Alzheimer

Alzheimer’s disease: what is new
in detection and treatment
Dr. Doha Rasheedy Ali
Lecturer of Geriatric medicine
Ain Shams University

Histopathology of Alzheimer’ s
dementia
1. Neuronal degeneration
2. Intracellular deposits known as neurofibrillary
tangles (NFTs).
3. Extracellular deposits known as senile plaques
(SPs).

NFTs structure
• Neurofibrillary tangle is composed of abnormal
fibrils measuring 10 nm in diameter that occur in
pairs and are wound in a helical fashion with a
regular periodicity of 80 nm.
• The primary constituent of the neurofibrillary
tangle is the microtubule-associated protein tau.
The tau within neurofibrillary tangles is
abnormally phosphorylated.
• There are a number of other protein constituents
associated with the neurofibrillary tangle, such as
ubiquitin, cholinesterases, and beta-amyloid

Distribution of NFTs
• Severe involvement is seen in:
1. the layer II neurons of the entorhinal cortex,
the cornu ammonis 1 and subicular regions of
the hippocampus, the amygdala,
2. the deeper layers (layers III, V, and superficial
VI) of the neocortex.
The extent and distribution of neurofibrillary
tangles in cases of Alzheimer's disease correlate
with both the degree of dementia and the
duration of illness.

SPs structure
• Extracellular polymorphous amyloid deposits
found in the brain most prominently in Alzheimer
disease but also in normal aging.
• Their 6- to 10-nm-wide filaments consist of a 39-
to 42-amino acid β-amyloid protein (β-AP) which
is derived from proteolysis of transmembrane
amyloid precursor protein (APP)
• A β is a normal cellular product and is present in
nanomolar concentrations in biological fluids, at
higher concentrations, it is extremely insoluble
and precipitates to form aggregates

• The most characteristic form of the amyloid
plaque, is characterized by a dense core of
aggregated fibrillar Aβ, surrounded by
dystrophic dendrites and axons, activated
microglia, and reactive astrocytes.
• The diffuse plaques: diffuse deposits of Aβ,
likely representing a prefibrillary form of the
aggregated peptide, are found without any
surrounding dystrophic neurites, astrocytes,
or microglia. These diffuse plaques can be
found in limbic and association cortices, as
well as in the cerebellum.

Vascular Amyloid Deposition
(Congophilic Angiopathy)
• Amyloid β protein accumulates in the walls of
small arteries and arterioles of the
leptomeninges and within the gray matter of
the cerebral cortex.
• These accumulations of Aβ within the vessel
walls do not appear to clog the vascular
lumina or otherwise interfere with the
function of these vessels.

• However, when the degree of vascular involvement is
severe, there is a tendency for spontaneous vascular
rupture leading to a focal accumulation of blood in the
brain tissues. Such hemorrhages are generally not
encountered in and around the lenticular nuclei and
thalamus, such as is seen as a result of uncontrolled
systemic hypertension.
• These hemorrhages tend to occur in the white matter
of the frontal and/or occipital poles, are often small
and multiple, and may be microscopic in size.
• When they are large (this is a relatively rare situation),
they may be multiple and are commonly called lobar
hemorrhages. Although rare, such lobar hemorrhages
represent one of the few fatal intracerebral
complications of Alzheimer's disease.

Granulovacuolar Degeneration
• This is a poorly understood lesion that consists of an
intraneuronal cluster of small vacuoles measuring 2
to 4 μm in diameter, each containing a small, dense
basophilic granule that typically measures
approximately 1 μm in diameter.
• Little is known about the nature of these lesions or
their significance. They are seen in brain specimens
derived from elderly individuals with normal
cognitive function.
• large numbers of such lesions in the boundary zone
between the CA1 and CA2 regions of the caudal
aspect of the hippocampus correlate well with a
diagnosis of Alzheimer's disease

Eosinophilic Rodlike Inclusions
(Hirano Bodies)
• intensely eosinophilic perineuronal lesions
encountered within the CA1 region of the
hippocampus.
• Identical inclusions in much smaller numbers are also
noted in some, but not all, cases of Alzheimer's
disease. Hirano bodies may also occasionally be
encountered in the brains of normal aged individuals
with intact cognition.
• Hirano bodies have a very characteristic ultrastructural
appearance consisting of parallel fibers that interweave
in a very regular crossing pattern reminiscent of the
appearance of a tweed fabric.

Synaptic Loss
• Masliah and coworkers have shown a 45% loss of
the extent of staining of presynaptic boutons in
cases of Alzheimer's disease in comparison with
normal controls and have argued that this loss of
the critical element for neuron-to-neuron
communication constitutes the major
morphological counterpart to cognitive loss in
Alzheimer's disease.

