Download Alzheimer`s Disease review: targets for early intervention

ALZHEIMER’S DISEASE REVIEW: TARGETS FOR EARLY INTERVENTION
by
Joshua A. Penderville
B.S., University of Pittsburgh, 2012
Submitted to the Graduate Faculty of
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Public Health
University of Pittsburgh
2015
UNIVERSITY OF PITTSBURGH
GRADUATE SCHOOL OF PUBLIC HEALTH
This essay is submitted
by
Joshua A. Penderville
on
April 15, 2015
and approved by
Essay Advisor:
Iva Miljkovic, MD, PhD
Assistant Professor
Epidemiology
Graduate School of Public Health
University of Pittsburgh
Essay Reader:
Pierre N. Azzam, MD
Physicians Faculty
Psychiatry
University of Pittsburgh
______________________________________
______________________________________
ii
Copyright © by Joshua Penderville
2015
iii
Iva Miljkovic, MD, PhD
ALZHEIMER’S DISEASE REVIEW: TARGETS FOR EARLY INTERVENTION
Joshua Penderville, MPH
University of Pittsburgh, 2015
ABSTRACT
Advances in health-related fields have brought higher life expectancy, but little progress has
been made in terms of quality of life for patients with Alzheimer’s Disease (AD). With an aging
population, the projected socioeconomic burden of AD is severe and of great public health
importance. In order to lessen the impact of the disease, effective therapeutics are needed, but
the multifactorial nature of AD impedes scientific progress. Current treatments, while having
some benefit in symptom management, do not modify disease progression and have limited
efficacy in later stages of AD.
For most chronic conditions, earlier treatment results in a better chance of slowing or
preventing disease progression. Recent clinical and laboratory findings are identifying likely
upstream components of AD and proposing several approaches to therapy. The purpose of this
essay is to summarize these findings, evaluate their potential for intervention, and highlight the
overall barriers that persist in AD treatment.
iv
TABLE OF CONTENTS
1.0
INTRODUCTION ........................................................................................................ 1
1.1
FEATURES OF ALZHEIMER’S DISEASE .................................................... 2
1.2
UNDERLYING DISEASE MECHANISMS ..................................................... 4
2.0
3.0
1.2.1
Cholinergic disruption .................................................................................... 4
1.2.2
Excitotoxicity .................................................................................................... 5
1.2.3
Changes in insulin signaling ........................................................................... 6
1.2.4
Neurotoxic effects of beta-amyloid ................................................................. 7
THERAPEUTIC APPROACHES .............................................................................. 8
2.1
NMDA-INHIBITORS ......................................................................................... 9
2.2
INSULIN THERAPY ........................................................................................ 10
2.3
ANTI-INFLAMMATORIES ............................................................................ 11
2.4
BETA-AMYLOID IMMUNOTHERAPY ....................................................... 11
2.5
EPIGENETIC INTERVENTIONS.................................................................. 12
DISCUSSION ............................................................................................................. 13
BIBLIOGRAPHY ....................................................................................................................... 16
v
LIST OF FIGURES
Figure 1. Plaques and tangles.......................................................................................................... 3
Figure 2. Cholinergic neuron signaling. ......................................................................................... 5
Figure 3. The role of insulin resistance in Alzheimer’s Disease .................................................... 6
Figure 4. Memantine interacts at NMDA receptor ....................................................................... 10
vi
1.0
INTRODUCTION
As life expectancy steadily rises, Alzheimer’s Disease (AD) continues to be an important public
health concern. AD is one of the top 10 leading causes of death in the United States. It ranks as
the 6th leading cause of death among US adults and the 5th among people ages 65-85. Beyond
age 65, the number of people with AD doubles every 5 years (Barnes & Yaffe, 2011). The
population aged 60 and over is expected to triple by 2050 (Hebert, Weuve, Scherr, & Evans,
2013). Without any effective intervention, the prevalence of AD in the United States will triple
as well, from 5 million in 2013 to 14 million by 2050 (Barnes & Yaffe, 2011).
