BIO 515 Mississippi College Alzheimer Disease Paper Review

Write a mini-review about a specific research paper – a “News & Views”

1. Primary Article

2. Review article 1 for reference

3. Review article 2 for reference

Address the “what”s, “how”s, “why”s, “what next”s

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Include: Introductory paragraph, background on area of research (including what was known before), experiments, conclusions and future experiments (unanswered questions).

International Journal of Nanomedicine
Dovepress
open access to scientiﬁc and medical research
Open Access Full Text Article
REVIEW
Alzheimer’s disease: pathogenesis,
diagnostics, and therapeutics
This article was published in the following Dove Press journal:
International Journal of Nanomedicine
Sneham Tiwari
Venkata Atluri
Ajeet Kaushik
Adriana Yndart
Madhavan Nair
Department of Immunology and NanoMedicine, Institute of NeuroImmune
Pharmacology, Herbert Wertheim
College of Medicine, Florida International
University, Miami, FL 33199, USA
Abstract: Currently, 47 million people live with dementia globally, and it is estimated to
increase more than threefold (~131 million) by 2050. Alzheimer’s disease (AD) is one of the
major causative factors to induce progressive dementia. AD is a neurodegenerative disease,
and its pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ)
plaques and intracellular neuroﬁbrillary tangles made of hyperphosphorylated τ-protein in
cortical and limbic areas of the human brain. It is characterized by memory loss and
progressive neurocognitive dysfunction. The anomalous processing of APP by β-secretases
and γ-secretases leads to production of Aβ40 and Aβ42 monomers, which further oligomerize
and aggregate into senile plaques. The disease also intensiﬁes through infectious agents like
HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aβ
peptides in central nervous system initiates microglial inﬁltration. Upon coming into vicinity
of Aβ, microglia get activated, endocytose Aβ, and contribute toward their clearance via
TREM2 surface receptors, simultaneously triggering innate immunoresponse against the
aggregation. In addition to a detailed report on causative factors leading to AD, the present
review also discusses the current state of the art in AD therapeutics and diagnostics,
including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology
as an efﬁcient therapeutic strategy to increase the bioavailability of drugs in the central
nervous system.
Keywords: amyloid beta, amyloidogenesis, amyloid precursor proteins, β-secretases, γsecretases, tau phosphorylation
Introduction
Correspondence: Madhavan Nair
Department of Immunology and NanoMedicine, Institute of NeuroImmune
Pharmacology, Herbert Wertheim
College of Medicine, Florida International
University, 11200 SW 8th Street, Miami,
FL 33199, USA
Tel +1 305 348 1493
Email nairm@ﬁu.edu
Alzheimer’s disease (AD) is a neurodegenerative and prominent proteinconformational disease (PCD)1,2 primarily caused by the aberrant processing and
polymerization of normally soluble proteins.3 When misfolded, soluble neuronal
proteins attain altered conformations, due to genetic mutation, external factors, or
aging, and aggregate, leading to abnormal neuronal functions and loss.4 AD’s
discovery as a neurodegenerative disease is attributed to Alois Alzheimer,
a German neurologist who examined a 51-year-old woman named Auguste Deter,
who was suffering with loss of memory, language, disorientation, and hallucinations. Her autopsy revealed plaques and tangles in the cerebral cortex,5 which
convinced him that this went beyond typical dementia. His discovery was followed
by further research that revealed the presence of neuritic amyloid β (Aβ) plaques in
dementia patients.6 Young onset of the disease is attributed to predisposition to PS1
genetic mutation, which is a rare but potent cause.7 Other neurodegenerative
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http://doi.org/10.2147/IJN.S200490
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Tiwari et al
diseases associated with abnormal protein conformations
are Parkinson’s disease, Creutzfeldt–Jakob disease,
Huntington’s disease, and Machado–Joseph disease,
which are caused by abnormalities in the α-synuclein,
Cellular Prion protein (PrPc), Scrapie prion protein (PrPSc
), Htt, and Ataxin3 proteins, respectively. Upon understanding the causal factors and pathogenesis mechanism of
the disease, it becomes of the utmost importance to
address such ﬁelds as AD mechanisms, pathogenesis, and
diagnosis, and ﬁnally how to design novel therapeutics
against it (Figure 1).
Diagnostic and imaging techniques include nanoparticle (NP)-based sensitive early-phase detection of AD biomarkers like Aβ and τ in cerebrospinal ﬂuid (CSF)
samples from patients. Nanomaterials can also be used as
contrast agents for imaging aggregated Aβ plaques. It is
imperative to understand the role of NPs in increasing the
efﬁcacy and bioavailability of the drug across the blood–
brainbarrier (BBB) into the central nervous system (CNS).
This review includes a detailed analysis of the pathogenic
pathway leading toward full-blown AD, addresses current
diagnostics and therapeutics available, and emphasizes the
potential role of nanotechnology in therapeutics against
disease progression.
AD pathogenesis
The ﬁeld of research toward understanding AD pathogenesis
and designing efﬁcient therapies is vast. AD is a highly
complex and progressive neurodegenerative disease.8 It is
one of the leading cause of dementia cases globally. In the US
alone, approximately 5.3 million Americans have AD, of
which 5.1 million are aged 65 years or older and 200,000
have younger-onset AD.9 Reported histopathological characteristics of AD are extracellular aggregates of Aβ plaques
and intracellular aggregations of neuroﬁbrillary tangles
(NFTs), composed of hyperphosphorylated microtubuleassociated τ. Aβ plaques develop initially in basal, temporal,
and orbitofrontal neocortex regions of the brain and in later
stages progress throughout the neocortex, hippocampus,
amygdala, diencephalon, and basal ganglia. In critical
cases, Aβ is found throughout the mesencephalon, lower
brain stem, and cerebellar cortex as well. This concentration
of Aβ triggers τ-tangle formation, which is found in the locus
coeruleus and transentorhinal and entorhinal areas of the
brain. In the critical stage, it spreads to the hippocampus
and neocortex.10 Aβ and NFTs are considered the major
players in disease progression, and this review focuses on
the cause, pathogenesis, and factors associated with progression of AD.
Amyloid β and AD pathogenesis
Amyloid pathogenesis starts with altered cleavage of amyloid
precursor protein (APP), an integral protein on the plasma
membrane, by β-secretases (BACE1) and γ-secretases to produce insoluble Aβ ﬁbrils. Aβ then oligomerizes, diffuses into
synaptic clefts, and interferes with synaptic signaling.11,12
Consequently, it polymerizes into insoluble amyloid ﬁbrils
that aggregate into plaques. This polymerization leads to activation of kinases, which leads to hyperphosphorylation of the
microtubule-associated τ protein, and its polymerization into
insoluble NFTs. The aggregation of plaques and tangles is
followed by microglia recruitment surrounding plaques. This
promotes microglial activation and local inﬂammatory
response, and contributes to neurotoxicity.
Alzheimer’s disease
Understanding
mechanisms and
pathogenesis
Diagnostics and
imaging techniques
Treatment/drugs
Efficacy in drug
delivery:
nanotechnology
Figure 1 Overview of ﬁelds of research that need to be elucidated to understand the pathophysiology of Alzheimer’s disease and develop therapeutic strategies against it.
