Transcript of "Understanding Alzheimer's disease and brain"
Newer drugs in pipeline for
Goal of Clinical Research are to SLOW or STOP
disease progression and PREVENT Alzheimer's
So early diagnosis is essential and various
initiatives are underway to identify at risk
individual, enable early diagnosis and track
Genetics of Alzheimer's Disease
AD has two types, Early onset and Late onset,
and both have genetic links.
1. Early-Onset AD
Early-onset AD is a rare form of AD, affecting only about 5 percent
of all people who have AD. It develops in people ages 30 to 60.
Some cases of early-onset AD, called familial AD (FAD), are
inherited. FAD is caused by a number of different gene mutations
on chromosomes 21, 14, and 1, and each of these muta-tions
forms abnormal proteins. Chromosome21 causes abnormal
amyloid precursor protein (APP). Chromosome 14 causes
abnormal presenilin 1.
Chromosome 1 leads to abnormal presenilin 2.
2. Late-Onset AD
Most cases of Alzheimer¶s are of the late-onset form, developing
after age 60.
One predisposing genetic risk factor is related to the
apolipoprotein E (APOE) gene found on chromosome 19. APOE
contains the instructions needed to make a protein that helps carry
cholesterol in the bloodstream. APOE comes in several different
forms, or alleles. Three forms²APOE e2, APOE e3, and APOE
occur. At present, APOE testing is used in a research setting to
identify study participants who may have an increased risk of
14 January 2007 online ed. of Nature Genetics,
study implicates gene SORL1 in late-onset
SORL1²Sortilin-related, low-density lipoprotein
receptor class A repeat-containing protein.
0 Gene involved in cellular sorting process for APP
Researchers found that when SORL1 is present at
low levels or in a variant form, beta-amyloid levels
increase and may harm neurons
Association with AD has been identified and
confirmed in three separate studies
Alzheimer's disease and brain
Plaques and tangles are the hallmark of
People with AD have lots of two abnormal structures:
-: beta-amyloid plaques, which are dense deposits of protein and cellular
material that accumulate outside and around nerve cells
-: neurofibrillary tangles, which are twisted fibers that build up inside the
Amyloid precursor protein (APP) is the precursor to amyloid plaque.
1. APP sticks through the neuron membrane.
2. Enzymes like alpha-secretase, beta-secretase, and gamma-
secretase cleave APP into fragments of protein, including beta-
amyloid (38 to 42).
3. Beta-amyloid fragments esp 42 are more vulnerable to form
insoluble plaques after inflammatory and oxidative stress.
4. These clumps disrupt the function of neurons ( connection of
neurons and cause death of neurons )
1 2 3
Neurons are internally supported by microtubules
and TAU protein help in stabilizing microtubules.
In Alzheimers TAU is hyperphosphorylated and
this leads to clumping of neurons.
Changes in brain
Other abnormal protein deposits
Reduced oxygen flow to tissues
Four main strategies in anti- amyloid therapy
1. Immunotherapy ( active and passive ) to modify
the process by which Amyloid beta is converted to
2. Secretase inhibitors
3. Selectively reduce beta amyloid 42, by shifting
production to less toxic 38 and 40.(tarenflurbil)
4. Inhibit aggregation of Amyloid beta, inhibiting
plaque formation. (tramiprosate- GAG)
The advances in our knowledge about the
mechanisms and risk factors associated with AD
have expanded the types of interventions under
study. These trials are examining a host of
possible interventions, including cardiovascular
treatments, hormones, type 2 diabetes treatments,
antioxidants, omega-3 fatty acids, immunization,
cognitive training, and exercise, among others.