AD is the leading cause of dementia. Dementia is a term that describes the disturbance of
multiple higher cortical functions, including memory, learning, comprehension, and language.
Early dementia symptoms are often confused with normal aging, which can prevent a timely
diagnosis. It is one of the main causes of disability later in life. In 2010, the estimated monetary
cost of dementia in the United States was as high as $215 billion (Hurd, Martorell, Delavande,
Mullen, & Langa, 2013). This number will only continue to rise as the prevalence of AD
increases.
The high economic burden and devastating effects on the quality of life of patients and
their families means that even a small delay in the onset and progression of AD would have a
significant impact on public health. As a result, a huge effort is underway to better understand,
prevent, and treat the disease. The focus is for earlier and more sensitive diagnostic techniques,
1
identification and prevention of high-risk populations, and efficacious treatment of symptoms.
This paper reviews present and future therapeutic targets and their barriers based on our current
understanding of AD etiology.
1.1
FEATURES OF ALZHEIMER’S DISEASE
Certain features of AD are well-documented. The most apparent are the symptoms of cognitive
impairment that develop due to a loss of brain tissue and function. The appearance of these
symptoms is usually when treatment is first sought. The accumulation of misfolded proteins and
deposits in the brain, referred to as tangles and plaques, is a histological marker for AD (Bartus,
2000).
Symptomatically, AD is characterized as a gradual decline in cognitive function that
typically begins before clinical diagnosis (Backman, Jones, Berger, Laukka, & Small, 2004).
Earlier phases of the disease are considered pre-clinical, when patients begin to experience a
slight loss of attention and some difficulty in remembering recent events. This phase is often
mistaken for normal aging, but in AD the symptoms continue to progress. In later phases,
memory loss becomes obvious with minor loss in language production and executive function.
These conditions would become worse until patients are completely dependent on others for
daily activities. In the final phases of the disease, patients lose their ability to communicate and
express emotion (Taler & Phillips, 2008).
The classic pathophysiological signs of an AD brain are the presence of misfolded
proteins called beta-amyloid “plaques” and neurofibrillary “tangles.”
Tangles are
hyperphosphorylated twisted filaments of tau, a cytoskeletal protein, and are visible within the
2
cell body (Goedert, Klug, & Crowther, 2006). Plaques are predominately deposits of betaamyloid, and are visible outside the cell (Hashimoto, Rockenstein, Crews, & Masliah, 2003).
The buildup of these products may disrupt normal cell functioning and be a key factor in the
progression of AD. Understanding what causes these proteins to form is another popular area of
research (Tiraboschi, Hansen, & Corey-Bloom, 2004).
Figure 1. Plaques and tangles
The appearance of plaques and tangles has been well documented in cases of Alzheimer’s disease.
The tangles are found within the cell and form when the tau protein becomes
hyperphosphorylated. The plaques are mainly deposits of beta-amyloid peptides outside of the
cell.
3
1.2
UNDERLYING DISEASE MECHANISMS
Although the dysfunction and loss of brain matter is the most unwanted and devastating effect of
AD, there is still a great deal of uncertainty in the mechanisms that cause it. A number of
theories were developed and updated based on the known features of the disease and newer
findings. While these hypotheses may not reflect a causative mechanism, they have been
implicated in the disease process in some way.
1.2.1 Cholinergic disruption
Cholinergic neurons, in particular, are affected in the development of AD (Terry, 2003). These
neurons utilize the neurotransmitter acetylcholine (ACh). Forebrain cholinergic pathways are
known to have an important role in higher functions, such as working memory, attention, and
awareness. Early studies of AD found disruption in these pathways correlated with the degree of
cognitive deficit (Francis, Palmer, Snape, & Wilcock, 1999). Specifically, this disruption may
involve the production of ACh, ACh receptors, or acetylcholinesterase (AChE), the enzyme that
breaks down ACh in the synaptic cleft. Healthy cholinergic signaling requires a balance of ACh
release to bind to receptors and AChE to degrade and remove ACh. In AD, this balance is
disrupted (Terry, 2003).