PATHOBIOLOGY OF ALZHEIMER’S
DISEASE

Amyloid Precursor Protein Processing
and Generation of Aβ
• (APP)
The β cleavage
sβAPP + β- APP-CTF
the ϒ cleavage
Aβ 40, Aβ 42
Removal to Extracellular matrix
oligomerization and aggregation
fibrils and amyloid plaques

• β-secretase, also called BACE1 (beta-site APP
cleaving enzyme 1)
• γ -secretase, a multimeric protein complex
containing presenilin, nicastrin, Aph-1, Pen-2,
and CD147.
• Proteolysis of APP with β secretase result in: a
large N-terminal fragment of the protein
(sβAPP) that is released in the extracellular
space and a small (∼12 kDa) membrane-
anchored fragment called β- APP-CTF (or C99).

The molecular mechanisms underlying the toxicity of Aβ
1. Inside the brain, Aβ is capable of forming a high-affinity
complex with the neuron-associated α7-nicotinic
acetylcholine receptor, leading to its subsequent endocytosis.
The resulting increase in neuronal Aβ burden eventually
causes cell lysis and ensuing extracellular accumulation of Aβ.
2. In addition to the nicotinic acetylcholine receptors, Aβ binds
to a variety of other receptors, including
neurotransmitter receptors, toll-like receptors, NOD-like receptors,
formyl peptide receptors, scavenger receptors, complement receptors,
pentraxins as well as the receptor for advanced glycation products
expressed on astrocytes, microglia and neurons.
These interactions induce the production of proinflammatory
molecules through signaling pathways, most of which involve
activation of microglia, and eventually culminate in neuronal
death

another molecular mechanisms of the
neurotoxicity
the C-terminal tail of APP can undergo further
processing at amino acid 664 of APP695 liberating
two small cytosolic fragments, Jcasp (from aa. 649
to 664 of APP695) and C31 (containing the last 31
amino acids of the C-terminus of APP, from aa. 665
to 695). Both these fragments are generated only
after γ cleavage, require caspase-mediated
processing of APP, and can activate proapoptotic
pathways in a variety of cellular systems

Biomarkers
• Researchers hope to discover an easy and
accurate way to detect Alzheimer's before
these devastating symptoms begin.

Brain Imaging/ neuroimaging
1. Structural
2. Functional
3. Molecular

A) Structural imaging
• studies have shown that the brains of people
with Alzheimer's shrink significantly as the
disease progresses.
• Research has also shown that shrinkage in
specific brain regions such as the hippocampus
may be an early sign of Alzheimer's.
• However, scientists have not yet agreed upon
standardized values for brain volume that would
establish the significance of a specific amount of
shrinkage for any individual person at a single
point in time.

QUANTITATIVE MAGNETIC RESONANCE
IMAGING BIOMARKERS
1. VOLUMETRIC MAGNETIC RESONANCE IMAGING:
• Medial temporal regions, such as the entorhinal cortex
and hippocampus, are typically affected earliest.
• Later on, atrophy affects lateral temporal as well as
medial and lateral parietal association cortex followed
by frontal regions and, finally, primary sensorimotor
cortices.
• So, It is not surprising that the hippocampus has been
targeted as the structure most likely to provide a reliable
volumetric biomarker of neurodegeneration in AD.
However, hippocampal atrophy is not specific to AD, nor is
all AD associated with severe hippocampal atrophy

Identifying the cut off volume
• The effects of age and intracranial volume, and
possibly gender and race, must be accounted for.
• An individual’s prior history of brain trauma,
alcoholism, drug abuse, and vascular risk factors
such as hypertension and smoking, would also likely
influence the measure, so it is unlikely that a
distinct “cutoff ” in hippocampal volume could be
identified that will reliably predict AD risk across
patients.
• However results showed a volume loss of 20% in
the hippocampus already present at a mild stage of
AD dementia.(Karow DS et al. 2010)

Volumetric assessment of combined
regions
• The combination of regions, naturally, improves classifier
sensitivity and specificity beyond that achieved through the
use of a single region.
• However, derivation of regional cortical volume or thickness
is more challenging and computationally expensive than
derivation of volumes for most subcortical structures, such as
the hippocampus and ventricular subregions.
• Hippocampal and wider medial temporal lobe (MTL)
degeneration is often associated with expansion of the
temporal horn of the lateral ventricle. Therefore, temporal
horn volumetry with comparison to normative values could
support that the individual’s hippocampus was previously
larger and had undergone degeneration, as opposed to
having been congenitally small.

• 2. diffusion tensor imaging (DTI)
• An assessment of white matter fibers using the
imaging technique of DTI has revealed that the
fibers connecting the hippocampus and
posterior cingulate gyrus are impaired in AD).
• The most commonly used index is fractional
anisotropy (FA) that is determined by the degree
of directionality (anisotropy) of the movement of
the water molecules. A reduced FA value is
reflective of axonal degradation and myelin
damage in the brain.
• However, it remains to be seen whether it can be
affected in preclinical stage.