Summary about the our present understanding of Alzheimer's
Previous works have shown a number of attributes shared by both familial and
sporadic AD. Mutations in the genes for b APP, presenilin-1 or -2, account for
nearly all of the early-onset familial cases of AD. Most late-onset AD is sporadic
yet subject to genetic influences, including the e 4 allele of apolipoprotein E and
a haplotype of polymorphisms in proinflammatory cytokine loci. Therefore, the
ongoing development or pathogenesis of the disease is clearly a complex
pathway involving numbers of complex mechanisms, most likely both genetic
and physiological. New pathogenic mechanisms continue to be suggested by
various methodologies. Most hypotheses include an overproduction or
accumulation of the 42-amino acid form of the amyloid b -peptide, produced from
b APP by the b - and g -secretases. However, there is also evidence for aberrant
phosphorylation, non-enzymatic glycosylation, oxidation, nitrosylation, and other
posttranslational modifications of multiple proteins. Thus, critical insights might
be gleaned from additional understanding of protein levels and alterations.
Phase 1 trials: Small studies in healthy volunteers
or patients that identify drug effects, measure side
effects of different doses, and explore efficacy.(
finding safe dose)
Phase 2 trials: Larger studies in patients that
evaluate efficacy and assess side effects.(screen
to determine the activity against disorder)
Phase 3 trials: Larger studies that build on earlier
results and determine efficacy and safety; results
form basis for FDA approval.
Phase 4 trials: Post- approval studies that provide
more information on risks, benefits, and optimal
Phase III interventional trials
Phase III clinical studies provide the chief
evidence for safety and effectiveness that the U.S.
Food and Drug Administration (FDA) considers in
deciding whether to approve a drug. The following
Alzheimer drugs in Phase III clinical studies are
³interventional drugs´ designed to slow or stop
the progression of the disease
Dimebon, a drug used in Russia for its antihistaminic
effect for over 2 decades, is also a ChEI and
N-methyl-D-aspartate (NMDA) inhibitor, the 2 mechanisms
of action of existing AD drugs. However, it is
now believed that dimebon¶s primary mechanism of
action in AD is stabilization of mitochondrial function.
Dimebon is now in Phase III of clinical development. Phase II
study in patients with mild to moderate AD, in which dimebon
20 mg TID was associated with significant benefit compared with
placebo. The main tolerability finding was a higher rate of incident
depression in the dimebon group compared with the placebo
1. Anti Amyloid immunotherapy (Passive)
Amyloid plaques, another of the pathologic hallmarks of AD, are
abnormal, insoluble, extracellular aggregates of Aȕ peptide.
Immunotherapy employing monoclonal antibodies to Aȕ is designed to
bind to and remove the beta-amyloid peptide that accumulates in the
brains of individuals with Alzheimer's. Bapineuzumab is given as a series
of injections, delivering antibodies to beta-amyloid. This approach is
called ³passive immunization,´ since the body is receiving the antibodies
via the drug, rather than generating the antibodies itself. This drug is
being tested in individuals with mild to moderate Alzheimer's.
Of these, the only one to have reached Phase III trials is bapineuzumab,
the subject of the largest clinical trial program to be undertaken for the
treatment of AD. Neurotoxicity which is a potential serious adverse effect
associated with previous anti-amyloid immunotherapies is addressed in
is another monoclonal antibody against Aȕ
peptide that has completed 1 Phase II trial
Phase III trials were initiated in May 2009 to evaluate
the safety and efficacy of LY2062430 400 mg IV administered
every 4 weeks for 80 weeks.
2. Active immunisation
Based on the amyloid cascade hypothesis, the therapeutic
strategy of active immunization targeting Aȕ has
generated widespread interest. The first-generation Aȕ
vaccine, AN1792, underwent a large Phase I trial, but during Phase
II there was 6% incidence of aseptic meningoencephalitis
led to discontinuation of the AN1792 development
program, many active immunization strategies
are now being pursued in Phase I and II trials like ACC-001 and
CAD106. These vaccines are given and antibody response are
evaluated along with cognitive response.
Aggregated Tau correlates closely with demetia symptoms.