4
Figure 2. Cholinergic neuron signaling
The signaling neuron releases acetylcholine, which binds to receptors of the receiving neuron.
Acetylcholinesterase is present to degrade acetylcholine. A balance of these two chemicals is
necessary for proper signaling. In the cholinergic deficiency theory, this interaction can become
unbalanced or these cholinergic synapses are lost.
1.2.2 Excitotoxicity
There is evidence that suggests various causes of excitotoxicity are factors in the development of
AD. Excitotoxicity refers to damage to or death of a neuron due to overstimulation. Glutamate
is the main excitatory neurotransmitter in the brain and is essential to many physiological
functions. It binds to several types of postsynaptic receptors that cause ion channels to open and
positively charged ions to enter the cell. Prolonged stimulation can result in activation of
enzymes that damage the cell. Research is exploring what causes excitotoxic conditions to occur
in AD.
It may be the result of chronically high levels of glutamate, changes in receptor
signaling, or a combination of several factors (Danysz & Parsons, 2003).
5
1.2.3 Changes in insulin signaling
Some studies suggest changes in brain insulin metabolism may be an important
pathophysiological factor underlying AD (Freiherr et al., 2013; De la Monte, 2012). Genetic and
lifestyle factors that result in insulin resistance increase the risk of AD (Patterson et al., 2008).
Insulin resistance is associated with cognitive decline and less total brain mass. In AD patients,
insulin desensitization is shown to be correlated with the magnitude of cognitive impairment.
Further support for this link between insulin and AD comes from observations of reduced brain
insulin receptor sensitivity, hypophosphorylation of the insulin receptor and second messengers,
and fewer total insulin receptors in AD patients (Talbot, 2012).
In this hypothesis, certain genetic and environmental factors contribute to an increase of
insulin resistance in the central nervous system (CNS). Insulin resistance results in inefficient
energy metabolism and contributes to the loss of synapses and neurotoxicity via increased
production of amyloid beta and phospho-tau proteins (Freiherr et al., 2013; De la Monte, 2012).
Figure 3. The role of insulin resistance in Alzheimer’s Disease
Multiple genetic and environmental factors alter the insulin response in the CNS. The change in
cellular metabolism leads to toxic buildup and neuronal death.
6
1.2.4 Neurotoxic effects of beta-amyloid
The amyloid hypothesis suggests the effects of the aggregation of beta-amyloid is the driving
force in AD neurodegeneration.
Increased production of amyloid precursor proteins and
ineffective breakdown of beta amyloid are genetic risks for AD (Polvikoski et al., 1995). Betaamyloid has been linked to oxidative stress and inflammatory pathways (Hoozemans, Veerhuis,
Rosemuller, & Eikelenboom, 1996; Misonou, Morishima-Kawashima, & Ihara, 2000). Recently,
it was suggested that N-APP, a small peptide derived from amyloid, has toxic effects. When
cleaved from the amyloid precursor protein (APP), this fragment has properties that allow it to
bind to a neuron receptor that initiates apoptosis, programmed cell death (Nikolaev, McLaughlin,
O'Leary, & Tessier-Lavigne, 2009).
7
2.0
THERAPEUTIC APPROACHES
The first class of drugs to become available were developed to address the cholinergic deficiency
in forebrain pathways. This was approached several different ways, such as increasing release of
ACh,
modifying
AChE,
and
targeting
ACh
receptors
directly.
However,
only
acetylcholinesterase inhibitors (AChEI) were successful in clinical trials. The hypothesized
therapeutic action of AChEI is the result of a longer ACh half-life and improved activation of
cholinergic neurons (Terry, 2003). The first AChEI, Tacrine, was approved for the treatment of
AD in 1993. Subsequently, donepezil, rivastigmine, and galantamine have become available and
have fewer side-effects (Giacobini, 2000).
