces capase-dependent loss of PSE-95 and synaptophysin through NMDA receptors. J. Alzheimer’s Dis. 22, 541–556 (2010).

11 Schneider LS, Dagerman KS, Higgins JPT et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch. Neurol. doi:10.1001/archneurol.2011.69 (2011) (Epub ahead of print).

12 Small G. The Memory Prescription. Hyperion Publishers, New York, NY, USA 113–161 (2004).

13 Frisardi V, Panza F, Seripa D et al. Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms. J. Alzheimer’s Dis. 22, 715–740 (2010).

14 Stessman J, Jacobs JM, Ein-Mor E et al. Normal body mass index rather than obesity predicts greater mortality in elderly people: the Jerusalem longitudinal study. J. Alzheimer’s Dis. 57, 2232–2238 (2009).

15 Kamat CD, Gadal S, Mhatre M et al. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J. Alzheimer’s Dis. 15, 473–493 (2008).

16 Summers WK. Alzheimer’s disease, oxidative injury, and cytokines. J. Alzheimer’s Dis. 6, 651–657 (2004).

17 Swaab DF, Dubelaar EJG, Hofman MA et al. Brain aging and Alzheimer’s disease; use it or lose it. Prog. Brain Res. 138, 345–375 (2002).

18 De la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 3, 184–190 (2004).

19 Lee H, Zhu X, Perry G et al. The fallacy of amyloid and cognition in Alzheimer’s disease. Drugs Aging 23(2), 179 (2006).

20 Castellani RJ, Lee H, Siedlak SL et al. Reexamining Alzheimer’s disease: evidence for a protective role for amyloid-b protein precursor and amyloid-b. J. Alzheimer’s Dis. 18, 447–452 (2009).

21 Arriagada PV, Grouwdon JH, Hedley-White ET et al. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992).

22 Trojanowski JQ, Lee VMY. The Alzheimer’s brain: finding out what’s broken tells us how to fix it. Am. J. Pathol. 167(5), 1183–1188 (2005).

23 Dickson DW. Neuropathology of non-Alzheimer degenerative disorders. Int. J. Clin. Exp. Pathol. 3(1), 1–23 (2009).

24 Ittner A, Ke YD, Eersel J et al. Brief update on different roles of tau in neurodegeneration. IUBMB LIFE. 63(7), 495–502 (2011).

25 Su B, Wang X, Lee H et al. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci. Lett. 468, 267–271 (2010).




26 Andorfer C, Acker CM, Kress Y et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 25, 5446–5454 (2005).

27 Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 188–197 (1999).

28 Eikelenbloom P, Stam FC. Immunoglobulins and complement factors in senile plaques: an immunoperoxidase study. Acta Neuropathol. 57, 239–242 (1982).

29 Griffin WS, Stanley LC, Ling C et al. Brain interleukin-1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).

30 Breitner JC, Gau BA, Welsh KA et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology 44, 227–232 (1994).

31 Mrak RE. Neuropathology and neuroinflammation idea. J. Alzheimer’s Dis. 18, 473–481 (2009).

32 Wozniak MA, Frost AL, Itzhak RF. Alzheimer’s disease-specific tau is induced by herpes simplex virus type 1. J. Alzheimer’s Dis. 16, 341–350 (2009).

33 Shima K, Kuhlenbäumer G, Rupp J. Chlamydia pneumoniae infection and Alzheimer’s disease: a connection to remember? Med. Microbiol. Immunol. 199(4), 283–289 (2010).

34 Martin BK, Szekely C, Brandt J et al. Cognitive function over time in the Alzheimer’s disease anti-inflammatory prevention trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch. Neurol. 65(7), 896–905 (2008).

35 Arvanitakis Z, Grodstein F, Bienias JL et al. Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology 70(23), 2219–2225 (2008).

36 Vlad SC, Miller DR, Kowall NW et al. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70(19), 1672–1677 (2008).

37 Beeri MS, Schmeidler J, Lesser GT et al. Corticosteroids, but not NSAIDs, are associated with less Alzheimer neuropathology. Neurobiol. Aging doi: 10.1016/j.neurobiolaging.2011.02.011 (2011) (Epub ahead of print).