Rember is a Tau- aggregation inhibitor. Phase II trial on
patients with mild to moderate Alzheimer's disease showed
81% reduction in rate of cognitive decline after 50 weeks of
Davunetide intranasal is another Tau-based drug in phase II
trial showing improvement with memory tests.
TRx0014 (Methylthioninium Chloride)
TRx0014 is a proprietary formulation of an old and
well-known drug, methylthioninium chloride (MTC),
or methylene blue, a deep-blue dye used as a tissue
stain in biology, as well as in analytical chemistry and
numerous industrial products (eg, ink). Its investigation
as a potential treatment for AD was based on its
reported ability to interfere with tau aggregation by
acting on self-aggregating truncated tau fragments. Phase II trial of
TRx0014 was success and phase III is expected to start soon.
The neurotoxic Aȕ peptide is generated by cleavage
of APP by ȕ- and Ȗ-secretases. Inhibitors of Ȗ-secretase
thus present an attractive option for AD therapy.
BMS-29989767 and LY411,57568 lowered levels of Aȕ
in the brain in animal studies of Ȗ-secretase inhibitors.
LY450139 is the first selective Ȗ-secretase inhibitor for
the treatment of AD to reach Phase III testing
Insulin, insulin receptors, and insulin-sensitive glucose transporters
are abundant in the medial temporal regions of the brain that
support the formation of episodic memory. Insulin signaling is now
known to play a role in memory functions and may also play a part
in the regulation of APP and Aȕ. In addition, Aȕ accumulation in the
brains of patients with AD may be the result of impaired clearance
of Aȕ by Aȕ-degrading enzymes, including insulin degrading
These findings suggest that insulin-related CNS abnormalities
may cause or exacerbate cognitive impairment, and that treatment
of insulin resistance may reduce the risk of AD or delay its
development. Rosiglitazone, a peroxisome proliferator±activated
receptor-Ȗ agonist originally developed and marketed for the
management of diabetes, is the leading drug in clinical
development for AD based on the insulin resistance hypothesis.
Huperzine A, derived from the Chinese herb Huperzia
serrata, was identified by Chinese scientists in the
1980s as a potent, reversible, and selective
acetylcholinesterase inhibitor. More recently, a variety of
potential neuroprotective effects have been reported that
may be of benefit in the treatment of AD. In a Phase II
conducted in the United States and completed in
November 2007, 210 patients with mild to moderate
AD received huperzine A 400 ȝg PO BID
for 16 weeks showed cognitive improvement. Phase III
CX717 belongs to a therapeutic class known as
ampakines, which are positive allosteric modulators
of AMPA (Į-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid)±type glutamate receptors. Ampakines have been found
to reduce age-associated memory deficits in animal models.
Two different doses of CX717 are being tested in a Phase II
pilot study in patients with mild to moderate AD.
ELND005 (formerly AZD 103) is a cyclohexanehexol
stereoisomer, scillo-inositol. Inositol has 8 possible
stereoisomeric forms, of which 3 are found in the human
brain. Among these, the most common form is myoinositol,
which is available as a nutraceutical. Only scilloinositol
has been found to reduce the accumulation of
soluble Aȕ oligomers and reverse memory deficits in the
brain of transgenic mice. Phase II trial of the safety and
efficacy of 3 doses of ELND005 is underway.
Reduced brain insulin signaling and low CSF-toplasma
insulin ratios have been observed in patients
with AD.72 After intranasal administration, insulinlike
peptides follow extracellular pathways to the
brain within 15 minutes. Insulin significantly improved
scores on measures of working memory
, attention, and functional status. Insulin was also associated
with a significant increase in the Aȕ 40/42 ratio. Phase II trials
of intranasal insulin aspart are currently in progress
Glycogen synthase kinase±3 (GSK-3) activity has
been associated with AD because of its role in the
phosphorylation of tau and regulation of the production
of Aȕ.120,121 Lithium has been found to inhibit
GSK-3 activity122 and to provide a significant and
dosedependent reduction in the expression of GSK-3b,
butnot GSK-3a, that was specific to hippocampal cells.
