Alzheimer disease

Alzheimer’s Disease :redefined
Ekbal Mohamed Abo-Hashem –MD
Prof .of Clinical Pathology
Mansoura University-Egypt

By the beginning of the 21st century, medicine has
achieved great successes that have significantly
extended the average life span, at least in developed
countries. The great advances in all fields of medicine,
will lead to an inevitable increase in human life span. As
a result, AD may become the most challenging medical
problem of this century.
This prospect, along with an essential lack of progress in the
treatment of AD, is extremely alarming. Clearly, this field is in
urgent need of new ideas.

Agenda :
PATHOGENESIS:
*Lysosomal malfunction
*Impaired autophagy
*Molecular effectors of autophagy :mTOR-neuroinflamation-endocannabinoidS.
*Abnormal Tau
*The BBB and immune privilege of the brain
*Genetic factors and the amyloid cascade
*Non-genetic factors
DIAGNOSIS :
*MRI and PET scans
*Laboratory tests :AB42-AB42/40 ratio-T-tau/A42-P-tau/A42
*Pre-synaptic biomarkers
*Genetic testing
*Key milestones in the history of AD

What is AD :
• Alzheimer’s disease (AD) is a neurodegenerative disease , mostly affecting people
after age of 65.It is characterized by a progressive loss of memory due to
dysfunction or loss of some brain cells responsible for cognition . Various theories
were put forward to explain its pathogenesis ,the earliest of which is that
implicating the aggregation of of amyloid beta (AB) and phosphorylated tau(p-
tau) inside neurons,resulting in its dysfunction and death .Now ,with the
marvelous advancements in molecular biology ,various explanations have been
put forward including complex pathophysiological processes e.g
oxidative stress, neuroinflammation, excitotoxicity,
mitochondrial dysfunction, proteolytic stress, and much
more .

INTRODUCTION
The active balancing of protein synthesis and degradation, or
proteostasis, is an ongoing and critical process in most cells. Proteins
must be created, carry out their requisite function, and then be recycled
once they are no longer needed or have become nonfunctional. Several
pathways are available for protein degradation, including the proteasome,
macroautophagy, microautophagy, and chaperone-mediated
autophagy. The autophagy-related pathways deliver proteins to
lysosomes, which are acidic organelles containing a host of
hydrolases,including many proteases.
Alzheimer as a lysosomal storage disease:(lysosomal
malfunction-lysosomal failure ):

Lysosomes are crucial for maintaining cellular homeostasis, but
they are also uniquely susceptible to problems when substrates
cannot be hydrolyzed. For example, genetic modifications
reducing the efficacy of a lysosomal hydrolase are the
most common cause of lysosomal storage disorders. These
devastating diseases involve “storage” of failed lysosomal bodies
within cells, which eventually leads to cell death and is particularly
problematic for postmitotic cells such as neurons. Symptoms in
lysosomal storage disorders usually emerge in infancy or childhood,
are often associated with neurodegeneration, and are typically fatal.

Long-lived proteins are a primary target of the lysosome
because they become modified and lose efficacy over
time. A well-known example of this occurs with
mitophagy, wherein old mitochondria are recycled in
their entirety. Contributing factors that lead to long-lived
protein deterioration include a variety of spontaneous
chemical modifications, i.e., modifications not under
enzymatic control ,including isomeration and
epimerisation .

Amyloid aggregates or proteins that are otherwise insoluble are also
targeted to lysosomes for degradation. Amyloid aggregation has also
captured the majority of attention as the potential cause of Alzheimer’s
disease (AD), but significant evidence also supports lysosomal storage as
an underlying cause. For example, AD shares many pathological
similarities with lysosomal storage disorders, including prolific storage of
failed lysosomal bodies, accumulation of senile plaques, and formation of
neurofibrillary tangles.. The lysosomal storage observed in AD
precedes formation of amyloid deposits, hinting that
lysosomal malfunction may occur upstream of the events
leading to extracellular amyloid aggregation.

In a healthy human central nervous system the
production rate of amyloid b ( Ab) peptides is generally
lower than their rate of clearance, at 7.6 and 8.3% per
hour, respectively .Autophagy is a key regulator of Ab
generation and clearance . Ab peptides are produced
through cleavage of amyloid precursor protein (APP) in
the autophagosomes during autophagic turnover of
APP-rich organelles .
BIOLOGICAL MECHANISMS LINKING AUTOPHAGY AND AD –
Ab Metabolism and the Autophagy

In AD the maturation of autophagolysosomes (i.e.,
autophagosomes that have undergone fusion with
lysosomes) and their retrograde passage toward the
neuronal body are hindered . This contributes to an
immense accretion of autophagic vacuoles in neurons. Such
accretion may be related to dysfunction of the ESCRT-III
complex. This dysfunction is associated with
neurodegeneration and may affect autophagosome
maturation by disrupting fusion of autophagosomes with
the endolysosomal system .