Although these drugs have been approved for treatment and are available, their benefit is
modest and limited to mild and moderate cases of AD. They are not believed to have any
significant effect on the underlying cause of neuronal death (Terry, 2003). As the disease
continues to progress unchecked, these drugs cannot overcome the effects of widespread loss of
cholinergic neurons, and benefits are no longer seen. Therefore, the focus is now on identifying
and developing therapeutics that target the disease earlier.
8
2.1
NMDA-INHIBITORS
If excitotoxicity is a major factor in AD, then a general decrease in activation may show
beneficial results. Evidence implicates that the N-methyl-D-aspartate (NMDA) receptors are
partially involved in excitotoxicity. NMDA are a class of glutamate-binding receptors that have
been targeted for therapy. They are unique because their ion channels are blocked by Mg2+. Not
only must glutamate bind to these receptors, but Mg2+ must be removed before positivelycharged ions can enter the cell. In this sense, Mg2+ acts as a switch to block NMDA receptors in
some conditions and allow movement of ions in other conditions (Reisberg et al., 2003).
Memantine is a NMDA-receptor antagonist and the only non-AChEI treatment for AD at
this time. Memantine binds to NMDA receptors with a higher affinity than Mg2+ (Danysz &
Parsons, 2003). For this reason, it may block the toxic overstimulation of neurons. In clinical
trials, patients with moderate to severe AD had significantly better clinical and cognitive
outcomes (Matsunaga, Kishi, & Iwata, 2015; Reisberg et al., 2003).
9
Figure 4. Memantine interacts at NMDA receptor
Memantine may prevent excitoxicity by blocking ion channels of NMDA receptors. In
normal conditions, glutamate will bind, but the ion channel is blocked by Mg +2. Changes
in membrane potential would push the Mg+2 out and allow more positive ions to enter the
cell, leading to overstimulation in some circumstances. Because memantine binds with a
higher affinity, the channel blockade remains intact and may prevent toxic conditions.
2.2
INSULIN THERAPY
Based on the hypothesis that alterations in insulin sensitivity results in toxic intermediates, a
pilot clinical trial examined the effects of intranasal insulin in AD and Mild Cognitive
Impairment (MCI) patients over 4 months. The study found improvement in memory, cognitive
function, and caregiver ratings of functional ability. These observations are further credited by
PET findings, which showed increased energy consumption in relevant brain regions tied to
these higher functions (Freiherr et al., 2013).
10
2.3
ANTI-INFLAMMATORIES
Epidemiologic evidence has shown that long-term use of non-steroidal anti-inflammatory drug
(NSAID) lowers risk of AD (Szekely, Town, & Zandi, 2007). Laboratory studies tend to show
that NSAIDs reduce inflammation associated with beta-amyloid and may inhibit its production
(Stuchbury & Münch, 2005; Hoozemans, Veerhuis, Rosemuller, & Eikelenboom, 1996). To
date, clinical trials that evaluated the efficacy of NSAIDs in AD treatment have not found a
significant beneficial effect (Miguel-Alvarez, 2015).
2.4
BETA-AMYLOID IMMUNOTHERAPY
Immunotherapy strategies against AD are being explored. The idea is to actively immunize
patients to target and reduce levels of beta-amyloid. Studies in animal models have shown this
can be an effective way of clearing plaques (Cannon et al., 2000). Subsequently, a randomized,
placebo-controlled trial in humans found that removal of amyloid plaques through immunization
did not prevent progressive neurodegeneration in humans (Holmes et al., 2008). Another trial
using a different antibody against beta-amyloid was interrupted due to patients developing
meningoencephalitis (Gilman, 2005). Further studies are underway with antibodies that target
more specific forms of beta-amyloid and its precursors that are evidently neurotoxic (Dodel et
al., 2010).