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Structure and function of APP
APP belongs to a family of associated proteins that includes
mammalian amyloid precursor like proteins (APLP1 and
APLP2), and Amyloid precursor protein-like (APPL) in
Drosophila. It is an integral transmembrane protein with extracellular domains (Figure 2). In a diseased state, APP generates
amyloidogenic fragments through differential cleavage by
enzymes.7 The physiological functions of APP remain less
understood. Studies with transiently transfected cell lines
show that APP moderates cell survival, growth, and motility,
along with neurite outgrowth and functions, which are attributed to the release of soluble ectodomains upon normal cleavage of APP.13,14 The importance of APP has been highlighted
by studies where neuronal abnormalities have been reported in
animals injected with APP RNAi,15 and APP-ectodomain
intracerebral injections have shown improved cognitive function and synaptic density.16 APP encodes type 1 transmembrane glycoprotein, which is cleaved either via
a nonamyloidogenic pathway (normal state) or via an amyloidogenic pathway (diseased state).17 APP releases various
polypeptides that arise possibly due to alternative splicing,
glycosylation, phosphorylation, or complex proteolysis.18,19
APP comprises 770 amino acids, of which Aβ includes 28
residues and an additional 14 residues from the transmembrane
domain of APP. At the cleavage site, α-secretase cleaves and
secretes large soluble ectodomain APPsα into the medium and
the C-terminal fragment C83 is retained in the membrane,
which is further cleaved by γ- secretase at residue 711, releasing soluble P3 peptide. Alternatively, in a diseased state,
abnormal cleavage is done by β-secretase releasing truncated
APPsβ and C-terminal fragment C99 is retained in the membrane and further cleaved by γ-secretase, releasing insoluble
Aβ peptides. Cleavage of both C83 and C99 by γ-secretase
releases the APP intracellular domain into the cytoplasm,
which is soluble and translocates to nuclei for further geneexpression function.5
Nonamyloidogenic pathway
APP undergoes constitutive and regulated cleavage. The αsecretase enzyme cleaves APP at residues 16–17 of the Aβ
domain and yield soluble and nonpathogenic precursors. In
neurons, ADAM10 and ADAM17 (metalloprotease) are
considered the major α-secretases. Processing by α-secretase
and γ-secretase generates the small hydrophobic fragment
p3, which is soluble and has a role in normal synaptic
signaling, but its exact functions are still to be elucidated.
It has been reported that cell-surface APP may get endocytosed as well, resulting in endosomal production of Aβ,
which leads to extracellular release and aggregation of Aβ.
The α-secretase processing releases the large soluble ectodomain APPsα, which acts a neuroprotective factor and also
has a role in cell–substrate adhesion. The presence of APPsα
associates with normal synaptic signaling and adequate
synaptic plasticity, learning, memory, emotional behavior,
and neuronal survival. Further, sequential processing
releases the APP intracellular domain, which translocates
into nuclei and facilitates nuclear signaling and geneexpression and -regulation pathways.20
Amyloidogenic pathway
APP is cleaved differently in the diseased state. Aβ is
released from APP through
sequential cleavages by BACE-1, a membrane-spanning
aspartyl protease with its active site situated in lumen, and γsecretase, an intramembrane aspartyl protease that is made
up of four proteins: presenilin, nicastrin, anterior pharynx-
Lumen
β
secretases
Cytosol
γ
secretases
α
secretases
γ40 γ42
Aβ
Transmembrane domain
Figure 2 An overview of the Aβ-pathogenesis hypothesis.
Note: Amino-acid sequence of the Aβ fragment and location of action of α-, β-, and γ-secretases in diseased neurons within a diseased amyloidogenic pathway.
Abbreviation: Aβ, amyloid β.
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defective 1 (Aph1), and Psen2 complexed together.21 This
complex contributes to the activity of γ-secretase, which
produces insoluble and neurotoxic Aβ fragments. βsecretase cleavage is the ﬁrst and rate-limiting step, making
a cut at the N-terminus of Aβ. It removes the majority of the
extracellular portion of the protein, leaving the C-terminal of
APP,22 which is further cleaved at the C-terminus of Aβ,
resulting in formation of the Aβ oligomers that further polymerize, forming aggregated plaques (Figure 3).
There are two main types of Aβ polymers that have
direct a role in plaque formation and induced neurotoxicity: Aβ40 and Aβ42. Aβ40 is abundant and less neurotoxic
than Aβ42, which is less abundant, highly insoluble,
severely neurotoxic, and more aggregation-prone and acts
as a toxic building fraction of Aβ assembly. Aβ40/Aβ42
aggregation results in blocked ion channels, altered calcium homeostasis, increased mitochondrial oxidative
stress, and diminished energy metabolism and glucose
regulation, which contributes to deterioration of neuronal
health and ﬁnally to neuronal cell death.
Hyperphosphorylation of τ and AD
AD is also characterized by the presence of NFTs. These
tangles are the result of hyperphosphorylation of the microtubule-associated τ protein.23 NFTs are fragments of paired
and helically wound protein ﬁlaments in the cell cytoplasm
of neurons and also in their processes. The τ protein has
a microtubule-binding domain and coassembles with tubulin
to form matured and stable microtubules.24,25 It has the
Nonamyloidogenic pathway (non-diseased)
γ-secretase
α-secretase
capability of stabilizing microtubules and forming interconnecting bridges between contiguous microtubules to form
a proper stable network of microtubules and hold them
together. When the τ protein comes into contact with the
kinases released, due to the abundance of Aβ in the environment, it gets hyperphosphorylated. Its hyperphosphorylation
leads to its being oligomerized. The tubule gets unstable, due
to dissociation of tubule subunits, which fall apart and then
convert into big chunks of τ ﬁlaments, which further aggregate into NFTs. These NFTs are straight, ﬁbrillary, and highly
insoluble patches in the neuronal cytoplasm and processes,
leading to abnormal loss of communication between neurons
and signal processing and ﬁnally apoptosis in neurons
(Figure 4).26 It has been reported that soluble Aβ controls
cleavage and phosphorylation of τ for NFT generation.7
Further, phosphorylation of τ is regulated by several
kinases, including Glycogen Synthase kinase 3 (GSK3β)
and cyclin-dependent kinase 5 (CDK5) activated by extracellular Aβ. Even though GSK3β and CDK5 are primarily
responsible kinases for τ hyperphosphorylation, other
kinases like Protein Kinase C, Protein Kinase A, ERK2,
a serine/threonine kinase, caspase 3, and caspase 9 have
prominent roles too, which may be activated by Aβ.27
GSK3β and CDK5 in AD
GSK3β regulates the cleavage of APP carboxyterminal
fragments. Lithium and kenpaullone (two GSK3 inhibitors) prevent GSK3 expression and contribute to inhibition
of Aβ production.28 As such, GSK3 inhibitors might
Amyloidogenic pathway (diseased)
β-secretase
γ-secretase
Aβ aggregates
Cellular membrane
C83
APP
C99
AICD
Cytosol
Figure 3 Alternative splicing of APP in amyloidogenic and nonamyloidogenic pathways.
Note: Cleavage of APP by α- and γ-secretases in normal state and alternative cleavage by β- and γ- secretases in diseased state.
Abbreviations: C83, 83-amino-acid carboxyterminal; C99, 99-amino-acid membrane-bound fraction; AICD, APP intracellular domain.
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Tau
Aβ overproduction
Tau
mislocalization
to dendrites
Amyloid plaques
Spine loss
Tau hyperphosphorylation
Neurofibrillary
tangles
Neuronal damage and death
Figure 4 Hyperphosphorylationof τ.
Note: Mechanism by which τ hyperphosphorylation leads to instability of the
microtubule and ﬁnally microtubule subunits fall apart leading to formation of
insoluble and big neuroﬁbrillary tangles.
Abbreviation: Aβ, amyloid β.
indirectly interfere with the generation of both Aβ plaques
and tangles in AD.