There are two pathways for disposing Ab peptides : Firstly,
they can be simply degraded by various Ab-degrading proteases,
including BACE1 and cathepsin D ( CTSD ) .
Secondly, Ab peptides can accumulate in autophagosomes of
dystrophic neurites (i.e., main constituents of neuritic senile
plaques in AD), thus being incorporated into primary intracellular
reservoir of toxic peptides . The second recycling path of Ab
peptides is especially prevalent in the brains of people suffering
from AD .
Summing up, impaired autophagy is a well-established
participating mechanism in the pathology of Ab
metabolism of AD.

Autophagic-lysosomal dysfunction could result in the
accumulation of aged and damaged mitochondria, which could
release factors leading to cell death. Changes in mitochondrial
gene expression and function are common in aged mammalian
brains, and mitochondrial dysfunction has been reported in brains
of patients with Alzheimer disease.
Therefore,antioxidative treatment and estrogen replacement
therapy to improve mitochondrial function have been proposed as
potential treatments for patients with Alzheimer disease.

Mechanistic Target of Rapamycin (mTOR) Pathway
Mechanistic target of rapamycin signaling pathway is
initiated by nutrients and growth factors and regulates
autophagy . Human studies suggest participation of
mTOR signalling in AD ..Decreased mTOR signaling
leads to reduction in levels of Ab and protects memory
of AD model mice from deterioration .
Molecular effectors of autophagy :

Moreover, studies on human cells have shown that mTOR
mediates intra and extra-cellular distribution of tau and its
phosphorylation and accumulation as well as resulting
behavioural effects of tau pathology . Finally, multiple
compounds tested for their efficacy as AD medication
impose their beneficial effect by inducing mTOR-
depending autophagy .
Summarizing, mTOR pathway is currently one of the most
promising targets for autophagy-related AD therapy.

Inflammation, autophagy and AD are suggested to
be connected processes..
AD and neuroinflammation feed autophagy (and each
other), while autophagy decreases inflammation in
the brain. Thus, the increase in autophagy may play
some protective role during the course of AD via
interaction with the immune system.
Neuroinflammation

Endocannabinoids are lipophilic molecules that, when released,
activate the cannabinoid receptors CNR1 and CNR2 (cannabinoid
receptor 1 and 2) . In a human AD, expression of the CNR1 receptor
was significantly reduced in the frontal cortex , while the expression
levels of the CNR2 receptor were increased in microglia cells in the
hippocampus, entorhinal cortex and frontal cortex .The high
expression of CNR2 receptor was correlated with the Ab42 levels
and senile plaque burden . All these findings suggest that there is a
non-trivial connection between endocannabinoids, autophagy, and
AD.
Endocannabinoids

Genes Common to Autophagy and AD :
Autophagy-Related 7 (ATG7)
BCL2
Beclin 1 (BECN1/ATG6)
Cyclin Dependent Kinase 5 (CDK5)
Clusterin (CLU/APOJ)
Cathepsin D (CTSD)
Forkhead Box O1 (FOXO1)
Glial Fibrillary Acidic Protein (GFAP)
Presenilin 1 (PSEN1)
Inositol 1,4,5-Trisphosphate Receptor Type 1
(ITPR1/IP3R1)
Ubiquilin 1
(UBQLN1)
Ubiquitin C-Terminal Hydrolase L1 (UCHL1)

THERAPEUTIC IMPLICATIONS OF THE INTERPLAY OF ALZHEIMER’S DISEASE
AND AUTOPHAGY
Carbamazepine (CBZ)
Carbamazepine-induced autophagy also protected against memory dysfunction and
increase in Ab content in brains of mouse model of AD
Latrepirdine
Latrepirdine stimulates mTOR- and Atg5- dependent autophagy and reduces
intracellular content of App metabolites, including Ab peptides, in the brain of mouse
Lithium
Clinical trials have shown that lithium may ameliorate AD and this effect may be
related to its mTOR-independent autophagy inducing activity.