B)Functional imaging
• functional MRI:Types: task-dependent fMRI and task-free, or
“resting-state,” fMRI (rsfMRI).
• the blood oxygenation dependent (BOLD) signal is used to
measure blood flow and blood oxygenation, which is believed
to correlate with changes in neuronal activity at a time scale
of a few seconds
• POSITRON EMISSION TOMOGRAPHY (FLUORODEOXYGLUCOSE IMAGING):
measures of brain glucose metabolism and cerebral blood
flow are markers of synaptic dysfunction, typically obtained
during resting state, but can be task dependent. A
characteristic pattern of hypometabolism in the
temporoparietal region of the cortex, which is involved in
episodic memory function, is present at the AD dementia
stage

Preclinical imaging
• FDG-PET hypometabolism in a subset of cognitively
normal subjects that carry the ApoE ε4 allelle have
detected changes in a subset of regions affected in AD
and these changes predict progression to MCI
• Functional MRI: Hyperactivation within the
hippocampus memory network during memory
performance occurs early in the MCI phase but
reduced hippocampus activation is visible shortly
before progressing to dementia, suggesting that such
hippocampus hyperactivation is a transient sign
impending clinical worsening.
• Therefore, resting state fMRI may be a more sensitive
measure than FDG PET to detect early changes
associated with AD pathology

C) Molecular imaging technologies
• are among the most active areas of research aimed at finding new
approaches to diagnose Alzheimer's in its earliest stages. Molecular
strategies may detect biological clues indicating Alzheimer's is under way
before the disease changes the brain's structure or function, or takes an
irreversible toll on memory, thinking and reasoning. Molecular imaging
also may offer a new strategy to monitor disease progression and assess
the effectiveness of next-generation, disease-modifying treatments.
• Several molecular imaging compounds are approved: a radioactive tracer
binds to beta-amyloid in the brain. It can be visualized during a positron
emission tomography (PET) brain scan, thereby revealing the presence of
amyloid plaques in the brains of living patients.
1. In 2012, the U.S. Food and Drug Administration approved the first
molecular imaging tracer for (brand name Amyvid but also known as
florbetapir F-18) PiB-PET
2. A second molecular imaging tracer (brand name Vizamyl but also known
as flutametamol F18) was approved in 2013.
3. A third molecular imaging tracer (brand name Neuraceq but also known
as florbetaben F18) was approved in 2014

• amyloid imaging is not recommended for routine
use in patients suspected of having Alzheimer's
disease.
• A Task Force of the Society of Nuclear Medicine
and Molecular Imaging (SNMMI) and the
Alzheimer's Association has published criteria in
which they believe the use of amyloid imaging
would be appropriate

Appropriate for
1. Patients with persistent or progressive
unexplained MCI
2. Patients satisfying clinical criteria for possible
AD because of unclear clinical presentation,
either an atypical clinical course or an
etiologically mixed presentation
3. Patients with progressive dementia and
atypically early age of onset (usually defined
as 65 years or less in age)

Not appropriate for
1. Patients with core clinical criteria for probable AD with
typical age of onset
2. To determine dementia severity
3. Based solely on a positive family history of dementia or
presence of apolipoprotein E ( APOE ) ε 4
4. Patients with a cognitive complaint that is unconfirmed
on clinical examination
5. Instead of genotyping for suspected autosomal mutation
carriers
6. In asymptomatic individuals
7. Nonmedical use (e.g., legal, insurance coverage, or
employment screening)

• Neuroimaging methods are capable of detecting
substantial brain changes not only in subjects with
AD dementia, but also in subjects in the mildly
symptomatic MCI due to AD and even in cognitively
normal subjects who may be in the preclinical stage
of AD

• Amyloid Beta
• Αβ 42 levels are decreased in cerebrospinal fluid
of Alzheimer’s disease patient (Frosch et al.,
2010). However, Aβ-40 is unchanged. In order to
find a biomarker which is more specific,
Ab42/AB40 ratio was calculated and found to be
useful in early and clinical phases of Alzheimer’s
disease

• CSF-Tau:
• Increased CSF-tau is present during the whole
course of the disease in Alzheimer’s disease
which suggests that it may be present before the
onset of clinical dementia.
• elevations of t-tau (total tau) and p-tau
(phosphorylated tau) 181, are sensitive
indicators of presymptomatic disease

Combined CSF tau, Aβ-42
• CSF ratio of phospho-tau to Aβ-42 is more
useful and can be recommended as an aid for
evaluating individuals suspected of dementia
due to Alzheimer’s disease

Pre clinical stage
• In MCI: Abnormal levels for Aβ-42 (<495pg mL-1)
and tau (>356 pg mL-1) were accompanied by
increased risks for progression to Alzheimer’s
disease
• Approximately 90 percent of patients with mild
cognitive impairment and pathologic
cerebrospinal fluid biomarkers will develop
Alzheimer’s disease within 9.2 years. Therefore,
these markers can identify individuals at high risk
for future Alzheimer’s disease least five to ten
years before conversion to dementia.