GSK3β activity in mitochondria has been associated with
increased oxidative stress.29 As such, GSK3β plays
a signiﬁcant role in AD pathogenesis, contributing to Aβ
production and Aβ-mediated neuronal death by increasing
τ hyperphosphorylation. Additionally, it has been reported
that τ phosphorylation gets affected by Aβ–CDK5 interaction. This interaction leads to cleavage of adjacent proteins, releasing cleaved peptides with lower solubility and
longer half-lives, which may also phosphorylate distant
proteins. Substantial research focusing on identifying and
classifying kinases accountable for pathogenic τ hyperphosphorylation points toward the primary pathogenic kinases
GSK3β and CDK5, in addition to mitogen-activated protein kinase (MAPK), ERK1 and -2, MAP Kinase (MEK),
microtubule afﬁnity-regulating kinase (MARK), c-Jun NH
(2)-terminal kinases (JNKs), p38, and PKA, among
others.30,31 Abnormal processing of APP leads to secretion
of Aβ, which affects GSK3 kinases, leading phosphorylation of the τ protein. This leads to aggregation of τ ﬁlaments that are insoluble and ﬁnally formation of huge
masses of NFTs in neurons.32
Genetic mutations: presenilin 1
mutation and AD
APP is not the only gene associated with AD. Presenilin
gene (PSEN1 and PSEN2), which are part of the γsecretase family, also mutate.33 Moreover, AD patients
may be predisposed to PS1 mutation leading to
familial AD at a young age.34 The γ-secretase complex is
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made up of four proteins: Psen1, Psen2, Aph1, and nicastrin. Psen, an aspartyl protease, attributes to the catalytic
core of the complex. Psen2 facilitates the maturation of
PSEN, whereas Aph1 stabilizes the complex.35 Nicastrin
acts as a receptor for γ-secretase substrates. There are 179
PSEN1 and 14 PSEN2 gene mutations that participate in
early-onset autosomal-dominant AD. These mutations
favor production of more toxic forms of amyloid, eg,
Aβ42 as opposed to Aβ40, which contributes in disease
progression.36
Epigenetics and AD
Epigenetics deals with the study of interactions between genes,
expression of genotypes, and various molecular pathways that
modify genotype expression into respective phenotypes.37
Epigenetics exploring neurological diseases, neuroepigenetics,
has developed fairly well and been widely studied in CNSassociated diseases comprising learning, motor, behavior, and
cognition pathologies and disorders.38,39 Epigenetics is important to understand the depth of effect of environment or paternal genes, nutritional habits, trauma, stress or learning
disabilities, exposure to chemicals or drug addiction on DNA
and resultant structural disturbances, mutations, or
changes.40,41 The involvement of epigenetics has recently
been explored in one of the most complex aging-related neurological diseases — AD.42 The onset of AD and its progress
involves a complex interplay of various factors like aging,
genetic mutations, metabolic and nutritional disorders, effect
of and exposure to environmental variables, and most importantly the involvement of social factors.43 There is a fair chance
that factors in addition to aging, eg, hypertension, diabetes,
obesity, and inﬂammatory disorders, may have an effect on AD
and be inducing epigenetic changes as well or might
induce AD-like pathogenesis at a young age. Associations
between DNA-methylation patterns in the brain and aging
are possible44 and have been reported in various regions of
the brain.45 Since DNA epigenetic mechanisms have a role in
memory formation and its maintenance, just as decrease in
DNA methylation deteriorates neuronal plasticity, leading to
memory loss, it is speculated that understanding of epigenetic
mechanisms is important to understand aging and associated
complexities in AD patients.46 In addition to DNA methylation, histone modiﬁcations may also play an important role.
Studies have explored histone acetylation in APP–PSEN1
double-mutant transgenic mice, where impairment in associative learning was connected to H4K14 histone-acetylation
reduction.47 Additionally Histone deacetylase (HDAC) inhibitors also have an effect on Aβ production and aggregation
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in AD mice. Studies involving their inhibitors, such as trichostatin A, valproic acid, and vorinostat, are promising. Therefore,
it becomes of the utmost importance to understand epigenetic
mechanisms involved in aging, in order to target ADassociated mechanisms and complexities.48
Microglial inﬁltration during plaque
formation leading to
neurodegeneration
In addition to extracellular Aβ plaques and NFTs due to τ
hyperphosphorylation, microglial inﬁltration in response to
these aggregates exacerbates AD pathogenesis. In addition
to plaques and tangles, a diversity of morphological variants of Aβ deposits is found in the AD brain. Extracellular
and intracellular Aβ and tangles cause extreme toxicity,
resulting in synaptic damage and increased reactive oxidative stress, which then leads to microglial inﬁltration
around the plaque areas. Microglia are resident phagocytes
in the CNS and play a vital role in the maintenance of
neuronal plasticity and synapse remodeling.49 Microglia
get activated by protein accumulation, which acts as
a pathological trigger, migrate, and initiate innate immunresponses (Figure 5).50 Aβ plaques activate Toll-like
receptors on microglia, leading to microglial activation
and secretion of proinﬂammatory cytokines and
chemokines.50
In AD, microglia can bind to Aβ via cell-surface
receptors, including SCARA1, CD36, CD14, α6β1 integrin, CD47, and Toll-like receptors.51,52 Following receptor
binding, microglia endocytose Aβ oligomers and NFT
ﬁbrils, which are eliminated by endolysosomal degradation. Microglial proteases like neprilysin and insulindegrading enzyme play major roles in the degradation.53
However, in severe cases of AD, microglial clearance of
Aβ is inefﬁcient, due to increased localized cytokine concentrations, which downregulate the expression of Aβphagocytosis receptors and decrease Aβ clearance.54 One
of the factors behind compromised AD clearance by
microglia is Triggering receptor expressed on myeloid
cells 2 (TREM2) mutation. TREM2 mutations are associated with increased AD severity. TREM2 is a cellsurface receptor of the Ig superfamily highly expressed
on microglia and involved in mediating phagocytic clearance of neuronal debris. It also binds anionic carbohydrates, bacterial products, and phospholipids and
transmits intracellular signals through the associated transmembrane adaptor DAP1255 and further phosphorylation
of downstream mediators.56
During AD, a rare mutation of TREM2 (R47H) has been
reported that plays a potent role in aggravating the risk of
developing AD.57 This mutation leads to inability of the receptors to clear Aβ from the CNS, contributing to Aβ accumulation and further intensiﬁcation of pathogenesis in AD patients.
β
secretases
γ
secretases
APP
PS1/2
mutations
Amyloid beta
Oxidative stress
inflammation
Amyloid beta
fibrils
Amyloid beta fibrils
activating microglias
Senile plaques
Altered kinase
and
phosphatase
Tau
Neurofibrillary
tangles
Neuronal damage and death
AD progression
Figure 5 Mechanism of neuronal damage and Alzheimer’s disease (AD) progression.
Note: Extracellular and intracellular amyloid β and tangles cause extreme toxicity, resulting in synaptic damage and increased reactive oxidative stress that then leads to
microglial inﬁltration around the plaque areas.
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Aβ and HIV1-associated
neurological disorders
Currently, disease-associated neurological disorders are the
biggest area of concern. In this era ofantiretroviral therapy
(ART), with the increase number of aged HIV patients, the
incidence of dementia or other neurocognitive functions is
increasing in aged patients when compared to younger
patients.58 In AD, there are neurological dysfunctions due to
abnormal accumulation of extracellular Aβ produced by alternate cleavage of APP. This Aβ deposition is also reported to
occur in the cortices of HIV patients when compared to agematched non-HIV controls.59–62 The increased AD-like indications, with increased Aβ levels, during HIV infection are not
well understood. It is hypothesized that Aβ deposition may be
a common factor aggravating in HIV1 infection, thus contributing toward HIV1-associated neurocognitive disorders. If Aβ is
the common factor between AD and HIV1-disease scenarios, it
becomes imperative to address targeting oftheAβ pathway and
end products with a single efﬁcacious drug molecule. With the
increase in aging in HIV patients, due to the introduction of
ART, a signiﬁcantly higher occurrence of dementia/neurocognitive dysfunctions has been observed in aged HIV1-infected
individuals than younger patients, and HIV1-associated dementia risk in these patients is three times that of younger people.58
The prevalence of HIV1-associated neurocognitive disorders is
increasing, as continuing ART medication causes subtle neurodegeneration, especially in hippocampal neurons. Additionally,
increased Aβ deposition is characteristic of HIV1-infected
brains, and it has been hypothesized that brain vascular dysfunction contributes to this phenomenon, with a critical role
suggested for the BBB in brain Aβ homeostasis.
State of the art: AD therapeutics
AD involves protein misfolding, which distorts cellular systems
and neuronal death. Protein misfolding results in either loss or
toxic gain of function of a protein. This might occur due to
abnormal protein aggregation, upon which the protein no longer
performs its normal role and fails to be cleared by the cellular
environment, leading to deleterious biological responses. There
are constant AD studies on inhibiting the production of misfolding proteins and their aggregation and spread to limit the
toxicity caused by abnormal proteins.63 The majority of ADtherapeutic approaches are focused on reducing levels of toxic
forms of Aβ and τ, the broad scope of neurodegenerative
processes underlying both early- and late-stage AD. Several
drugs have been analyzed and have reached Phase I, II, and III
clinical trials. Table 1 summarizes the drugs speciﬁc to amyloid
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that are being studied and which target sufﬁciently fundamental
and proximate degenerative mechanisms.64,65
However, all these current therapeutic (eg, rivastigmine,
galantamine, and donepezil) targets appear secondary, and
none is currently thought to be causally involved in the development of AD. Therapy failure frequently occurs due to the
unfavorable pharmacokinetics and pharmacodynamics of
drugs. Pharmacotherapy failure is the result of inadequate
physical chemistry of drugs (such as hydrophobicity), unfavorable absorption by biological membranes, unfavorable pharmacokinetic parameters (such as intense and plasma
metabolism), instability of drugs (oxidation, hydrolysis, or
photolysis), and toxicity to tissue (hepatotoxicity, neurotoxicity, or kidney toxicity).