Memantine
The NMDA (N-methyl-D-aspartate) receptors antagonist memantine is widely
used for treatment of moderate-to-severe AD. It shows good tolerance and
some efficacy in AD treatment .This effect may be to some extent mediated
by memantine ability to influence autophagy in either mTOR-dependent or
mTOR-independent manner
Nicotinamide
long-term treatment with nicotinamide (Vitamin B3/PP) reduces Ab and tau
pathologies as well as cognitive decline in a mouse model of AD. The effect
of nicotinamide is likely mediated by enhancement of the acidification of
lysosome or autophagolysosome, leading to reduced autophagosome
accretion

Protein Phosphatase 2A Agonists
Clinical trials have suggested that protein phosphatase 2A agonists, such
as metformin, can inhibit the hyperphosphorylation of tau .
Rapamycin
Rapamycin, a selective inhibitor of target-of-rapamycin complex 1
(TORC1) and thus modulator of the mTOR pathway activity, improved
learning and memory and reduced Ab and tau pathology in the brains of
AD mouse model .
Resveratrol
Resveratrol, a grape-derived polyphenol, and its derivatives decreased
extracellular Ab peptide accumulation by activating autophagy via AMPK
signaling pathway .

Tau is one of the microtubule-associated proteins that promote assembly of tubulin
to microtubules and stabilize them. As a cytoskeletal protein, it is expressed mainly
in neurons, which develop long processes such as axons and dendrites for
neuronal transmission. The human tau gene is localized in the region of 17q21 on
the long arm of chromosome 17.. Tau is localized mainly in axons, but is also
present in the somatodendritic compartment in a phosphorylated state. Tau is a
natively unfolded protein; In AD brains, tau is accumulated in a
hyperphosphorylated state in the pathological Inclusions(p-tau) .. Ultrastructurally,
it is observed as a unique filamentous structure, paired helical filaments
(PHFs), which are fibrils/filaments of 10 nm diameter .
Abnormal Tau in AD Brain

These structures are referred to as neurofibrillary tangles
(NFTs) if they are formed in neuronal cell bodies, while they
are referred to as threads if they are formed in dendrites or
axons. Both are basically bundles of PHFs or related straight
filaments (SFs).
Although tau pathology can be seen in many dementing
disorders, it is characteristic for each disease and can be
used for classification of the disease phenotypes.

Tau pathology develops 20 years before the
appearance of amyloid ( A) pathology ,no AD cases
are found showing only A pathology without tau
pathology . Therefore, it is hypothesized that A may
be secreted from the axon terminals of cells with tau
pathology ,meaning that tau pathology may be the
cause of A pathology. Furthermore, the clinical status
of AD patients correlates better with the NFT burden
than with AA deposition .

• This is very important for developing therapeutic
strategies, because drugs targeted to A are unlikely to be
effective on tau aggregation and related neurodegeneration
if A are simply secreted from cells with tau pathology. As a
result, there is increasing interest in tau-targeted therapies
aimed at inhibiting tau fibril formation with chemical
compounds and promoting abnormal tau clearance by
using antibodies or vaccination indeed, tau aggregation
inhibitor therapy is already under clinical trial .

. Spatiotemporal progression of neurofibrillary pathology in Alzheimer disease.
The intensity of the red color is proportional to the density of neurofibrillary tangles.
The bright red color shows atrophied areas.
MTL, medial temporal lobe; MC, motor cortex; SSC, somatosensory cortex; VC, visual cortex.
(Reproduced with permission, Copyright 2002, the US National Academy of Sciences).

THE BBB AND THE IMMUNE PRIVILEGE OF THE BRAIN
The BBB is formed by cerebral capillary endothelial cells and acts as a
physical barrier formed by the tight junctions between adjacent
endothelial cells ,these distinguish the vasculature of the brain from that in
most other organs.
The BBB maintains the stable environment required for normal
functioning of neuronal circuits.
However, the BBB is an imperfect obstacle for penetration of small water-
soluble molecules. For example, a large number ofCNS-effective drugs
easily permeate the BBB. In contrast, the BBB is mostly impermeable to
macromolecules, including immunoglobulins (Igs). and immunocompetent
cells into the brain .

These data suggest that one of the most critical
functions of the BBB is the isolation of the brain from
the organism’s immune system. Combined with other
mechanisms (the absence of a lymphatic system, low
level of major histocompatibility complex molecule
expression, local production of immunosuppressive
factors, and others), the BBB provides immune privilege
of the brain.
BBB destruction leads to the entry of blood-borne AA into the brain
where it binds selectively to neurons involved in memory formation.