Despite this suggestive basic science, no
further clinical development of lithium has been pursued
since the 2005 completion of a small Phase II trial.
Ongoing concerns about the safety, tolerability, and
monitoring requirements associated with clinical use of
lithium constitute a serious impediment to its further
development for the prevention of AD.
Phosphodiesterases (PDEs) are an important family
of proteins that regulate intracellular levels of cyclic
adenosine monophosphate. Compounds that inhibit
PDE4 are neuroprotective, neuroregenerative, and antiinflammatory,
and preclinical studies have indicated
that PDE4 inhibitors may counteract deficits in longterm
memory caused by overexpression of mutant
forms of human APP. A Phase II trial of the PDE4
inhibitor was completed in late 2007, results yet to publish.
PBT2 is a metal protein±attenuating compound that
affects the Cu2(+)- and Zn2(+)-mediated toxic oligomerization
of Aȕ seen in AD. As such, it is considered
an antifibrillar agent with a unique mechanism of action.
The receptor for advanced glycation end products
(RAGE) has been found to bind to Aȕ and mediate its
transport across the blood±brain barrier.134 A series of
elegant experiments in mouse brain slices of entorhinal
cortex (the first area of the brain to exhibit damage in
AD) indicated that the RAGE±Aȕ complex suppresses
long-term potentiation, at least in part via activation
of p38 mitogen-activated protein kinase.Thus suggested that an
inhibitor of RAGE might have therapeutic benefit in AD. A large
Phase II safety and efficacy trial is now underway.
PRX-03140 is a highly selective, small-molecule agonist
of 5-HT4, a specific G-protein±coupled receptor.
In preclinical studies, PRX-03140 was found to improve
cognitive function by increasing levels of acetylcholine,
soluble APP, and brain-derived neurotrophic
factor in regions of the brain known to be important
for memory. PRX-03140 has entered Phase IIb
Raloxifene, a selective estrogen-receptor modulator,
is approved for the treatment and prevention of osteoporosis
in postmenopausal women. After 3 years of treatment, the 120-mg
dose, but not the 60-mg dose, was associated with a reduction in
risk for MCI (RR = 0.67) or AD (RR =
0.52). This finding, supported by evidence suggesting
that estrogen may have a protective effect against
Dementia, led to the clinical development of raloxifene
for the treatment of AD. Phase II trial underway.
RO5313534 is a partial nicotinic Į7±receptor agonist.
Three doses of RO5313534 were evaluated in a Phase IIa trial in
80 patients with mild to moderate AD.
SB742457, a small-molecule antagonist of 5-HT6, is
in the second round of Phase II testing. In preclinical
studies, antagonists of 5-HT6 were found to variably
enhance cholinergic, glutamatergic, noradrenergic,
and dopaminergic neurotransmission; in human studies,
they were associated with benefit in terms of several
tests of learning and memory.
SK-PC-B70M is composed of the oleanolic glycoside
saponin±enriched fraction of Pulsatilla koreana (Korean
pasque flower), which has been found to have
neuroprotective and cognition-enhancing effects in animal
models. A Phase II study in patients with mild to
moderate AD was completed in January 2009.
Omega-3 Fatty Acids
Docosahexaenoic acid- omega-3 Fatty acid found
in fish oil slower the rate of cognitive decline in
patients who did not carry the apolipoprotein E 4
From all these one thing seems clear: if disease
modifying drugs are to be effective in slowing or
stopping Alzheimer's disease, they should be
administered early in the course of the disease,
ideally before symptoms become apparent. Thus
reinforcing the need to identify high- risk
individuals as early as possible.
There is a great deal of hope that with early
diagnosis and effective treatment, Alzheimer's
disease will become a preventable and treatable
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