Several treatment strategies have been proposed and
attempted for the removal of Aβ. Several drugs are employed
for Aβ degradation, but the majority of drugs that showed
promising results in in-vivo studies were not able to clear
human clinical trials and failed, creating an urgent need to
develop new strategies. Many of the available drugs lose their
efﬁcacy while crossing the BBB and are minimally bioavailable
in the brain. This requires a new area of study that expands into
efﬁcacious neuroprotective strategies speciﬁc to the CNS. NPs
are intriguing candidates for this purpose, because of their
potential for multifunctionalization, enabling them to mimic
the physiological mechanisms of transport across the BBB.
This barrier is an important physical fence made of cells protecting the brain from potential hazardous substances in the
bloodstream; however, it also prevents the passage of 98% of
available neuropharmaceuticals and diagnostics.
Diagnostics for AD: labeling and
imaging
Current AD diagnosis is primarily based on neuropsychological testing. A clinical diagnosis of AD requires neuroimaging and monitoring accepted biomarkers, eg,
concentrations of Aβpeptides (Aβ1–42:Aβ1–40 ratio) as
well as total and hyperphosphorylated τ (Thr181 and
Thr231) proteins in the CSF. Amyloid oligomers and plaque accumulation can also be imaged with 18F-ﬂorbetapir
(or alternatively 11C Pittsburgh compound B) positronemission tomography (PET) but nonlinear association
between Aβ content in CSF and PET scans remains of
concern. However, CSF sampling is relatively invasive
and is not always well tolerated or feasible in a number
of elderly patients. Noninvasive imaging methods, such as
ﬂudeoxyglucose PET, which gives insights into brain
metabolism, are of great clinical utility. Indeed, altered
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Table 1 Drugs speciﬁc to amyloid that target fundamental and proximate degenerative mechanisms
Agents
Trials
Target
Action
Aducanumab
Albumin + immunoglobulin
Phase I
Phase I
Antiamyloid
Antiamyloid
AZD3293 (LY3314814)
Phase I
Antiamyloid
BACE1 inhibitor
CAD106
CNP520
Phase I
PhaseI
Antiamyloid
Antiamyloid
Amyloid vaccine
BACE inhibitor
E2609
PhaseI
Antiamyloid
BACE inhibitor
Gantenerumab
Nilvadipine
PhaseI
PhaseI
Antiamyloid
Antiamyloid
Monoclonal antibody
Calcium-channel blocker
Solanezumab
ATP
PhaseI
PhaseII
Antiamyloid
Antiamyloid
Monoclonal antibody
Amyloid misfolding and toxicity
Monoclonal antibody
Polyclonal antibody
Atomoxetine
PhaseII
Antiamyloid
Adrenergic uptake inhibitor
AZD0530 (saracatinib)
Crenezumab
PhaseII
PhaseII
Antiamyloid
Antiamyloid
Kinase inhibitor
Monoclonal antibody
JNJ54, -861, -911
PhaseII
Antiamyloid
BACE inhibitor
Posiphen
Sargramostim (GM-CSF)
PhaseII
PhaseII
Antiamyloid
Antiamyloid
Selective inhibitor of APP production
Amyloid removal
UB311
Phase II
Antiamyloid
Monoclonal antibody
Valacyclovir
Aducanumab
Phase II
PhaseIII
Antiamyloid
Antiamyloid
Antiviral agent
Monoclonal antibody
KHK6640
PhaseIII
Antiamyloid
Amyloid-aggregation inhibitor
Lu AF20513
LY2599666 + solanezumab
PhaseIII
PhaseIII
Antiamyloid
Antiamyloid
Polyclonal antibody
Monoclonal antibody combination
NGP 555
PhaseIII
Antiamyloid
γ-secretase modulator
MK8931 (verubecestat)
Phase III
Antiamyloid
BACE inhibitor
cerebral metabolism (hyper- and hypometabolism) has
been associated with different stages of AD. Magnetic
resonance imaging (MRI) at increasing ﬁeld strength and
resolution is another helpful, noninvasive approach for
identiﬁcation of functional abnormalities. MRI is utilized
for detection and identiﬁcation of amyloid plaques utilizing iron oxide NPs as contrast agents or tagged with
ﬂuorescent probes to make detection efﬁcient.66 These
iron oxide NPs are reported to bind to N terminal of Aβ
, aiding their imaging. Additionally, nonﬂuorescent or
ﬂuorescent rhodamine tagged γFe2O3 NPs have been
reported to label Aβ ﬁbrils selectively and remove them
from solubilized Aβ, by employing external magnetic
ﬁeld.67,68 In addition to iron NPs, there have been reports
of polystyrene-block-poly (n-butyl cyanoacrylate) NPs
encapsulating thioﬂavin T to target Aβ.69 Gold NPs have
been used in MRI as contrasting agents to study structural
stages in Aβ self-assembly70 and ﬂuorescent semiconductor nanocrystals (quantum dots) for labeling.71
For sensing soluble forms of Aβ from CSF, an ultrasensitive NP-based biobarcode system that speciﬁcally detects
soluble oligomers with the aid of oligonucleotide (DNA
barcode)-modiﬁed AuNPs and magnetic microparticles
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functionalized with monoclonal/polyclonal antibodies have
been used,72 as well as electrochemical sensing utilizing
click chemistry, which involves AuNPs and assembled
monolayers thereon to interact with Aβ peptide,73 and ultrasensitive electrical detection for Aβ1–42 using scanning tunneling microscopy.74 These recently achieved technological
and conceptual achievements have considerably
improved AD diagnosis. Once AD is diagnosed, the therapeutic choice concerns the treatments that are only diseasemodifying and offer relatively limited beneﬁt.
Need for nanotechnology as
a therapeutic strategy across the
BBB
There are promising drugs against Aβ toxicity,75 but in
order to explore their maximum effect on CNS cells,
there is a need of nanocarriers to be employed.
Availability of drugs in the CNS is the major issue
faced in the ﬁeld of therapeutics against AD. The main
reason is the presence of a fully functional semipermeable BBB, which poses as an obstacle for transmigration
of neurotherapeutic molecules (like drugs, peptides,
International Journal of Nanomedicine 2019:14
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Tiwari et al
vectors, and molecules) across it, into the CNS. The
BBB and its selective transport of molecules into the
brain oppose efﬁcacious delivery of therapeutic agents.
In addition, the BBB also negatively affects drug efﬁcacy and tolerance, because large doses of drugs are
needed to reach levels above the minimum effective
concentration in the brain. Nanotechnology inclusive of
nanoparticulate systems offer an opportunity to overcome such problems and can be used as Trojan-horse
systems for transporting active molecules across the
BBB (Figure 6), thus reducing toxicity and improving
therapeutic efﬁcacy.76,77
The use of drugs in nanoplatforms or nanodevices results
in enhancement of their pharmacokinetics and pharmacodynamics, as well as reduces the toxicity. An essential aspect in
nanomedicine development is the delivery of drugs and controlled release of drugs into disease sites. Therefore, the
effectiveness of a treatment can be increased by incorporating nanotechnology-based drug-delivery systems. These new
Blood brain barrier
Capillary
Capillary
Brain
NPs
Figure 6 Semipermeable blood–brain barrier and transmigration route of the
nanoparticles (NPs).
International Journal of Nanomedicine 2019:14
platforms aim to improve bioavailability across the BBB,
pharmacokinetics, and pharmacodynamics of drugs while
reducing their side effects.