• Impairments of the BBB caused by either genetic or nongenetic AD
risk factors allow the immune system to attack the neurons involved
in memory formation and storage.
• The slow development of AD suggests that antigen concentration on
the neuron surface is low and the autoimmune reaction is not strong
enough for immediate neuron killing. But it may provoke memory-
associated neurons to be particularly sensitive to AA and
neurofibrillary pathologies, which are present to some extent in the
brains of all elderly people .
• Neuron degeneration progressing in the brain - not fully protected by
the BBB - leads to nonspecific brain inflammation.

1.The primary event is the A-amyloid (AA)
deposition at the walls of cerebral capillaries (i.e. cerebral
amyloid Angiopathy-CAA), leading to blood-brain barrier (BBB)
impairment.
The AA deposits are represented by red ellipses;
unaffected tight junctions between endothelial cells are marked
by small arrows.
2.The BBB impairment allows the immune system to attack
specifically the neurons that are involved in memory
formation and consolidation (purple neurons).
3.This autoimmune attack makes memory-associated neurons
vulnerable to AA deposition and the formation of neurofibrillary
tangles (black bars).
Four successive stages of neuron degeneration are shown
from bottom to top. Eventually, progressive neuron
degeneration initiates nonspecific brain inflammation, leading
to the breakdown of all cognitive functions at later stages of AD
Sequence of events leading to development of AD after impairment of BBB

Typical features of an adaptive immune response have been found in
the brains of AD patients, particularly in the medial temporal lobe.
These features include the following:
1) An increased content of parenchymal Igs and Ig positive neurons
2) Significant increases in numbers of T lymphocytes
3) The activation of microglia , which may mediate the immune cell
specific functions, including the functions of antigen-presenting cells
4) The expression of major histocompatibility complex class II
molecules by reactive microglia.

The formation of tight junctions between the endothelial cells of
cerebral capillaries during embryonic development is induced by
signals originating within the neural tissue.
One of the signalling systems involved is the canonical Wnt/A-
catenin pathway
Wnt ligands (primarily Wnt7a/7b) secreted by brain precursor cells,
mainly astrocytes, bind to the Frizzled/LRP (lipoprotein Receptor-
related protein) complexes on the surface of cerebrovascular
endothelial cells . This leads to the stabilization of intracellular A-
catenin, which enters the nucleus to activate the expression of
claudins, the membrane proteins that function as the primary seal
for the tight junctions between endothelial cells

. FZD, Frizzled receptor; LRP5/6, lipoprotein receptorYrelated proteins 5 and 6; GSK3, glycogen synthase
kinase 3; TCF, T cell factorYdependent transcription; JAM, junctional adhesion molecule; TJ, tight junction.
Modified Figure 1 from Polakis (175) (Reproduced with permission, Copyright 2008, the Rockefeller University Press).
The role of the canonical Wnt/A-catenin signalling system in blood-brain barrier (BBB)
formation

The identification of the signaling system
inducing BBB formation and its subsequent
stabilization may contribute to the development
of therapeutic approaches to maintaining BBB
integrity.

Genetics and the Amyloid Cascade Hypothesis :
Although most cases of Alzheimer disease are sporadic and idiopathic, mutations in
three genes have been identified as being responsible for a small fraction of early-onset
Alzheimer disease, also known as familial Alzheimer disease (FAD) ,or early-onset AD.
This type of Alzheimer disease accounts for approximately 5% of all Alzheimer disease
cases. These genes are those coding for :
*APP,
*presenilin 1 (PS1,also known as PSEN1),
*and presenilin 2 (PS2, also known as PSEN2).
AD is not ‘‘brain aging’’ but a definite form of neuropathology.Therefore, it is important to
consider specific genetic and nongenetic factors leading to both early- and late-onset AD.
Genetic and non-genetic factors in AD :

Other genetic factors leading to FAD include APP locus
duplication and polymorphisms in the APP promoter region..
Mutations in all three genes were shown to increase the
production and aggregation of b-amyloid which were neurotoxic ,
an effect that was extensively used to support the amyloid
cascade hypothesis.
Autosomal dominant mutations in the PS1 and PS2 genes
account for as much as 50% of all FAD cases . More than 30
mutations in the APP gene and more than 180 mutations in PS1
and PS2 genes have been identified.