11
2.5
EPIGENETIC INTERVENTIONS
Only a small portion of early onset-AD cases is known to be the result of rare genetic mutations
(Tanzi, 2012). The vast majority of AD cases that develop seems to be sporadic, which suggests
environmental factors, such as epigenetics, are involved. Epigenetics refers to any acquired or
heritable modifications on DNA that can affect gene expression and function without altering the
DNA sequence itself. These pathways act as the mediators between the environment and the
genome. Stress, environmental toxins, and other external conditions can affect gene expression
through epigenetic changes (Adwan & Zawia, 2013).
The literature suggests histone acetylation and DNA methylation may be key epigenetic
mechanisms that influence AD (Adwan & Zawia, 2013). Histone acetylation has a role in
learning and memory (Levenson et al., 2004). It is regulated by two groups of enzymes, histone
acetyltansferases (HATs) and histone deacetylases (HDAC) (Feng, Fouse, & Fan, 2007). In
particular, HDAC seems to have a role in AD pathology. Overexpression of HDACs has been
seen in the CNS of AD patients (Gräff et al., 2012). Higher levels of HDAC correlate to the
amount of neurofibrillary tangles. In contrast, DNA methylation is significantly reduced in
neurons of AD patients. Moreover, these low levels are localized to neurons that contain tangles
(Ding, Dolan, & Johnson, 2008).
Further findings implicate low methylation with
overexpression of other AD intermediates, such as beta-amyloid (Adwan & Zawia, 2013).
12
3.0
DISCUSSION
The success of Memantine is clinical trials resulted in the first and only non-cholinergic FDAapproved treatment. Moreover, it showed improvements in moderate to severe stages of AD,
where AChEIs had less of an effect. Although its discovery highlighted the heterogeneity of
AD, the benefit of Memantine is quite modest in absolute terms. In patients already exhibiting
moderate symptoms, it has failed to give evidence of slowing disease progression. Further
studies are needed to assess the effect reduced overstimulation through Memantine has on preclinical AD.
Targeting conditions further upstream is more likely to result in disease-modifying
effects. However, this is difficult as AD, like most chronic conditions, is heterogeneous. There
are several behavioral, environmental and genetic factors involved. It shares many of the same
risk factors as cardiovascular disease. Sedentary lifestyle, high saturated fat diet, diabetes, and
obesity increase risk of AD (Patterson et al., 2008). These factors support the hypothesis that
metabolic changes through insulin sensitivity are the fundamental cause of neurodegeneration.
While a pilot study on intranasal insulin had promising results, the study was small and short in
duration (Freiherr et al., 2013). In addition, there is concern about the long-term efficacy of
chronic insulin administration, which is shown to desensitize pathways in peripheral tissues (De
la Monte, 2012). Nevertheless, these preliminary findings suggest an insulin or insulin receptor-
13
modifying therapy is a valid approach. Intranasal insulin requires further investigation of a
larger sample over a longer period of time.
The therapeutic approach of targeting and reducing inflammation has not gained much
ground. Although observational studies showed a protective effect of anti-inflammatories,
clinical trials have been unable to show any efficacy (Miguel-Alvarez, 2015). The inflammatory
response seen in AD may contribute to the neurodegenerative cascade, but it has not been a
promising target for treatment. However, the protective effect observed and the interaction of
NSAIDs with beta-amyloid suggests it may be relevant in stages prior to the clinical appearance
of AD (Hoozemans, Veerhuis, Rosemuller, & Eikelenboom, 1996; (Stuchbury & Münch, 2005).
If this is the case, it may be a valuable prevention strategy. A better understanding of prediagnosis conditions and studies investigating the preventative potential of NSAIDs are needed.