• Aβ42 levels, Aβ40 levels , Aβ42 /40
• about 26 investigations have been performed to evaluate
both Aβ40 and Aβ42 as useful diagnostic markers.
However, the results of these studies were contradictory
because some report an association between a decline in
plasma Aβ40 and Aβ42 levels as well as in the Aβ42/Aβ40
ratio with development of AD, while other studies found
no correlation between plasma Aβ and AD.
• factors associated with Aβ plasma levels are age,
creatinine levels , high density lipoproteins , body mass
index , race and sex .
• Like CSF levels, plasma levels show a circadian fluctuation.
Therefore, standardization of sampling time is important.
• further clinical research and assay development are
needed before measures of plasma Aβ can be interpreted
as biomarkers for AD.

PLASMA TAU FORMS
• using classic systems tau is virtually undetectable in
MCI and/or AD.
• Recently, an ultra-sensitive immunoassay for
quantification of tau protein in serum samples was
published and is based on antibodies reacting with all
tau isoforms, both normal and phosphorylated tau.
• Preliminary data also show increased serum tau levels
in AD patients, with about twice as high levels as in
cognitively normal elderly. These data suggest that
serum tau may have a potential as a screening tool for
the identification of AD

PLASMA PROTEOMICS
• 18-plasma protein profile, consisting of endocrine and hormone-like
proteins, which identified AD patients from controls with a high
specificity. But clinically significant protein markers of AD did not
replicate across cohorts.
• ↑NT-proBNP, CRP, pancreatic polypeptide, fatty acid binding
protein, etc.
• plasma Beta-site APP Cleaving Enzyme (BACE-1), and soluble forms
of Amyloid Precursor Protein were found to significantly elevated in
plasma from AD patients, which may offer diagnostic value in AD.
• cystatin C, A1AcidG, ICAM1, CC4, pigment epithelium-derived
factor [PEDF], A1AT, RANTES, ApoC3) were strongly associated
with disease severity and disease progression
• These markers were characterized by a good diagnostic value in
correctly classifying AD patients and HCs that may in addition entail
a value in progression from MCI to AD.

• complement factor H [CFH] and alpha-2-
macroglobulin [A2M]) serum amyloid P (SAP),
complement C4 (CC4), and ceruloplasmin, all of
which have been implicated in AD pathogenesis.
• Clusterin, also known as apolipoprotein J, is a
heterodimeric glycoprotein expressed in the
majority of mammalian tissues is associated with
hippocampal atrophy and clinical progression.
• Transthyretin (TTR) and apolipoprotein A1
(ApoA1) to be associated with faster declining AD
subjects

• Neuronal and glial derived proteins (such as S100B
have also been studied in this regard. Glial derived
protein S100B (S100 calcium binding protein B) is
responsible for, proliferation of melanoma cells,
neurite extension stimulation of Ca2+fluxes,
astrocytosis and axonal proliferation, inhibition of
PKC-mediated phosphorylation and inhibition of
microtubule assembly.
• In a developing brain it functions as a neurotrophic
factor and neuronal survival protein. Hence, serum
levels of S100B are studied as a marker for brain
functional condition reflect morphological status in
AD. serum levels of S100B are significantly reduced
with a positive correlation between S100B levels and
AD severity.

• Individual blood biomarkers have been
unsuccessful in defining the disease pathology,
progression and thus diagnosis. This directs to
the need for discovering a multiplex panel of
blood biomarkers as a promising approach with
high sensitivity and specificity for early diagnosis

Biomarkers associated with vascular
risk, metabolic and inflammation states
• Total cholesterol:
Evidence from cell culture and animal studies
demonstrate that the production, aggregation, deposition
and recycling of cerebral Aβ as well as its neurotoxicity
may be modulated by cholesterol.
However, we still do not have a complete understanding
of how cholesterol levels can influence AD pathogenesis,
and despite early evidence from observational studies
that cholesterol lowering by statins might reduce the risk
of dementia.

Oxysterols
• The brain eliminates excess cholesterol by excreting
two oxidized oxysterols into the circulation:
24Shydroxycholesterol and 27-hydroxycholesterol
• Levels of 24S-hydroxycholesterol appear to reflect
brain production (and number of neurons) as well as
hepatic elimination.
• Although evidence suggests that oxysterols play a
role in AD pathogenesis by interacting with Aβ and
regulating astrocytic production of APOE, the precise
mechanisms are not clear.
• data on the association of circulating oxysterols with
incident dementia are scarce.

• Homocysteine, vitamins B12 and folate, and
related metabolites:
• Plasma homocysteine and methylmalonic acid,
and more recently holotranscobalamin, have been
shown to be better indicators of vitamin B12
status and associated with risk of incident
dementia and AD.
• Considerable evidence suggests that an elevation
of total plasma homocysteine (tHcy) is associated
with a subsequent higher risk of AD. The
mechanisms underlying this association remain
uncertain and it is not clear whether tHcy is an AD
risk factor or merely a risk marker.