38 Finch CE, Tanzi RE. Genetics of aging. Science 278, 407–411 (1997).

39 Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine (3rd Edition). Oxford University Press, Oxford, UK 721–751 (2001).

40 Lovell MA, Robertson JD, Teesdale WJ. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 158, 47–52 (1998).

41 Martinez-Torres FJ, Wagner S, Kluge B. Expression and activity of matrix metalloproteinases (MMPS) 2 and 9 in a murine model of herpes simplex virus encephalitis. Presented at: 32nd Neuroscience Meetings. Orlando, FL, 4 November 2002 (Program No 395.12).

42 Obrenovich ME, Joseph JA, Atwood CS et al. Amyloid b: a (life) preserver for the brain. Neurobiol. Aging 23, 1097–1099 (2002).

43 Rottkamp CA, Raina AK, Zhu X et al. Redox active iron mediated amlyoid-beta toxicity, Free Radic. Biol. Med. 30, 447–450 (2001).

44 Nair NG, Perry G, Smith MA et al. NMR studies of zinc, copper, and iron binding to histidine, the principal metal ion complexing site of amyloid-b peptide. J. Alzheimer’s Dis. 20, 57–66 (2010).

45 Moreira PI, Santos MS, Oliveira CR et al. Alzheimer’s disease and the role of free radicals in the pathogenesis of the disease. CNS Neurol. Disord. Drug Targets 7, 3–10 (2008).

46 Bowman GL, Shannon J, Frei B et al. Uric acid as a CNS antioxidant. J. Alzheimer’s Dis. 19, 1331–1336 (2010).

47 Bonda DJ, Wang X, Gustaw-Rothenberg KA et al. Mitochondrial drugs for Alzheimer disease. Pharmaceuticals (Basel) 2(3), 287–298 (2009).

48 Summers WK, Martin RL, Cunningham M et al. Complex antioxidant blend improves memory in community dwelling seniors. J. Alzheimer’s Dis. 19, 429–439 (2010).

49 De la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer’s disease? Neurol. Res. 15, 146–153 (1993).

50 Salmina AB, Inzhutova AI, Malinovskaya A et al. Endothelial dysfunction and repair in Alzheimer-type neurodegeneration: neuronal and glial control. J. Alzheimer’s Dis. 22, 17–36 (2010).

51 De la Torre JC. The vascular hypothesis of Alzheimer’s disease: bench to bedside and beyond. Neurodegenerative Dis. 7, 116–121 (2010).

52 Summers WK, DeBoynton VL, Marsh GM et al. Comparison of seven psychometric instruments used for evaluation of treatment effect in Alzheimer’s disease. Neuroepidemiology 9, 193–207 (1990).

53 Comijs HC, Dik MG, Deeg DJ et al. The course of cognitive decline in older persons. results from the longitudinal aging study Amsterdam. Dement. Geriatr. Cogn. Disord. 17, 136–142 (2004).

54 Petersen RC. Mild cognitive impairment as a diagnostic entity. J. Internal Med. 256, 183–194 (2004).

55 DeKosky ST, Williamson JD, Fitzpatrick AL et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 300, 2253–2262 (2008).

56 Grodstein F, Chen J, Willett WC. High-dose antioxidant supplements and cognitive function in community dwelling elderly women. Am. J. Clin. Nutr. 77, 975–984 (2003).

57 Aisen PS, Schneider LS, Sano M et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 15, 1774–1783 (2008).

58 Jamison RL, Hartigan P, Kaufman JS et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA 298, 1163–1170 (2007).

59 Sabbargh MN. Drug development for Alzheimer’s disease: where are we now and where are we headed? Am. J. Geriatr. Pharmacother. 7(3),167–185 (2009).

60 Grundman M, Black R. Clinical trials of bapineuzumab, a b-amyloid target immunotherapy in patients with mild to moderate Alzheimer’s disease. Alzheimer’s Dement. 4(4), T166 (2008).

61 Wei P, Walls M, Qiu M et al. Evaluation of selective g-secretase inhibitor PF-03084014 for its antitumor efficacy and gasterointestinal safety to guide optimal clinical trial design. Mol. Cancer Ther. 9(6), 1618–1628 (2010).