The field of epigenetics has revealed possible upstream targets for AD intervention. The
aim of an epigenetic intervention against AD is to enhance transcription of genes involved in
learning and memory formation while also reducing the transcription of proteins of the toxic
intermediates (Adwan & Zawia, 2013). Although this area of research is young, it offers
promise. Not only does it provide a mechanism to prevent or slow disease progression, but the
promotion of memory formation could improve symptoms. HDAC inhibition and methylation
promotion have been identified as possible routes of reducing AD intermediates. However,
further research is needed before the safety and efficacy of these interactions are known. In the
future, epigenetic changes could provide an early diagnostic tool, prior to the molecular changes
associated with AD.
Immunotherapy is a promising approach to AD treatment. The ability to interact with the
amyloid family on a molecular level has been established. However, the specific therapeutic
14
target remains uncertain. The increased risk seen in previous studies means safety is of great
concern as new antibodies are proposed. Further evidence on the molecular changes resulting in
toxic conditions will provide more specific targets of immunization that have a better risk
profile.
The variety of approaches to treatment research reflects the heterogeneous nature of AD.
Not a single condition is definitively the cause of neuronal loss. As in other chronic conditions,
it is likely the interaction and combination of several factors that eventually result in observable
cognitive symptoms. For this reason, unreliable and late diagnosis continues to be a barrier. In
the current state, accurate assessment of the benefit to risk ratio in drug trials is difficult. As our
understanding of AD pathogenesis grows and diagnostic techniques become more sensitive, our
ability to detect treatment effect will become more powerful.
15
BIBLIOGRAPHY
Adwan, L., & Zawia, N. H. (2013). Epigenetics: A novel therapeutic approach for the treatment
of Alzheimer's disease. Pharmacology & Therapeutics, 139(1), 41-50.
doi:10.1016/j.pharmthera.2013.03.010
Atri, A., Shaughnessy, L. W., Locascio, J. J., & Growdon, J. H. (2008). Long-term Course and
Effectiveness of Combination Therapy in Alzheimer Disease. Alzheimer Disease &
Associated Disorders, 22(3), 209-221. doi:10.1097/WAD.0b013e31816653bc
Backman, L., Jones, S., Berger, A., Laukka, E. J., & Small, B. J. (2004). Multiple cognitive
deficits during the transition to Alzheimer's disease. Journal of Internal Medicine, 256(3),
195-204. doi:10.1111/j.1365-2796.2004.01386.x
Barnes, D. E., & Yaffe, K. (2011). The projected effect of risk factor reduction on Alzheimer's
disease prevalence. Lancet Neurology, 249(6), 288-290. doi:10.1016/S14744422(11)70072-2
Bartus, R. T. (2000). On Neurodegenerative Diseases, Models, and Treatment Strategies:
Lessons Learned and Lessons Forgotten a Generation Following the Cholinergic
Hypothesis. Experimental Neurology, 163, 495-529. doi:10.1006/exnr.2000.7397
Cannon, C., Barbour, R., Burke, R., Games, D., Grajeda, H., Guido, T., . . . Bard, F. (2000).
Peripherally administered antibodies against amyloid β-peptide enter the central nervous
system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine,
6, 916-919. doi:10.1038/78682
Danysz, W., & Parsons, C. G. (2003). The NMDA receptor antagonist memantine as a
symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical
evidence. International Journal of Geriatric Psychiatry, 18, S23-S32. doi:10.1002/gps.938
De la Monte, S. (2012). Brain Insulin Resistance and Deficiency as Therapeutic Targets in
Alzheimer's
Disease.
Current
Alzheimer
Research,
1,
35-66.
doi:10.2174/156720512799015037
Ding, H., Dolan, P. J., & Johnson, G. V. (2008). Histone deacetylase 6 interacts with the
microtubule-associated protein tau. Journal of Neurochemistry, 106, 2119-2130.
doi:10.1111/j.1471-4159.2008.05564.x
Dodel, R., Neff, F., Noelker, C., Pul, R., Du, Y., Bacher, M., & Oertel, W. (2010). Intravenous
immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence.