In brief, recent nanotechnology advancements propose
effective diagnostic and therapeutic options. Targeted drug
delivery with the aid of NPs 100 nm in size can effectively
increase drug bioavailability across the BBB into the CNS
with minimal or no side effects. Furthermore, these nanomaterials are designed to be biocompatible, hence reducing toxicity, plus with the advancement in their magnetic
and optical properties, they may be efﬁcient alternative
agents for an early diagnosis.78 The delivery of saxagliptin
via dipeptidyl peptidase 4 enzyme–inhibitor molecules is
now being explored for its activity in the therapy of AD,
with the aid of a chitosan–L-valine conjugate used to
prepare NPs encapsulating saxagliptin. These NPs are
stable and crossed the BBB efﬁciently.79 Furthermore,
one of the most efﬁcient nanocarriers is magnetoelectric
NPs (MENPs), which have been studied well for their
potency in delivering drugs across the BBB noninvasively
and on-demand release of drugs to target areas without
adverse effects. The on-demand release feature is really
important, as it ensures delivery of exact amounts of
drugs, which is efﬁcacious physiologically without causing toxicity.80–83 Their applications in drug delivery have
been well reported in the ﬁeld of neuroAIDS and AD.83–86
Research interest in nanotherapeutics, ie, utilizing
nanocarriers to carry drugs across the BBB, is growing
continuously and positively, as these NPs aid efﬁcient
drug-delivery systems. The advantages of NPs over plain
drugs or microdrug systems are many, including bigger
surface area (higher drug loading) and a diverse range of
biomaterials, organic (natural or synthetic polymers), and
inorganic (metals) compounds for NP production. The
interaction between the drug moiety and NPs is diverse.
It can be covalent binding, the presence of an ionic surface
charge (ionic binding), direct adsorption, or surface binding, and entrapment of the drug. NP surfaces can be
modiﬁed as well to aid drug binding, such as with
PEGylation, which is the process of covalent/noncovalent
amalgamation of polyethylene glycol (PEG) to the
surface.87–91 Additionally, they increase target speciﬁcity
via ligand binding. NPs can be modiﬁed and imbued with
unique physicochemical properties, ie, the addition of
metal or electrical attributes, like MENPs, which facilitates drug transport across the BBB, on demand with the
introduction of externally applied electric or magnetic
ﬁelds, increasing the drug delivery severalfold. NPs can
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5549
Tiwari et al
have their surface charges altered to interact with the BBB
(negatively charged), hence introducing ionic interaction
or pull toward the BBB. This charge alteration increases
the drug-loading capacity of NPs and aids in on-demand
release of the drugs.
MENPs are one of the most effective NP types for
noninvasive and image-guided personalized therapy
against CNS diseases. They have a unique magnetoelectric
actuation effect, which allows longitudinal noninvasive
monitoring utilizing MRI,92,93 contributing to imageguided therapy. In addition, liposomal NPs are also potent
candidates in drug delivery, as they can be easily surfacemodiﬁed, facilitating loading of both the hydrophilic and
hydrophobic drugs, and aid sustained release across the
BBB. They can also be tagged with ﬂuorescent lipids,
which can help in image-guided therapy by being able to
be observed under microscopy. Plasmonic carbonnano–
tube–based systems against CNS diseases have been well
studied.
Challenges for clinical translation
With the advent of NPs, various types, such as gold NPs,
metal NPs, silver NPs, silica, hydrogels, liposomes,
and magnetic NPs, are being employed in drug-delivery
studies at a rapid rate. NPs are being explored for CNS
drug delivery at the clinical level. The US Food and Drug
Administration (FDA) and National Institutes of Health are
supporting the concept of personalized nano-medicine,
which may usher in a revolution in drug delivery across
the BBB, contributing to better health care and more opportunities to combat CNS diseases.94 The success of preclinical studies on CNS nanomedicine95–98 may act as a base to
examine these strategies at a clinical level to test biocompatibility, toxicity, efﬁcacy, availability at the human-patient
level. Clinical translation of these NPs against CNS diseases
at the patient level depends on a lot of factors, eg, patient
diversity, genetic and environmental effects, combination of
multiple diseases, toxicity, efﬁcacy, and bioavailability in
the brain. Based on the patient-disease proﬁle, these NPs
can be designed and modiﬁed to provide personalized nanomedicine, which can be more beneﬁcial to the individual.
This requires proper understanding of the disease mechanism, and even predictive methods utilizing bioinformatics
can be utilized to understand disease progression and then
design the therapeutic accordingly. With respect to CNS
therapy, several studies have highlighted the importance of
nanotechnology application for disease diagnosis, drug
delivery, and theranostic application. Though, the majority
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of current research is at the preclinical level, the success of
these preclinical and in vivo studies provides promising
potential to be translated to clinical levels. Safety, efﬁcacy,
and regulatory issues are the major challenges for the progression of personalized nanomedicine to treat CNS diseases clinically. Novel methods like ultrasound-mediated
BBB disruption by opening the BBB noninvasively applying external stimulation like focused ultrasound or electromagnetic ﬁelds can be promising, but these methods may
result in side effects like neurobehavioral distortions or
induced infection from entry of unwanted molecules during
forced opening of the BBB.99 Therefore, controlled parameters of these stimulations are very critical at clinical
levels, as not only can they modulate the intrinsic properties
of the introduced NPs by heating them or modifying their
surfaces they can also disrupt the homeostasis of the CNS
by disturbing BBB permeability, causing inward ﬂow of
unwanted circulating molecules into the CNS, leading to
neurotoxicity, dysfunction, immunohyperactivation, inﬂammation, release of reactive oxygen species, synaptic
damage, and oxidative stress, contributing to fatal neuronal
injury.96,97 Therefore, even though nanotechnology-based
research is promising, it has a long way to go to be translated from bench to bedside therapy. There is an urgent need
to addressing the issues of toxicity, bioavailability, pharmacokinetics, clearance, and metabolism of NPs for successful
clinical trials. There challenges, highlighted by the FDA,
focus on biodistribution of NPs, modes of administration,
ability of NPs to carry multiple drugs, efﬁcacious transmigration across the BBB, risk assessments, toxicity, standards, safety, procedures, and validation.100 The quest to
address the biocompatibility issues, surface functionalization, endosomal entrapment, enzymatic degradation, and
off-targeting issues is ongoing through the introduction of
surface functionalization, preservation strategies to minimize side effects of external stimulation, and maintaining
the availability of drugs in the CNS for longer periods.
Progression toward personalized nanomedicine is challenging, but it is critical for successful future clinical trials to
make nanotherapeutics available at the patient level.
Summary and future perspectives
AD is a neurodegenerative disease affecting people worldwide. Clinically, it is characterized by the presence of extracellular amyloid plaques and intracellular NFTs, resulting in
neuronal dysfunction. Amyloid aggregation happens due to
differential cleavage of APP sequentially by β-secretase and
γ-secretase, leading to release of extracellular Aβ40/
International Journal of Nanomedicine 2019:14
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Aβ42. AD is also characterized by the presence of NFTs.
These tangles are the result of hyperphosphorylation of the
microtubule-associated protein τ. GSK3 and CDK5 are the
kinases primarily responsible for phosphorylation of τ. In
addition to plaque and tangle aggregation, microglial aggregation at the site also plays a vital role in triggering innate
immunoresponses against aggregation. A rare mutation
paralyzes the regular functioning of microglial surface receptors, contributing to AD intensiﬁcation. Understanding all
these factors and then designing therapeutics speciﬁc to
targeting them is the need of the hour.
AD is one of the most common neurodegenerative diseases
today, but unfortunately101 there is no cure available currently.
Several treatments are being employed to combat the cognitive
and behavioral deﬁcits associated with AD. Development of
a targeted efﬁcacious therapeutic approach against AD is still in
its developmental stage, and thus the need of the hour is to look
at cellular factors closely associated with disease pathogenesis
and target these for improvement of quality of life for AD
patients. Cellular factors discussed in this paper, like Aβ, APP,
secretases, CDK5, and GSK3β, could be key targets for
a therapeutic approach. It is of the utmost importance to understand the limitations of drug bioavailability in the CNS due to
the tightly controlled permeability of the BBB. Drugs that
targetAβsynthesis or suppress formation of NFTs can stop or
reverse AD. Nanomedicine offers an attractive approach to
delivering drugs across the BBB.85,86,102,103 Nanotechnology
pertains to nanosized drug molecules and their efﬁcient delivery
and controlled release in the brain by external magnetic ﬁelds,
which could be a promising factor in therapeutics for AD. The
need of the hour is to unravel the mechanisms of the genesis
of AD, its early detection using state-of-the-art biosening
devises, speciﬁc targeting of the molecules associated with the
disease’s manifestation, and efﬁcient delivery of optimum drugs
to the brain using novel nanotechnology approaches. Further,
studies of comorbidities of AD with other diseases or viral
infections are also very important to understand and exploit
therapeutic approaches.