62 Mandel RJ. CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer’s disease. Curr. Opin. Mol. Ther. 12(2), 240–247 (2010).

63 Pettit GR, Cherry Herald L, Doubek DL, Herald DL, Arnold E, Clardy J. “Isolation and structure of bryostatin 1”. J. Am. Chem. Soc. 104 (24), 6846–6848 (1982).

64 Von Burstin VA, Xiao L, Kazanietz MG. Bryostatin 1 inhibits phorbol ester-induced apoptosis in prostate cancer cells by differentially modulating protein kinase C (PKC) delta translocation and preventing PKCdelta-mediated release of tumor necrosis factor-alpha. Mol. Pharmacol. 78(3), 325–332 (2010).

65 Kuzirian AM, Epstein HT, Gagliardi CJ et al. “Bryostatin enhancement of memory in Hermissenda”. Biol. Bull. 210(3), 201–214 (2010).

PeRsPective Summers


66 Stephens T, Brynner R. Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine. Perseus Books Group, New York, NY, USA, 101–120 (2001).

67 Doody RS, Gavrilova SI, Sano M et al. Effect of dimebon on cognition, activities of daily living, behavior, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Lancet 372(9634), 207–215 (2008).

68 Mitchell TM, Shinkareva SV, Carlson A et al. Predicting human brain activity associated with meanings of nouns. Science 320, 1191–1195 (2008).

69 Gluck M, Mercado E, Myers CE: Chapter 3: episodic and semantic memory In: Learning and Memory (1st Edition). Worth Publishers, NY, USA, 83–122 (2008).

70 Cohen NJ. Preserved learning capacity in amnesia: evidence for multiple memory systems, In: The Neuropsychology of Memory. Squire LR, Butters N (Eds). Guilford Press, NY, USA, 83–103 (2003).

71 De la Torre. Alzheimer’s disease is incurable but preventable. J. Alzheimer’s Dis. 20, 861–870 (2010).

72 Scherder EJA, Bouma A, Steen AM. Isolated TENS in Alzheimer’s disease. Biol. Psychiatry 43, 417–424 (1998).

73 Widerlov E, Brane G, Ekman R et al. Elevated CSP somatostatin concentrations in demented patients parallel improved psychomotor functions induced by integrity promoting care. Acta Psychiatr. Scand. 79, 41–47 (1989).

74 Graf A, Wallner C, Schubrt V et al. The effects of light therapy on Mini-Mental state examination scores in demented patients. Biol. Psychiatry 50, 725–727 (2001).

�� Websites101 Namenda

www.drugs.com/pro/namenda.html. (Accessed 7 May 2011)

102 Selkoe D. The amyloid hypothesis www.alzforum.org/res/adh/cur/knowntheamyloidcascade.asp (Accessed 20 April 2011)

103 NIH Clinical Trials clinicaltrials.gov/ct2/results?term=Alzheimer%27s+disease (Accessed 4 May 2011)

104 Boston Diagnostic Aphasia Examination www4.parinc.com/Products/Product.aspx?ProductID=BDAE (Accessed 18 April 2011)

105 Elan and Transition Therapeutics Announce Modifications to ELND005 Phase II Clinical Trials in Alzheimer’s Disease www.transitiontherapeutics.com/media/news.php

106 Semagacestat, a g-secretase inhibitor www.fiercebiotech.com/special-reports/top-10-phase-iii-failures-2010/semagacestat-top-10-phase-iii-failures (Accessed 7 May 2011)

107 Posiphen, a g-secretase inhibitor www.rxpgnews.com/research/aging/dementia/alzheimers/article_1987.shtml (Accessed 7 May 2011)

108 Latrepirdine fails in clinical trials http://abcnews.go.com/Health/Alzheimers/pfizers-promising-alzheimers-drug-fails-study/story?id=9998774 (Accessed 20 July 2011)

Documents

Current and future treatments of memory complaints and ... · PDF filedrugs that enhanced cholinergic ... The cost of the 5.3 million Alzheimer’s patients in the USA exceeds US$100