Possible mechanisms:
1. Homocysteine promotes calcium influx and generation of
toxic free oxygen radicals, thus accelerating DNA damage
within hippocampal neurons
2. A metabolite of homocysteine, homocysteic acid,
activates excitotoxic glutamatergic N-methyl-D-aspartate
receptors
3. Elevated tHcy levels promote the homocysteinylation of
proteins, thus altering protein function
4. inhibit Na+/K+-ATPase activity
5. Homocysteine increases presenilin-mediated Aβ
generation and potentiates the neurotoxicity of insoluble
Aβ deposits
6. promotes tau hyperphosphorylation
7. Homocysteine could increase dementia risk via its
vasculotoxic effects on large arteries

Insulin and amylin
• Diabetes is associated with a higher risk of dementia,
possibly due to dysfunction in insulin signaling pathways in
the brain since peripheral and perhaps central insulin
resistance is a defining characteristic of type 2 diabetes.
• The mechanisms underlying the insulin–dementia
association are not clear, and may include decreased
clearance of Aβ by the insulin-degrading enzyme (which
preferentially binds insulin but has a physiological role in
Aβ clearance), increased tau hyperphosphorylation, or an
indirect effect such as potentiating vascular injury or the
adverse effects of inflammation.
• Amylin, or islet amyloid polypeptide, an amyloidogenic
peptide hormone produced by the pancreas along with
insulin, was recently shown to be present in the brains of
persons with AD but a prospective association of
circulating amylin levels and risk of AD has not been
demonstrated.

PLATELET MEMBRANE PROTEOME AS A
SOURCE OF PERIPHERAL BIOMARKERS
FOR ALZHEIMER’S DISEASE

platelets share many similarities with synaptic terminals in neurons
and have been used as a model for studying synaptic vesicle
metabolism.
1. both platelets and neurons secrete and respond to
neurotransmitters and share many of the same secretory pathways
and transporters for neurotransmitter uptake and packaging.
2. Platelets also contain a high concentration of amyloid precursor
protein (APP) and possess α, β, and ϒ –secretases.
3. Increased levels of activated platelets have been reported in
patients with early AD compared to healthy, age-matched controls,
and the platelet activation state has been positively correlated with
the rate of cognitive decline measured by the mini mental status
exam (MMSE). However, some studies [JAREMO et al., 2012]
reported a decrease in platelet activity in AD.
4. studies have reported that patients with amnestic mild cognitive
impairment (MCI) with elevated levels of activated platelets were at
an increased risk of progression to AD within 3 year

Whole platelet proteome and subproteomes have been profiled using
liquid chromatography coupled with tandem mass spectrometry (LC-
MS/MS)
• 144 proteins were determined significantly altered in the platelet
membrane proteome in patients with probable AD.
• In particular, proteins encompassing the α -secretory granule
pathway including α, β, and ϒ -chains of fibrinogen,
thrombospondin-1 (THBS1), von Willebrand factor and fibronectin
were dramatically reduced in AD.

Calmodulin in lymphoblast
• There is a functional relationship between
Ca2+/calmodulin (CaM) and the main signaling
pathways controlling cell survival or death depending
upon growth factor availability. current evidence
relates the process of neuronal apoptosis occurring in
AD to the aberrant re-entry of differentiated neurons
into the cell cycle
• Researches detected significantly increased levels of
CaM in AD lymphoblasts.
• CaM level was higher in AD > MCI> controls. Thus it is
considered a useful biomarker to help in early
diagnosis of AD, enabling one to discriminate AD
from other dementias with high levels of sensitivity
and specificity.

BUCCAL CELLS ASSOCIATED
ALZHEIMER MARKERS

Buccal micronucleus cytome
biomarkers
• Frequencies of basal cells (P < 0.0001),
condensed chromatin cells (P < 0.0001) and
karyorrhectic cells (P < 0.0001) were found to
be significantly lower in Alzheimer’s patients.
• These changes may reflect alterations in the
cellular kinetics or structural profile of the
buccal mucosa, and may be useful as potential
biomarkers in identifying individuals with a
high risk of developing AD

Altered Cytological Parameters in Buccal
Cells(Francois et al.,2014)
An automated buccal cell assay was developed using laser scanning
cytometry (LSC) to measure buccal cell type ratios, nuclear DNA
content and shape, and neutral lipid content of buccal cells.
• DNA content was significantly higher in all cell types in both MCI
(P<0.01) and AD (P<0.05) compared with controls.
• Abnormal nuclear shape (circularity) was significantly increased in
transitional cells in MCI (P<0.001) and AD (P<0.01) when
compared to controls.
• In contrast, neutral lipid content (as measured by Oil red O “ORO”
staining) of buccal cells was significantly lower in the MCI group
(P<0.05) compared with the control group.
• The ratio of DNA content/ORO in buccal basal cells for both MCI
and AD was significantly higher compared to the control group.
• The changes in the buccal cell cytome observed in this study could
prove useful as potential biomarkers in identifying individuals with
an increased risk of developing MCI and eventually AD.