Amyloid cascade hypothesis :
Generation of b-amyloid from APP involves three proteases/secretases—
a, b, and g.
* Cleavage of APP by b-secretase and g-secretase produces the b-amyloid
peptide, the secreted ectodomain APP, and an intracellular fragment
called APP intracellular domain.
• By contrast, cleavage of APP by a-secretase and gsecretase results in a
p3 peptide, the secreted ectodomain APP, and the APP intracellular
domain.
• Because APP cleavage by a-secretase prevents b-amyloid formation,
this process has been called the nonamyloidogenic pathway, and the
process involving b-secretase has been named the amyloidogenic
pathway.

b-amyloid oligomers could bind to the cellular prion
protein (PrPc) , suggesting that PrPc may function as a
receptor for b-amyloid oligomers. Binding of b-amyloid
oligomers to PrPc blocked the formation of long-term
potentiation, a widely recognized cellular mechanism for
certain forms of learning and memory. This finding
provided a potential mechanism for synaptic dysfunction
in Alzheimer disease.

To date, polymorphism in the apolipoprotein E (ApoE)
gene is the only confirmed genetic risk factor for sporadic
Alzheimer disease. Apolipoprotein E is involved in lipid transport
and exhibits three alleles (e2, e3, e4). Many studies have
demonstrated that the presence of the e4 allele is a risk factor for
sporadic Alzheimer disease and late onset FAD. Compared to
individuals who do not have an ApoE e4 allele, individuals who
have one e4 allele are at a 2-fold to 3-fold increased risk for
Alzheimer disease, and individuals who have two e4 alleles are at
a 12-fold increased risk for Alzheimer disease.

ApoE may affect b-amyloid aggregation and clearance. All
cells of the body produce b-amyloid throughout life, though
neurons produce the highest amounts of b-amyloid. The age-
dependency of b-amyloid accumulation and Alzheimer
disease onset suggests that intrinsic properties of aged
brains precipitate the pathologic cascade.
The ApoE e4 allele is also associated with an earlier age of
Alzheimer disease onset , The e2 allele is associated with a
lower risk for Alzheimer disease.

Nongenetic (Environmental) Risk Factors :
Cerebrovascular disorders may represent serious risk factors
for AD. Similarly to genetically determined cases, AD
provoked by vascular disorders develops very slowly. For
example, there is a positive correlation between the risk for
AD and midlife hypertension; and middle-age onset diabetes ,
chronic brain ischemia or atherosclerosis, as well people who
survived strokes in middle age,and brain trauma, for example,
retired boxers and football players are at high risk for AD-like
pathology.

What Are the Benefits of Early Diagnosis?
Early, accurate diagnosis is beneficial for several reasons. Beginning
treatment early in the disease process may help preserve daily
functioning for some time, even though the underlying Alzheimer’s
process cannot be stopped or reversed.
Having an early diagnosis helps people with Alzheimer’s and their
families:
•Plan for the future
•Take care of financial and legal matters
•Address potential safety issues
•Learn about living arrangements
•Develop support networks

In general, AD biomarkers have a potential to be used to
support a clinical diagnosis, especially in the early stages of
the disease, to predict disease progression, to monitor
effects of novel drug candidates in clinical trials, and last also
in clinical research to deepen our understanding of the
pathogenesis of the disease .

The identification of A and phosphorylated tau aggregates as the main
components of plaques and tangles, respectively , opened the
possibility to find AD biomarkers by developing assays for proteins
related to the core pathology of the disease (plaques, tangles, and
neuronal degeneration), and evaluate their performance as diagnostic
tests in CSF samples from AD patients and controls. For brain
disorders such as AD, the advantage of CSF over blood is its
proximity to the brain parenchyma, and that proteins are secreted
from the brain extracellular space to the CSF.

MRI may provide a reasonably accurate, non-invasive surrogate
for cerebrospinal fluid (CSF) biomarkers, reducing the need for
lumbar puncture in discriminating AD from frontotemporal lobar
degeneration (FTLD). A structural brain pattern was derived
from MRI that predicts the ratio of total tau to β-amyloid in CSF,
to discriminate AD from FTLD. In this way, they were able to
differentiate between the 2 dementia types 75% of the time.

The availability of amyloid PET made it possible to identify amyloid
pathology in vivo, and thereby also offered the possibility to compare the
AD CSF biomarkers, especially A42, with amyloid load directly in patients
and cognitively unimpaired elderly.
These findings suggest that CSF A42 may be the earliest AD biomarker,
becoming positive before amyloid PET and neurodegeneration.