Abbreviations
AD, Alzheimer’s disease; Aβ, Amyloid β; BBB, blood–
brain barrier; CNS, central nervous system; CSF, cerebrospinal ﬂuid; NFTs, neuroﬁbrillary tangles; PCD, protein-conformational disease.
Acknowledgments
The authors acknowledge ﬁnancial support from NIH grant
R01DA034547 and the Florida Department of Health’s Ed
International Journal of Nanomedicine 2019:14
Tiwari et al
and Ethel Moore Alzheimer’s Disease Research Program
(grant # 8AZ04). We would also like to acknowledge the
Dissertation Year Fellowship 2018 awarded to ST (graduate
student) by the University Graduate School, Florida
International University, Miami, FL, USA.
Disclosure
The authors report no conﬂicts of interest in this work.
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International Journal of Nanomedicine 2019:14
DRUG THERAPIES IN…
Clinical Medicine 2016 Vol 16, No 3: 247–53
Drug treatments in Alzheimer’s disease
ABSTRACT
Authors: Robert Briggs, A Sean P KennellyB and Desmond O’NeillC
Despite the signiﬁcant public health issue that it poses, only
ﬁve medical treatments have been approved for Alzheimer’s
disease (AD) and these act to control symptoms rather than
alter the course of the disease. Studies of potential diseasemodifying therapy have generally been undertaken in patients
with clinically detectable disease, yet evidence suggests that
the pathological changes associated with AD begin several
years before this. It is possible that pharmacological therapy
may be beneﬁcial in this pre-clinical stage before the neurodegenerative process is established. Techniques providing
earlier diagnosis, such as cerebrospinal ﬂuid biomarkers and
amyloid positron emission tomography neuroimaging, are key
to testing this theory in clinical trials. Recent results from trials
of agents such as aducanumab are encouraging but must also
be interpreted with caution. Such medicines could potentially
delay the onset of dementia and would therefore markedly
reduce its prevalence. However, we currently remain a good distance away from clinically available disease-modifying therapy.
KEYWORDS:: Alzheimer’s disease, pharmacological therapy,
amyloid
Introduction
Dementia is a general term for a decline in cognitive ability
severe enough to interfere with daily life. Alzheimer’s disease
(AD) accounts for almost three-quarters of cases of dementia,
with the remainder accounted for by vascular dementia (VaD),
mixed Alzheimer’s and VaD, dementia with Lewy bodies, and
frontotemporal dementia.
To many clinicians, the contrast between the significant
advances in the last two decades in medical treatment for a
wide range of illnesses, including targeted therapies, such
as herceptin, for many cancers, as well as revolutionary
combination drug therapies for HIV, and the lack of progress
Authors: Aresearch fellow, Centre for Ageing, Neuroscience and the
Humanities, Trinity Centre for Health Sciences, Tallaght Hospital,
Dublin, Ireland; Bconsultant geriatrician and stroke physician,
Centre for Ageing, Neuroscience and the Humanities, Trinity Centre
for Health Sciences, Tallaght Hospital, Dublin, Ireland; Cconsultant
geriatrician and professor of medical gerontology, Centre for
Ageing, Neuroscience and the Humanities, Trinity Centre for Health
Sciences, Tallaght Hospital, Dublin, Ireland
© Royal College of Physicians 2016. All rights reserved.
CMJv16n3-Briggs.indd 247
in the pharmacological treatment of dementia due to AD and
other causes is surprising. However, it is increasingly clear that
whereas the former illnesses are almost invariably well-defined
and circumscribed disease entities, the syndrome of dementia
is a multifactorial condition for most patients,1 and even within
diagnostic entities such as AD, it is likely that there are subclassifications of therapeutic significance.
Both of these findings have significant ramifications
for treatment. The enmeshing of vascular disease and
neurodegenerative illness in later life mean that dementia in
later life is best viewed as a geriatric syndrome. The relevance of
this conceptualisation is that geriatric syndromes, such as falls,
rarely respond to single interventions, and pharmacological
interventions are likely to succeed best in terms of one
component of a package, which might include medication
review, nutrition and exercise intervention, and cognitive
stimulation/training, an approach supported by a recent
multi-modal intervention study among older people at risk of
developing dementia.2
Despite the significant public health issue that dementia
poses, to date only five medical treatments have been approved
for AD, involving only two classes of drugs, and these act to
control symptoms rather than alter the course of the disease.
Additionally, relatively few clinical trials have been undertaken
in AD in the last decade, and these have had a 99.6% failure
rate.3 As a result, the goal of disease-modifying therapy remains
elusive, with the currently available medications acting to
control symptoms only. In this review, we summarise current
pharmacological treatment for AD, as well as highlighting
potential future therapies, while reflecting on the underlying
aetiological mechanisms on which these treatments are based.
Neurodegenerative pathways implicated in AD
Several overlapping mechanisms have been proposed to explain
the underlying pathology of AD, and both current and potential
future treatments are based on modification of these pathways
(Fig 1).
Amyloid cascade hypothesis
The amyloid hypothesis of AD began to gain traction in the
1990s, and centres on abnormal processing of the amyloid
precursor protein (APP), leading to production of amyloidbeta (Aβ).4 Secretase enzymes cleave APP and aberrancy
of this process, specifically mutations in gamma and betasecretases, can lead to the abnormal production of Aβ.5 Aβ
247
23/04/16 11:14 AM
Robert Briggs, Sean P Kennelly and Desmond O’Neill
Amyloid precursor protein
A
Amyloid-beta generaon
Fig 1. Aetiology of Alzheimer’s
disease with therapeutic
targets. A – secretase enzyme
inhibitors; B – NMDA receptor
modulators, eg memantine;
C – immunotherapy, including
immunisation and direct antiamyloid therapy, including monoclonal antibodies; D – anti-tau
therapy; E – anti-inﬂammatory
treatments, including NSAIDs;
F – anticholinesterase inhibitors,
eg donepezil. APP = amyloid precursor protein; NFTs = neuroﬁbrillary tangles; NMDA = N-methyl-Daspartate; NSAIDs = non-steroidal
anti-inﬂammatory drugs.
Amyloid-beta
aggregaon
Excitotoxicity
B
C
E
NFTs
Neurotoxicity
Tau hypothesis
Tau is a protein expressed in neurons that normally functions
in the stabilisation of microtubules in the cell cytoskeleton.7
Hyperphosphorylation causes it to accumulate into these NFT
masses inside nerve cell bodies. These tangles then aberrantly
interact with cellular proteins, preventing them from executing
their normal functions. Hyperphosphorylation occurs
downstream of Aβ, with research suggesting that accumulation
of Aβ may initiate this process.8 Additionally, there is evidence
that toxic tau can enhance Aβ production via a feedback loop
mechanism.9
Cholinergic hypothesis
An initial breakthrough in AD came in the 1970s with
the demonstration of a cholinergic deficit in the brains of
patients with AD, mediated by deficits in the enzyme choline
acetyltransferase.10 This, along with the recognition of the role
of acetylcholine in memory and learning, led to the cholinergic
hypothesis of AD and stimulated attempts to therapeutically
increase cholinergic activity. Cholinergic depletion is a late
feature of the neurodegenerative cascade. Cholinesterase
inhibitors block the cholinesterase enzyme, which breaks down
acetyl choline at the synaptic cleft, potentiating cholinergic
transmission.
Excitotoxicity
Excitotoxicity, defined as overexposure to the neurotransmitter
glutamate, or overstimulation of its N-methyl-D-aspartate
CMJv16n3-Briggs.indd 248
Neuroinﬂammaon
D
Amyloid
plaques
can then trigger a cascade leading to synaptic damage and
neuron loss, and ultimately to the pathological hallmarks
of AD: amyloid plaques and neurofibrillary tangles (NFTs)
composed of hyperphosphorylated tau protein, with resulting
neurodegeneration (Fig 1).6
248
Hyperphosphorylaon
of Tau
F
Neurotransmier
deﬁcit
Clinical demena
(NMDA) receptor, plays an important role in the progressive
neuronal loss of AD.11 It is thought that loss of cholinergic
neurons is affected by this process, resulting in excessive influx
of calcium into cells.