• Anosmia or olfactory dysfunction resulting in loss of smell
is common in neurodegenerative diseases such as
Parkinson’s or AD and may appear as one of the early
symptoms.
• Furthermore, olfactory dysfunction has been found to be
commonly associated with memory deficiency in
transgenic mouse models of AD.
• the olfactory epithelium exhibited increased oxidative
damage in AD. HNE-pyrrole (a product of lipid oxidation)
and heme oxygenase-1 (a catalytic enzyme involved in
degradation of heme) levels were found to be increased in
neurons and epithelial cells from olfactory biopsy sections
in AD compared to healthy controls.
• Immunohistochemistry showed Increased levels of Aβ and
hyperphosphorylated Tau were also observed in the
olfactory epithelium in AD.

• Many different biomarkers in different
peripheral tissues were examined and
contradictory results were obtained.
• This is an important field of ongoing research.
Hopefully simple non invasive biomarker will be
found.

• The symptomatic drugs currently on the
market for Alzheimer’s disease (AD) have no
effect on disease progression

• Therapeutic Targets Focusing on A𝛽 Cascade
Hypothesis:
• Inhibition of A 𝛽 Production:
• 𝛽-Secretase (BACE1) Inhibitor: further testing
indicated that the drastic inhibition would result
in hypomyelination and behavioral abnormalities
such as seizures. This is because, except from
APP, BACE1 has a series of substrates, like
neuregulin-1, related to myelination
(Thiazolidinediones can activate PPAR𝛾 to inhibit
𝛽-secretase and promote ubiquitination to
degrade amyloid load. MK- 8931, LY2886721 are
in phase 1 trial

• 𝛾-Secretase Inhibitors (GSI) and Modulators Several
𝛾-secretase inhibitors (GSIs) have been launched in
clinical trials. Many reduced the A𝛽 production in
plasma or CSF but few successfully avoided the side-
effects. Haematological and gastrointestinal toxicity,
skin reactions, and changes to hair color
• Semagacestat is the first 𝛾- secretase inhibitor that
have been taken into Phase 3 clinical trials. however
they were discontinued due to increased risk of skin
cancer and infection and lack of efficacy
• Avagacestat (BMS-708163), begacestat, and NIC5-15
are such Notch-sparing GSIs under clinical trials.

• the concept of 𝛾-secretase modulators (GSMs) was
established with the expectation of nonsteroidal anti-
inflammatory drugs (NSAIDs). A subset of NSAIDs, like
ibuprofen, indomethacin, and sulindac sulfide,
disconnected from their cyclooxygenase (COX) properties
were discovered to be able to selectively reduce the
production of A𝛽42 at the cost of elevated shorter
peptide A𝛽38. This finding promoted the GSMs as
promising therapeutic candidates for Alzheimer’s disease,
however, clinical trials were disappointing. The weak
potency of tarenflurbil can be attributable to low CNS
penetrationas shown in phase 1 trial
• Another GSM CHF-5074 based on R-flurbiprofen
ameliorated brain A𝛽 load and improved the animals’
performance in behavior tests. The drug’s safety and
tolerability have been evaluated and are undergoing a
phase 2 trial.

𝛼-Secretase Activator.
• Agonists of muscarinic, glutamate, and serotonin receptors,
statins, oestrogens, testosterone, and protein kinase C
activators belong to this drug classification that can motivate
𝛼-secretase activity, and they have been launched in clinical
trials, but data indicating their use in AD is limited.
• Etazolate (EHT-0202), a selective GABAA receptor modulator,
has completed a phase 2 trial in patients with mild to
moderate AD.
• Bryostatin-1, a macrocyclic lactone, caused a decline of brain
A𝛽40/42, improved behavior test in AD mouse model and
was under a phase 2 trial, but the specific information is
inaccessible.
• A follow-up study evaluating one year simvastatin treatment
in 120 cognitively normal and middle aged adults, effect on
CSF levels of A𝛽42, t-tau, and p-tau181, is ongoing.

Anti- 𝛽-Amyloid Aggregation
• Antiaggregates.
• Metal Complexing Agents
• Active Immunization
• Passive Immunization

Antiaggregates
1. tramiprosate, derived from proprionic acid
demonstrated poor CNS penetration and the weak
potency.
2. Scyllo-inositol is thought to effectively impede A𝛽
aggregation, promote misfolding, modulation, and
accelerate aggregates disassociation, can cross blood
brain barrier, in phase 2trials.
3. Epigallocatechin-3-gallate (EGCg), a polyphenol from
green tea, via disrupting unfolded peptide,
stimulated 𝛼-secretase activity and inhibited A𝛽
aggregation in animal models, a phase 3 trial with
early AD patients with EGCg is being conducted.