Drugs, 70(5), 513-528. doi:10.2165/11533070-000000000-00000
16
FENG, J., FOUSE, S., & FAN, G. (2007). Epigenetic Regulation of Neural Gene Expression and
Neuronal
Function.
Pediatric
Research,
61,
58R-63R.
doi:10.1203/pdr.0b013e3180457635
Fonseca, A. C., Resende, R., Oliveira, C. R., & Pereira, C. M. (2010). Cholesterol and statins in
Alzheimer's
disease:
Current
controversies.
Experimental
Neurology.
doi:10.1016/j.expneurol.2009.09.013
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholinergic hypothesis
of Alzheimer's disease: a review of progress. Journal of Neurology Neurosurgery and
Psychiatry, 66(2), 137-147. doi:10.1136/jnnp.66.2.137
Freiherr, J., Hallschmid, M., Frey II, W., Brunner, Y., Chapman, C., Holscher, C., . . . Benedict,
C. (2013). Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic
Research and Clinical Evidence. CNS Drugs, 2013(27), 505-514. doi:10.1007/s40263013-0076-8
Giacobini, E. (2000). Cholinesterase Inhibitors Stabilize Alzheimer Disease. Neurochemical
Research. doi:10.1023/A:1007679709322
Gilman, S. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an
interrupted tria. Neurology, 64(9), 1553-1562.
Goedert, M., Klug, A., & Crowther, R. A. (2006). Tau protein, the paired helical filament and
Alzheimer's disease. J Alzheimers Dis, 9, 195-207.
Gräff, J., Rei, D., Guan, J., Wang, W., Seo, J., Hennig, K. M., . . . Tsai, L. (2012). An epigenetic
blockade of cognitive functions in the neurodegenerating brain. Nature, 483, 222-226.
doi:10.1038/nature10849
Hashimoto, M., Rockenstein, E., Crews, L., & Masliah, E. (2003). Role of protein aggregation in
mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's
diseases. Neuromolecular Med, 4(1-2), 21-36.
Hebert, L. E., Weuve, J., Scherr, P., & Evans, D. (2013). Alzheimer disease in the United States
(2010–2050) estimated using the 2010 census. Neurology, 80(19), 1778-83.
doi:10.1212/WNL.0b013e31828726f5
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., . . . Nicoll, J. A.
(2008). Long-term effects of Aβ 42 immunisation in Alzheimer's disease: follow-up of a
randomised, placebo-controlled phase I trial. Lancet. doi:10.1016/S0140-6736(08)610752
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., . . . Nicoll, J. A.
(2008). Long-term effects of Aβ 42 immunisation in Alzheimer's disease: follow-up of a
randomised, placebo-controlled phase I trial. Lancet, 372(9634), 216-223.
doi:10.1016/S0140-6736(08)61075-2
17
Hoozemans, J. M., Veerhuis, R., Rosemuller, J. M., & Eikelenboom, P. (1996). Soothing the
Inflamed Brain: Effect of Non-Steroidal Anti-Inflammatory Drugs on Alzheimers
Disease Pathology. CNS & Neurological Disorders - Drug Targets, 10(1), 57-67.
doi:10.2174/187152711794488665
Hurd, M., Martorell, P., Delavande, A., Mullen, K. J., & Langa, K. M. (2013). Monetary Costs
of Dementia in the United States. The New England Journal of Medicine, 368(14), 13261334. doi:10.1056/NEJMsa1204629
Leon, R., Garcia, A., & Marco-Contelles, J. (2011). Recent advances in the multitarget-directed
ligands approach for the treatment of Alzheimer's disease. Medical Research Reviews,
33(1), 139-189. doi:10.1002/med.20248
Levenson, J. M., O'Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., & Sweatt, J. D.
(2004). Regulation of Histone Acetylation during Memory Formation in the
Hippocampus.