Other important aetiological mechanisms
Vascular disease
While traditionally it was felt that vascular disease was the
underlying factor in the development of VaD, it is clear that
vascular burden also plays a role in AD pathogenesis, and
that there is significant overlap between these two dementia
subtypes.12 Vascular risk factors, such as high BMI, smoking,
hypercholesterolemia and hypertension, have been associated
with an increased risk of developing clinical AD.13 While
vascular lesions such as cerebral amyloid angiopathy and
white matter hyperintensities are common in patients with
AD,14 hypertension is also associated with the development of
specific neuropathological hallmarks of AD such as NFTs,15
and this association appears to be stronger when hypertension
is present in mid rather than late life.16 Thus, vascular disease
may directly affect amyloid plaques or NFTs by increasing their
formation or reducing their elimination from the brain.17
Given these findings, it would seem to follow that control of
vascular risk factors may slow the rate of decline of cognition
in patients with AD; however, this is not yet supported by data
from randomised controlled trials.18
Diabetes and hyperinsulinaemia
There is a well-established association between diabetes
and AD19 and while vascular burden undoubtedly plays a
role in this, it appears insulin dysregulation and abnormal
central nervous system (CNS) insulin metabolism20 are
also important independent factors. Insulin can cross the
blood–brain barrier and is also produced in the CNS. Some
studies have suggested a role for CNS insulin in controlling tau
© Royal College of Physicians 2016. All rights reserved.
23/04/16 11:14 AM
Drug treatments in Alzheimer’s disease
phosphorylation and protecting against Aβ accumulation via
insulin degrading enzyme,21 while others have demonstrated
lower levels of insulin in the cerebrospinal fluid (CSF) of
people with AD.22 The potential pathway for this involves
peripheral hyperinsulinaemia downregulating insulin uptake
across the blood–brain barrier because of oversaturation above
physiological levels.23 This results in the downregulation
of insulin-degrading enzyme in the brain, which mediates
amyloid clearance. Less insulin signalling may also enhance the
activity of the enzyme glycogen synthase kinase 3, which can
promote formation of tau and NFTs.24
These findings have led to the theory that drugs used in
diabetes may be able to modify the pathophysiology of AD25
and a study of intranasal insulin as a therapy in mild cognitive
impairment (MCI) and AD is currently being conducted after
encouraging results from small pilot studies.26
Apolipoprotein gene
The Apo epsilon 4 (Apoe4) allele of the apolipoprotein (apo)
gene, coding for a protein involved in cholesterol metabolism
and lipid transport, has been identified as the primary genetic
risk factor for AD.27 Individuals with one copy of the e4 allele
have a three-fold higher chance of developing AD, while those
with two alleles have an odds ratio of 14.9 for developing AD.28
The mechanism by which Apoe4 increases the risk of AD
remains unclear but it may act via its effect on Aβ aggregation
and clearance, thereby influencing the onset of Aβ deposition.
Other proposed mechanisms include effects on synaptic
function, neurotoxicity, hyperphosphorylation of tau, and
neuroinflammation.29 It has been proposed that modulation
of the Apo-related receptor at the blood–brain barrier may
offer a therapeutic target to affect Aβ clearance, while other
therapeutic options may include modulation of Apoe4 levels
or converting Apoe4 to Apoe3, but clinical trials are currently
lacking in this regard.30
Neuroinflammation
Neuroinflammation, an inflammatory response in the CNS
characterised by accumulation of glial cells, appears to be
a central event in AD pathophysiology.31 The brain was
traditionally considered an ‘immune-privileged’ organ,
isolated from the immune system by factors such as the
blood–brain barrier and apparent inability of brain immune
cells to mount an innate immune response, 32 but opinion
on this has subsequently shifted dramatically. In the 1990s,
seminal epidemiological evidence suggested that antiinflammatory drugs may have a protective effect in AD33
and neuroinflammatory cascades are now considered an
important target for treatment in AD,34 and both amyloid
plaques and NFTs may act as drivers for this immune
response.
Unfortunately, meta-analyses have demonstrated no benefit
of non-steroidal anti-inflammatory drugs, aspirin or steroids
over placebo in patients with already symptomatic AD; 35
however, some evidence suggests that naproxen may have a role
in prevention of AD in healthy older people.36 It may be that
the therapeutic window for such treatment occurs early in the
disease process and as such, by the time symptoms emerge, this
opportunity has been lost.37
© Royal College of Physicians 2016. All rights reserved.
CMJv16n3-Briggs.indd 249
Drug therapy
Much of the research in AD in the last decade has been directed
towards disease-modifying therapy that will alter the course
of the disease rather than act on symptoms alone, however
the lack of effective disease-modifying drugs arising from
these studies reflects the challenges involved in developing
a therapeutic agent with potential to modify the course of a
disease as complex as AD.38
Approved drug treatments
Cholinesterase inhibitors
Tacrine was the first-generation cholinesterase inhibitor but was
limited by hepatotoxic side effects.39 Donepezil, rivastigmine
and galantamine then followed, with the former probably the
most widely used agent.
Efficacy appears similar between these different agents so
choice should be based on cost, individual patient tolerance and
physician experience.
Donepezil is prescribed at an initial dose of 5 mg in the
evening, increased to 10 mg after one month if appropriate.40
Response is gauged by a rating of better memory, function or
behaviour by the patient or carer: there is no point in trying
to measure change with brief mental status schedules such as
the mini mental state examination, as these are not designed
to detect clinically relevant change. If there is no response
after three months of treatment it is reasonable to consider
stopping the medicine at that stage although opinions around
this can differ. Common side effects are gastrointestinal,
fatigue and muscle cramps, and all patients should have an
electrocardiogram prior to commencing a cholinesterase
inhibitor because of the risk of sick sinus syndrome and other
conduction abnormalities. Care should be taken if considering
commencing a cholinesterase inhibitor in a person with a
history of peptic or duodenal ulcer disease. Small numbers
of patients may exhibit an acute worsening of cognition or
agitation on starting; in which case, the medicine should be
stopped immediately.
Average effects on cognition and function are generally
modest41 and response rates are variable, with around onethird of patients showing no benefit and a smaller proportion
(around one-fifth) showing larger benefit. It is expected that
about one-third of patients may not tolerate a cholinesterase
inhibitor because of side effects.
Memantine
Memantine uncompetitively blocks the NMDA receptor42 and,
thus, may be neuroprotective by preventing neuron loss, as
well as improving symptoms by helping to restore function of
damaged neurons (Fig 1).
Memantine is initially prescribed at a dose of 5 mg daily,
increasing weekly by 5 mg to a maximum dose of 20 mg.40
It is generally well tolerated, with fewer side effects than
cholinesterase inhibitors, although dizziness, headache,
somnolence, constipation and hypertension can occur.
Memantine has been shown to have modest benefits in
moderate to severe AD, with little evidence supporting its
use in milder AD.43 Additionally, the addition of memantine
to donepezil monotherapy may be beneficial in those with
249
23/04/16 11:15 AM
Robert Briggs, Sean P Kennelly and Desmond O’Neill
mid-stage AD or who are deteriorating cognitively.44 Neither
memantine nor donepezil are beneficial in MCI.
While these medications represent our best current available
pharmacological treatments in AD, they have relatively
small average overall effect and do not alter the course of
the underlying neurodegenerative process. It is likely that
the down regulation of cholinergic transmission occurs
too far downstream in this process for treatments such as
cholinesterase inhibitors to exhibit such an effect.45 With this
in mind, targeting the pathological process ‘upstream’ has also
been the focus of much attention (Fig 1).
Potential future drug treatments
Anti-amyloid therapy
Until recently, several high-profile clinical trials of
pharmacological agents targeted at modifying this amyloid
cascade have been undertaken, with largely disappointing
results. These agents generally had three different target sites:
directly targeting Aβ, and either the gamma or beta-secretase
enzymes involved in APP cleavage.46
Beta-secretase enzyme
Small molecule beta-secretase inhibitors have demonstrated
reduced CSF beta-amyloid compared to controls. Phase II/
III clinical trials of two agents, AZD3293 and MK-8931, are
underway and due to be completed in 2019.47
Gamma-secretase enzyme
Phase III clinical trials of semagacestat, a small molecule
gamma-secretase inhibitor,48 including over 3,000 patients,
were discontinued in 2010 because of no improvement in
cognition in the study group and worsening cognition at higher
doses compared to controls.49 Incidence of skin cancer was also
higher in the study group.