Metal Complexing Agents.
• After A𝛽 peptides were produced and released into
extracellular fluids, metals like Zn and Cu can motivate
oligomerization into fibrils, so chelators or metal
complexing agents that can interfere with reaction of
metal ions with A𝛽 are likely to be a therapeutic
strategy.
• Clioquinol (PBT2), metal-induced A𝛽 inhibitors, also
has a potent CNS permeability. PBT2 can redistribute
metal ions to neurons promoting metalloproteinase
expression and thus an increment of A𝛽 degradation. A
phase 2 trial was completed and it proved a decrease
of A𝛽42 concentration in CSF and an improvement of
cognitive and behavioral performance

active immunization
• In 1999, Schenk et al published the first active
immunization study in transgenic mouse model. Initial
findings revealed a reduction of plaque deposition in
aged mice after administration of Aβ-42. Treatment in
young mice prevented Aβ plaque formation. No signs
of damage were observed in the brains of treated
animals.
• Later, two other groups reported the immunization of
different AD mouse models using aggregated Aβ-42
improvement in cognition was observed by evaluation
with the Morris water maze which correlated with
reduction of amyloid plaque burden.

• Not only full Aβ1–42 immunizations effective, but
fragments of Aβ peptide including tandems of
Aβ(1–15) also induced reduction of plaque load
and lowered levels of Aβ-40 and Aβ-42 in the
brain, which correlated with an efflux of Aβ to the
blood.
• Complications for Aβ immunization, included
microbleeds and iron deposits in the choroid
plexus

Passive immunization
• Studies in mice immunized with mouse
monoclonal antibodies against Aβ peptide
indicated that the antibody can cross the blood–
brain barrier and reduce amyloid plaques as
well as levels of soluble Aβ-42.

Summary of clinical trials of immunization

• According to reports published in the New England
Journal of Medicine, the phase 3 clinical trials of
two high-profile Alzheimer’s disease (AD)
antibodies against the aggregation-prone peptide
amyloid beta (Aβ), bapineuzumab and
solanezumab, have failed to improve clinical
outcomes in patients with late onset AD (2014)

SMER28: accelerating the breakdown
of beta-amyloid by autophagy
•autophagy is a process reduces the buildup of beta amyloid
in isolated cells and might be utilized to eliminate the
buildup of beta-amyloid in the brains of Alzheimer’s patients.
• Autophagy is a process cells use to “clean out” the debris
from their interiors, including unwanted materials such as
the protein aggregates that are hallmarks of Alzheimer’s
disease.
• The scientists discovered that a compound called SMER28
lowers the level of beta-amyloid found in nerve cells. This
occurs because SMER28 stimulates autophagy, which then
rids the cell of beta-amyloid.

• Inhibit abnormal phosphorylation
• Inhibit aggregation

Kinase Inhibitors
• Protein kinase, a group of critical enzymes responsible for tau
overphosphorylation, is a prerequisite for the tau-induced
toxicity.
• redundancy of kinase interactions and uncertainty of which
enzyme specifically catalyzes the phosphorylation that we are
focusing on, are major challenges in research.
• glycogen synthase kinase 3 beta appears to engage in AD
pathogenesis given its impact on cellular signaling and gene
description, it is responsible for 31% of the pathological
phosphorylation sites of tau protein.
• Lithium and valproate reduced tau phosphorylation and
prevented reversed aspects of tauopathy in animal models but
did not show cognitive improvement in clinical trials with AD
patients.
• Development of some paullone, indirubin, and maleimide
family-derived GSK3𝛽 inhibitors is stuck in the preclinical trials
concerning the cytotoxic effects.

• Cyclin dependent kinase 5 (cdk5) is another
kinase tightly associated with tau pathology. Cdk5
regulating protein was found in AD brain and thus
is probably causing a pathophysiological tau
phosphorylation .
• Cdk5-selective inhibitors were demonstrated to
penetrate BBB and reduce elevated A𝛽 level by
regulating cdk5and are at preclinical status.
• The test of several compounds targeting other
protein kinases, like cdk1/2/9, p38, Erk1/2, JNK,
casein kinase, and DYRKIA brought disappointing
outcomes, and trials were discontinued due to
the poor efficacy or severe adverse effects.

Inhibition of Tau Aggregation
• Methylene blue) is a tau antiaggregant. Preclinical
data revealed a learning deficit reversing property
and a completed phase 2 trial proved that this agent
can slow down AD progression with a good
bioavailability.
• TRx0237, another methylene blue, has an improved
drug absorption, bioavailability, and tolerability.
Since 2008, intensive investigation of this agent
began, and growing evidence indicated that TRx0237
benefits neuroprotection and A𝛽 clearance in
transgenic mice and improves spatial learning in rats.
The antiaggregation properties were reported by
some papers, and three phase 3 studies are ongoing.

• Epothilone D (BMS-241027) is a microtubule stabilizer, via
inhibition of tau release from microtubule to maintain the
transportation function of axon, and on the other hand,
precludes formation of tau aggregation. This agent
restored behavioral and cognitive deficits, inhibited
neuron loss, and curbed the tauopathy in animal models.
Epothilone can penetrate BBB and exert a better efficacy
at low concentration and now undergoes a phase 1
clinical trial
• Nicotinamide, the precursor of coenzyme NAD+, reduces
phosphorylated tau and protects microtubules
stabilization in mouse model. Nicotinamide has been
launched into clinical studies suggesting that it is safe and
well tolerated and a phase 2 clinical trial is ongoing in
patients with mild-to moderate Alzheimer’s disease.