Journal
of
Biological
Chemistry,
279,
40545-40559.
doi:10.1074/jbc.M402229200
Matsunaga, S., Kishi, T., & Iwata, N. (2015). Memantine Monotherapy for Alzheimer's Disease:
A
Systematic
Review
and
Meta-Analysis.
PLoS
One,
10(4).
doi:10.1371/journal.pone.0123289
Miguel-Alvarez, M. (2015). Non-steroidal anti-inflammatory drugs as a treatment for
Alzheimer's disease: a systematic review and meta-analysis of treatment effect. Drugs
Aging, 32(2), 139-147. doi:10.1007/s40266-015-0239-z
Misonou, H., Morishima-Kawashima, M., & Ihara, Y. (2000). Oxidative Stress Induces
Intracellular Accumulation of Amyloid β-Protein (Aβ) in Human Neuroblastoma Cells.
Biochemistry, 39(23), 6951-6959. doi:10.1021/bi000169p
Nikolaev, A., McLaughlin, T., O'Leary, D. D., & Tessier-Lavigne, M. (2009). APP binds DR6 to
trigger axon pruning and neuron death via distinct caspases. Nature.
doi:10.1038/nature07767
Patterson, C., Feightner, J. W., Garcia, A., Hsiung, G. R., MacKnight, C., & Sadovnick, A. D.
(2008). Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention
of Alzheimer disease. Canadian Medical Association Journal, 178(5), 548-556.
doi:10.1503/cmaj.070796
Polvikoski, T., Sulkava, R., Haltia, M., Kainulainen, K., Vuorio, A., Verkkoniemi, A., . . .
Kontula, K. (1995). Apolipoprotein E, Dementia, and Cortical Deposition of β-Amyloid
Protein.
New
England
Journal
of
Medicine,
33(19),
1242-1247.
doi:10.1056/NEJM199511093331902
Pozueta, J., Lefort, R., & Shelanski, M. L. (2013). Synaptic changes in Alzheimer's disease and
its models. Neuroscience, 251, 51-61. doi:10.1016/j.neuroscience.2012.05.050
18
Reisberg, B., Doody, R., Stöffler, A., Schmitt, F., Ferris, S., & Möbius, H. J. (2003). Memantine
in Moderate-to-Severe Alzheimer's Disease. New England Journal of Medicine, 348(14),
1333-41. doi:10.1056/NEJMoa013128
Stuchbury, G., & Münch, G. (2005). Alzheimer’s associated inflammation, potential drug targets
and future therapies. Journal of Neural Transmission. doi:10.1007/s00702-004-0188-x
Szekely, C. A., Town, T., & Zandi, P. P. (0). NSAIDs for the Chemoprevention of Alzheimer’s
Disease. doi:10.1007/1-4020-5688-5_11
Tabet, N. (2006). Acetylcholinesterase inhibitors for Alzheimer’s disease: anti-inflammatories in
acetylcholine clothing! Age Ageing, 35(4), 336-338. doi:10.1093/ageing/afl027
Talbot, K. (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients is
associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal
of Clinical Investigation, 122(4), 1316-1338. doi:10.1172/JCI59903
Taler, V., & Phillips, N. A. (2008). Language performance in Alzheimer's disease and mild
cognitive impairment: A comparative review. Journal of Clinical and Experimental
Neuropsychology, 5, 501-556. doi:10.1080/13803390701550128
Tanzi, R. E. (2012). The genetics of Alzheimer disease. Cold Spring Harb Perspect Med, 2.
Terry, A. V. (2003). The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related
Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug
Development. Journal of Pharmacology and Experimental Therapeutics, 306(3), 821-827.
doi:10.1124/jpet.102.041616
Tiraboschi, P., Hansen, L. A., & Corey-Bloom, J. (2004). The importance of neuritic plaques and
tangles to the development and evolution of AD. Neurology, 62(11), 1984-1989.
doi:10.1212/01.WNL.0000129697.01779.0A
19