Assays for proteins related to the core pathology of the
disease (plaques, tangles, and neuronal degeneration), and
evaluation of their performance as diagnostic tests in CSF
and blood samples from AD patients ,together with
comparing their levels to those with mild cognitive
impairment (MCI ) represent a new era in lab. workup for
those patients .
In comparison to other diagnostic tools, laboratory medicine
tests influence up to 70% of clinical decisions and thus have a
central position in clinical medicine
LABORATORY TESTS IN AD :

For brain disorders such as AD, the advantage of CSF over
blood is its proximity to the brain parenchyma, and that
proteins are secreted from the brain extracellular space to the
CSF. CSF can be collected by lumbar puncture, a diagnostic
procedure in which a needle introduced into the subarachnoid
space in the lumbar region (L3/L4 or L4/L5), i.e., at a level that
is safely below the end of the spinal cord.

the most commonly used ELISA, the so-called INNOTEST
assays,were used to measure CSF levels of total tau (T-tau),
phosphorylated tau (P-tau), and the 42 amino acid isoform of
amyloid- (A42) were used ,about 2 decades ago These showed a
marked increase in both CSF T-tau and P-tau in AD, together with
a marked decrease in A42, a CSF biomarker change that today is
known as the “Alzheimer profile”.
Early assay developments and clinical
neurochemical studies

Extended clinical follow-up studies (4–7 years) showed a very
high sensitivity (95%) for the core AD CSF biomarkers to identify
prodromal AD, and also a high specificity to differentiate
prodromal AD from stable mild cognitive impairment ( MCI)
cases and those developing other dementias
Alzbiomarker database, see
http://www.alzforum.org/alzbiomarker.

The Aβ42/40 ratio compensates for factors complicating Aβ42
measurements
Recent studies suggest that the A42/40 ratio has better concordance
with amyloid PET than A42 , and that the CSF A42/40 ratio is also
valuable in the clinical setting
In addition to the A42/40 ratio, the ratios between T-tau/A42 and P-
tau/A42 have also been evaluated and , all three ratios show very high
concordance
The most commonly used methods for measurement of the core AD
CSF biomarkers A42, T-tau, and P-tau in clinical studies and routine
diagnostics are ELISAs, and the Luminex technology

Disappointingly, between-laboratory CVs have been around 15–25% for the ELISA and
Luminex methods since the beginning, indicating the need of more automated analytical
techniques.For this reason , the Alzheimer’s Association quality control (QC) program
for CSF biomarkers was started in 2009
Standardization efforts :
In clinical chemistry, the highest level of standardization is through a Certified
Reference Material (CRM). For the AD CSF biomarkers, a “Gold Standard” large CSF
pool with known exact biomarker levels was produced, from which aliquots can be
distributed to kit vendors and large laboratories for harmonization of levels between
assay formats, and to secure long-term (batch-to-batch) stability of assays.

CSF levels of tau and phosphorylated tau are often elevated in AD, whereas
amyloid levels are usually low. Amyloid levels are low because the amyloid is
deposited in the brain rather than the CSF. By measuring both proteins,
sensitivity and specificity of at least 80%—and more often 90%—can be
achieved.
At present, however, routine measurement of CSF tau and amyloid is not
recommended except in research settings. Lumbar puncture for
measurement of tau and amyloid may become part of the diagnostic workup
when effective therapies that slow the rate of progression of AD are
developed, particularly if the therapies are specific for AD and carry
significant morbidity

Analyses are performed on fully automated laboratory instruments ,which
can also measure T-tau and P-tau ,and a number of companies are building
assays on fully automated laboratory, meaning that clinical laboratories can
choose between different platforms for their clinical routine measurements
.
These new types of assays will serve as the basis for highly stable and
precise results for CSF biomarkers, which, together with certified
reference materials, will allow for the establishment of uniform worldwide
cut-off levels. This will lead to a more general use of CSF biomarkers in
the routine diagnostic evaluation of patients with suspected AD,

Measurement of neurogranin in CSF may serve as a biomarker for dendritic instability
and synaptic degeneration. After developing novel monoclonal antibodies to measure
neurogranin by ELISA, high CSF levels were found to predict prodromal AD in mild
cognitive impairment( MCI)
Dendritic proteins: Neurogranin
A set of synaptic proteins covering different components of the synaptic unit (dendrites
– neurogranin, presynaptic plasma membrane – SNAP-25, synaptic vesicles – SYT1)
may be valuable tools in clinical studies on the relevance of synaptic dysfunction and
degeneration in AD pathogenesis, and maybe also in the clinical evaluation of patients.
Presynaptic biomarkers

NfL forms part of the internal "scaffolding" for nerve cells. When nerve cells are
damaged, NfL seeps into the CSF and then into the blood. This can occur with
neurodegenerative diseases like AD as well as other types of brain damage
In individuals with an early-onset AD genetic mutation, the NfL was higher at
baseline and rose significantly over time . The speed at which NfL increased in
their blood, rather than the concentration of NfL, could be used to predict when
that person would start experiencing AD symptoms. The rate of NfL change was
associated with some but not all tests for AD progression, such as memory tests
and imaging scans
Neurofilament light chain (NfL) protein