• EVP-6124, a selective agonist of the 𝛼-7 nicotinic
acetylcholine receptor, has finished a phase 2
trial showing safe and well tolerated results and
recently(Oct 2013) entered two phase 3 trials to
test the cognitive benefits. Quite a few other
clinical trials testing nicotinic agonists are
ongoing (ladostigil hemitartrate, phase 2;
ispronicline, phase 1), completed (RO5313534),
or terminated (ABT-089).

• A transmitter that indirectly modulates neuron
degeneration and memory deficits is serotonin (5-
HT). Growing evidence indicated that inhibition of 5-
HT6 could facilitate Ach release and via elevated
cholinergic transmission, memory and learning
defects were likely to be ameliorated.
• 5-HT6 antagonists were widely reported in many
studies to rescue anticholinergic drugs-induced
amnesia .Recently, two agents, PRX-03140(5-HT4
antagonist) and SB-742457(5-HT6 antagonist),
completed the phase 2 trials. Lu AE58054, an
antagonist of the serotonin 6 (5-HT6) receptor was
recently progressed into a phase 3 trial with 930 mild
to moderate AD patients in combination with AchE
inhibitor donepezil.

Neurotrophin
• Nerve growth factor (NGF) as a neurotrophin plays a
critical role promoting survival and maintaining the
function of cholinergic neurons. In AD patients,
transcription and translation levels of NGF were changed.
suggesting that NGF supplementation probably is a
treatment approach for Alzheimer’s disease. NGF with
unfavorable size and polarity is a peptide that cannot
cross,, so to safely and efficiently deliver it to the brain will
be a great challenge. However, efforts have been made to
overcome this obstacle.
• An example of strategy is as follows: CERE-110 uses adeno-
associated virus to transfer a gene that makes NGF and is
injected into AD patients’ brain. This approach undergoes a
phase 2 study.

WAVE 1
• WAVE 1 is a protein and a key regulator of
connections between brain cells. It controls the
formation of new cell connections which influence
thinking and behavior. This knowledge will one day
allow doctors to administer drugs that may either
prevent the loss of brain cell connections in
Alzheimer’s or stimulate the growth of new
connections to restore memory and lost function.

delta-9-tetrahydrocannabinol
• University of South Florida (USF Health)
• Extremely low levels of the compound in
marijuana known as delta-9-
tetrahydrocannabinol, or THC, may slow or
halt the progression of Alzheimer's disease, a
recent study.2014

Microglia targeted therapy
• Researchers at Standford University discovered that nerve
cells die because cells which are supposed to clear the brain
of bacteria, viruses and dangerous deposits, stop working.
• These cells, called 'microglia' function well when people are
young, but when they age, a single protein called EP2 stops
them operating efficiently.
• Now scientists have shown that blocking the protein allows
the microglia to function normally again so they can hoover
up the dangerous sticky amyloid-beta plaques which
damage nerve cells in Alzheimer's disease.
• The researchers found that, in mice, blocking EP2 with a
drug reversed memory loss and myriad other Alzheimer’s-
like features in the animals.
• Now Stanford is hoping to produce a compound which only
blocks EP2 to prevent unnecessary side effects.

1. Qiutian Jia, et al., Potential Therapeutic Strategies for Alzheimer’s Disease
Targeting or Beyond 𝛽-Amyloid: Insights from Clinical Trials. BioMed Research
International.2014
2. Castello et al., Moving beyond anti-amyloid therapy for the prevention and
treatment of Alzheimer’s disease. BMC Neurology 2014, 14:169.
3. Abdul Hye et al., Plasma proteins predict conversion to dementia from prodromal
disease. Alzheimer’s & Dementia 10 (2014) 799-807.
4. Thomas etal., Buccal micronucleus cytome biomarkers may be associated with
Alzheimer’s disease. Mutagenesis vol. 22 no. 6 pp. 371–379, 2007.
5. Gupta et al., Multiplex biomarkers in blood. Alzheimer’s Research & Therapy 2013,
5:31.
6. Donovan et al., Exploring the potential of the platelet membrane proteome as a
source of peripheral biomarkers for Alzheimer’s disease. Alzheimer’s Research &
Therapy 2013, 5:32
7. Esteras et al., Calmodulin levels in blood cells as a potential biomarker of
Alzheimer’s disease. Alzheimer's Research & Therapy 2013, 5:55
8. Franc¸ois et al., Altered Cytological Parameters in Buccal Cells from Individuals with
Mild Cognitive Impairment and Alzheimer’s Disease. Cytometry Part A 00A: 0000,
2014
9. Ewers et al., Neuroimaging markers for the prediction and early diagnosis of
Alzheimer’s disease dementia. Trends Neurosci. 2011 August ; 34(8): 430–442.

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