Tarenflurbil, related to the NSAID flurbiprofen, has been
shown to reduce levels of Aβ by modulating the gammasecretase enzyme, but demonstrated no improvement in
cognition or function compared with placebo in phase III trials
involving almost 1,700 patients.50
Immunisation
The initial human clinical trial of active immunisation against
Aβ with the agent AN 1792 was stopped because of cases
of meningoencephalitis in 6% of subjects.51 Subsequently,
phase II trials of passive immunisation with intravenous
immunoglobulin containing Aβ antibodies in a small number
of patients with mild to moderate AD has been shown to be
safe and potentially efficacious but phase III studies found no
evidence for slowing progression of AD.52
Monoclonal antibodies
Bapineuzumab, a monoclonal antibody to Aβ,53 underwent a
phase III clinical trial from 2007 to 2012 in patients with mild
to moderate AD. It was shown to reduce the rate of amyloid
accumulation in Apoe4 carriers but did not demonstrate any
treatment effect on either cognitive or functional outcomes
despite engaging its target.54
250
CMJv16n3-Briggs.indd 250
However, another monoclonal antibody, solanezumab,
completed two phase III trials in 2012 and failed to reach
predefined end points in patients with mild to moderate AD.55
Subsequently, pooled analysis showed that cognitive scores in
a subgroup of patients with milder symptoms showed small
benefits and an extension study, where those previously taking
placebo crossed over to solanezumab, was undertaken. The
difference in cognitive scores between these two groups was
sustained for a further two years, suggesting that, while the
absolute benefit was small, solanezumab had a potentially
disease-modifying effect during the placebo-controlled
phase.56
While this may represent the first evidence of disease
modification on AD, results must be interpreted with caution57
and EXPEDITION 3, a placebo-controlled trial in mild AD,
is ongoing with the aim of clarifying the results seen in this
cohort.
Another monoclonal antibody, aducanumab, has shown
promising results in patients with pre-clinical and mild AD.
Phase Ib studies of 165 patients with pre-clinical/mild AD,
demonstrated dose-dependent reductions in brain Aβ, as well
as dose-dependent slowing of mini mental state examination
and clinical dementia rating at one year and phase III studies
are commencing soon.58
Tau-targeted therapy
Tau-targeted strategies that are currently in clinical trials
include agents to prevent hyperphosphorylation, as well as those
targeting microtubule stability and aggregation.59 Both lithium
and valproic acid may act to inhibit tau phosphorylation60 but
randomised controlled trials of these agents were negative.61
More recently, a phase II clinical trial of methylthioninium, a
tau aggregation inhibitor, has demonstrated minor benefits in
cognition in patients with both mild and moderate AD after
50 weeks therapy and there are plans to proceed to phase III
trials.62
Future directions
Studies of potentially disease-modifying therapy up to now
have generally been undertaken in patients with clinically
detectable, established disease, while mounting evidence
suggests that the pathological changes associated with dementia
begin to occur several years before the emergence of the clinical
syndrome.63 It is possible then that pharmacological therapy
may be more beneficial in this pre-clinical stage before the
neurodegenerative process has been established. Techniques to
provide earlier diagnosis are key to testing this theory in clinical
trials, facilitating trials in presymptomatic phases.
Early diagnosis
Currently, earlier diagnosis of AD is primarily based on CSF
and neuroimaging biomarkers, reflected in new research
diagnostic criteria for AD.
Cerebrospinal fluid biomarkers
Reflecting the underlying neuropathology of AD, CSF markers
of amyloid and tau are reliable diagnostic tools to detect
dementia. CSF Aβ42 is decreased in patients with AD, possibly
© Royal College of Physicians 2016. All rights reserved.
23/04/16 11:15 AM
Drug treatments in Alzheimer’s disease
because of deposition of the peptide in plaques.64 However, a
decreased ratio of Aβ42/Aβ40 appears to be a more reliable
marker than Aβ42 alone. Elevated total tau is a very sensitive
marker for detection of AD but is also increased in other
dementias, including VaD and frontotemporal dementia,
while elevated phosphorylated tau, the major component of
NFTs, is more specific than total tau. Combinations of these
CSF markers have been used to improve diagnostic potential
in early stages of AD, for example, MCI patients with both low
Aβ42 and high tau levels were shown to have a substantially
increased risk of developing AD.65 Despite this, the
discriminatory power of CSF biomarkers in the differential
diagnosis remains somewhat suboptimal as a lone diagnostic
test66 and current strategies for presymptomatic evaluation
involve combining results with neuroimaging findings.
Neuroimaging
Traditionally, structural neuroimaging in AD was used to rule
out alternative diagnoses when presentations were atypical,
eg brain tumours. However, functional imaging modalities
such as 18F-fluorodeoxyglucose positron emission tomography
(FDG-PET), are now able to detect loss of neuronal function
in asymptomatic individuals by measuring cerebral metabolic
rates of glucose metabolism (CMRglc), a surrogate marker for
neuronal activity.67 Patients with early AD demonstrate reduced
CMRglc in parietotemporal, frontal and posterior cingulate
cortices.68 These changes have also been shown to precede the
onset of symptoms in individuals genetically at risk for AD,69 as
well as in patients with MCI.70 However, there is some overlap
of the hypometabolic regions found in AD with those found
in other dementia subtypes, and the additional use of amyloid
PET, which can estimate amyloid plaque surface area, improves
diagnostic accuracy.71
Re-evaluating research diagnostic criteria
The need for presymptomatic diagnosis of AD has dictated
that new research diagnostic criteria have been proposed,
formalising the view that AD exists on a continuum from the
presymptomatic phase, to a symptomatic, pre-dementia phase
(MCI) and then to AD.72 In these new criteria, biomarkers
are used to establish the presence of presymptomatic AD in
research subjects with no or very subtle overt symptoms. Three
pre-clinical stages of AD are proposed for research purposes:
asymptomatic amyloidosis, asymptomatic amyloidosis with
neurodegeneration, amyloidosis with neurodegeneration and
subtle cognitive decline.73
These diagnostic criteria will facilitate a more formalised
approach to the diagnosis of presymptomatic AD and provide
a framework for studying early interventions in AD. While this
definition of presymptomatic AD is certainly useful to, and
will be primarily used in the research environment, we must
also be mindful of the ethical implications of presymptomatic
diagnosis of a disease with relatively ineffective available
medical treatment.
Better trial design
Better selection of patients for clinical trials may yield
more favourable clinical outcomes. For example, the ‘mild
to moderate’ AD group may be too heterogeneous, and
© Royal College of Physicians 2016. All rights reserved.
CMJv16n3-Briggs.indd 251
treatment effects within subgroups could be lost, as seen in
the solanezumab trials. As well as earlier diagnosis, advanced
biomarker analysis may also facilitate better selection of study
subjects by allowing selection of patients with more uniform
underlying pathology for targeted trials. This individualised
approach would mirror several cancer therapies where bespoke
treatment is targeted at specific patients, using markers such as
HER2.
Conclusion
Given the rising prevalence of dementia, and the relative
inadequacy of current available pharmacological treatment,
the need to develop and implement new therapies is pressing.
Recent results from trials of agents in AD with potential
disease-modifying effects are encouraging but must also be
interpreted with caution. Such medicines could potentially
delay the onset of dementia and would therefore markedly
reduce its prevalence and impact;74 however, currently
we remain a good distance away from clinically available
disease-modifying therapy. One would hope, however, that
with advancing neuroimaging techniques and biochemical
biomarkers, and an enhanced understanding of the underlying
pathological processes involved, that this becomes a realistic
goal in the near future.
In addition, while focus on the development of new therapies
is very welcome, we must also be mindful that dementia is a
multifaceted, complex disease, which by its nature directs a
need for a multidisciplinary approach to care. Our focus in
managing patients with dementia must remain well rounded
and holistic, concentrating not just on pharmacological therapy
but also on the complex biopsychosocial aspects of caring for
this group of patients. ■
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