MOVING FROM CSF TO BLOOD: THE PROMISE OF SCREENING
TOOLS
Brain proteins enter the bloodstream.However, blood is a more challenging matrix than
CSF for brain biomarkers, for several reasons :
First, the minute amounts of brain proteins entering the blood have to be measured in
a matrix containing very high levels of plasma proteins, such as albumin and IgG,
introducing a high risk of interference in analytical methods.
Second, brain proteins released into blood may be degraded by proteases,
metabolized in the liver or cleared by the kidneys, which will introduce a variance that
is unrelated to brain changes and difficult to control for. This limits the potential of
finding blood biomarkers for AD.
Nevertheless, technical developments in the field of ultrasensitive immunoassays and
mass spectrometry have given new hopes

Current Alzheimer’s disease diagnosis is based on the determination
of amyloid-beta monomers and aggregates by enzyme-linked
immunosorbent assays and mass spectrometry. These methods are
reliable but are expensive, time-consuming, labor intensive, and
relatively insensitive. Thus, new methods with low cost and high
sensitivity, selectivity, and simplicity are desirable for amyloid-beta
peptide detection. biosensors for amyloid-beta peptides and their
aggregates arenow developed, including surface plasmon
resonance, localized surface plasmon resonance, electrochemistry,
resonance light scattering, and dot-blot immunoassays.

Appropriate bioreceptors have also been
devised to achieve highly sensitive and
selective quantification of AD biomarkers by
using transducers.. The most commonly used
bioreceptors are aptamers and antibodies.

Blood-based biomarkers represent a less invasive and potentially
cheaper approach for aiding Alzheimer's disease (AD) detection
compared with cerebrospinal fluid and some neuroimaging
biomarkers.

Neurofilament light
. A possible future application for plasma NFL is as a screening
test at the first clinical evaluation of patients with cognitive
disturbances, e.g., at the primary care unit. Here, plasma NFL
might serve as simple, non invasive, and cheap screening tool,
primarily to rule out neurodegeneration.
The following markers can be measured in plasma for suspected AD:
Amyloid B
Tau protein

FGG, γ-fibrinogen; 2DGE, 2D gel electrophoresis; CFI, complement factor-I;;
G-CSF, granulocyte-colony stimulating factor; IFN-γ, Interferon-gamma;
ApoA1, apolipoprotein A1; ApoE, apolipoprotein E; ApoC3, apolipoprotein
C3; SAP, serum amyloid-P; TTR, transthyretin; PPY, pancreatic polypeptide;
C2, Complement C2; SAA, Serum amyloid A-1 protein; C9, Complement C9;
MBL, Mannose-binding protein C; CHK1, Serine/threonine-protein kinase
Chk1; IL, Interleukin; eIF-5A-1, Eukaryotic translation initiation factor 5A–1;
MCIs, stable MCI patients; MCIc, MCI converting to AD; RANTES, Regulated
on Activation, Normal T Cell Expressed and Secreted; NSE, neuron-specific
enolase; BDNF, brain derived neurotrophic factor; NCAM, neural cell
adhesion molecule; PDGF, platelet-derived growth factor; TNF, tumor
necrosis factor; CDC37, C-C motif chemokine 19; CFH, complement factor H
Other blood-based protein biomarkers of AD by endophenotype approach
including brain atrophy and rate of cognitive decline may include :

Genetic testing
Researchers have identified certain genes that increase the risk of
developing Alzheimer's and other rare "deterministic" genes that directly
cause Alzheimer'sdisease
Risk genes: APOE-e4, is the strongest risk gene for Alzheimer's, this test is
mainly used in clinical trials to identify people at higher risk of developing
Alzheimer's. Carrying this gene mutation only indicates a greater risk; it
does not indicate whether a person will develop Alzheimer's or whether
a person has Alzheimer's. Genetic testing for APOE-e4 is controversial
and should only be undertaken after discussion with a physician or
genetic counselor

Amyloid precursor protein (APP), discovered in 1987, is the first gene with
mutations found to cause an inherited form of Alzheimer's.
Presenilin-1 (PS-1), identified in 1992, is the second gene with mutations
found to cause inherited Alzheimer's. Variations in this gene are the most
common cause of inherited Alzheimer's.
Presenilin-2 (PS-2), discovered in 1993, is the third gene with mutations
found to cause inherited Alzheimer's.
Deterministic genes: genes that cause autosomal dominant Alzheimer's disease
(ADAD) or "familial Alzheimer's," a rare form of Alzheimer's that accounts for 1-5
percent of all cases. ADAD runs strongly in families and tends to begin earlier in life,
sometimes as early as one’s 30s.

Genetic testing for APP and presenilin mutations
Testing for the APP and presenilin genes associated with early-onset
autosomal dominant AD should be offered in the following situations :
•In symptomatic patients with early-onset AD who have a family
history of dementia or an unknown family history .
•In persons with a family history of autosomal dominant dementia
with one or more cases of early-onset AD
•In relatives with a mutation consistent with early-onset AD (ie, PS-1,
PS-2,APP)

Key milestones in history of AD

Alzheimer’s disease was first described in 1906. In the century since then,
scientists have made remarkable strides in understanding how the disease affects
the brain and are learning how to make life better for patients and their families.
Below are some key milestones.
--------------------
Discovery
1906: German physician Alois Alzheimer describes the haunting case of Auguste
D., a patient with profound memory loss and other psychological changes. An
autopsy of her brain showed dramatic shrinkage and abnormal deposits in and
around nerve cells.
1910: Emil Kraepelin, a German psychiatrist who worked with Dr. Alzheimer, first
names “Alzheimer’s disease” in his book “Psychiatrie.”
1968: Researchers develop the first validated measurement scale for assessing
cognitive and functional decline in older adults.
--------------------
Research
1974: An act of Congress establishes the National Institute on Aging (NIA), the
primary federal agency supporting Alzheimer’s research.
1976: Neurologist Robert Katzman identifies Alzheimer’s as the most common
cause of dementia and a major public health challenge
Key milestones in the history of AD

--------------------
Awareness
1980: The Alzheimer’s Association was founded and has since become the
largest private, non-profit source of funding for Alzheimer’s research.
1984: Researchers George Glenner and Caine Wong identify “a novel
cerebrovascular amyloid protein” known as beta-amyloid — the chief
component of Alzheimer’s brain plaques and a prime suspect in triggering
nerve cell damage.
1984: The NIA begins funding a network of Alzheimer’s Disease Centers at
flagship medical institutions, including Emory University.
1986: Researchers discover that tau protein is a key component of tangles
— the second pathological hallmark of Alzheimer’s disease and another
prime suspect in nerve cell degeneration.
1987: The Alzheimer’s Association assists the NIA and Warner-Lambert
Pharmaceutical Co. (now Pfizer) in launching clinical trials of tacrine, the
first drug specifically targeting symptoms of Alzheimer’s disease.
1987: Researchers identify the first gene associated with rare, inherited
forms of Alzheimer’s disease.
--------------------

Treatments
1991: The NIA established the Alzheimer’s Disease Cooperative
Study, a nationwide medical network to facilitate clinical research
and conduct federally funded clinical trials.
1993: Researchers identify APOE-e4, a form of the apolipoprotein-E
(APOE) gene on chromosome 19, as the first gene that raises risk
for Alzheimer’s.
1993: The Food and Drug Administration approves tacrine
(Cognex) as the first drug specifically targeting Alzheimer’s
memory and thinking symptoms. Four more drugs are approved
over the next 10 years.
1995: Researchers announce the first transgenic mouse model that
developed Alzheimer’s-like brain pathology after it was inserted
with one of the human genes linked to a rare form of Alzheimer’s.
1999: Reports are published showing that injecting transgenic
“Alzheimer’s” mice with beta-amyloid prevents them from
developing plaques and other Alzheimer’s-like brain changes

.
--------------------
Hope
2003: The Alzheimer’s Association partners with the NIA to launch the National
Alzheimer’s Disease Genetics Study, an initiative to collect blood samples from
families with members who developed Alzheimer’s disease to identify additional
Alzheimer’s risk genes.
2004: Emory becomes one of 50 sites nationwide to participate in the Alzheimer’s
Disease Neuro-imaging Initiative study. The goal is to establish standards for
obtaining and interpreting brain images to identify high-risk individuals, provide
early detection, and monitor treatment effects.
2008: Emory neurologist James J. Lah develops a memory screening test to detect
memory problems

A Brighter Era
Although the number of people with AD continues to increase
daily, our time is a brighter era in the history of AD and other
dementias. More than a hundred new medications are now
being tested and many nonpharmacologic interventions, some
of them preventive, are being explored. Even if the damage of
later stages of AD are impossible to cure or reverse, current
investigations offer the hope of arresting or slowing the
disease’s effects – and perhaps identifying and preventing
progression at an earlier, even asymptomatic stage

Alzheimer disease

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