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The Electrophysiological Phenomenon of

Alzheimer's Disease: A Psychopathology Theory

Ezra C. Holston

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Disease: A Psychopathology Theory, Issues in Mental Health Nursing, 36:8, 603-613, DOI:
10.3109/01612840.2015.1015696

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Issues in Mental Health Nursing, 36:603–613, 2015
Copyright © 2015 Taylor & Francis Group, LLC
ISSN: 0161-2840 print / 1096-4673 online
DOI: 10.3109/01612840.2015.1015696
The Electrophysiological Phenomenon of Alzheimer’s
Disease: A Psychopathology Theory
Ezra C. Holston, PhD, RN
University of Tennessee—Knoxville, College of Nursing, Knoxville, Tennessee, USA
The current understanding of Alzheimer’s disease (AD) is based
on the Aβ and tau pathology and the resulting neuropathologi-
cal changes, which are associated with manifested clinical symp-
toms. However, electrophysiological brain changes may provide a
more expansive understanding of AD. Hence, the objective of this
systematic review is to propose a theory about the electrophysi-
ological phenomenon of Alzheimer’s disease (EPAD). The review
of literature resulted from an extensive search of PubMed and
MEDLINE databases. One-hundred articles were purposively se-
lected. They provided an understanding of the concepts establish-
ing the theory of EPAD (neuropathological changes, neurochem-
ical changes, metabolic changes, and electrophysiological brain
changes). Changes in the electrophysiology of the brain are foun-
dational to the association or interaction of the concepts. Building
on Berger’s Psychophysical Model, it is evident that electrophysio-
logical brain changes occur and affect cortical areas to generate or
manifest symptoms from onset and across the stages of AD, which
may be prior to pathological changes. Therefore, the interaction of
the concepts demonstrates how the psychopathology results from
affected electrophysiology of the brain. The theory of the EPAD
provides a theoretical foundation for appropriate measurements
of AD without dependence on neuropathological changes. Future
research is warranted to further test this theory. Ultimately, this
theory contributes to existing knowledge because it shows how elec-
trophysiological changes are useful in understanding the risk and
progression of AD across the stages.
INTRODUCTION
Alzheimer’s disease (AD) is the most common type of de-
mentia and is the sixth leading cause of death in the USA
(Tejada-Vera, 2013). By 2050, over 10 million people will be
diagnosed with AD in the USA alone (Alzheimer’s Association,
AA, 2014). Healthcare costs will exceed $160.5 billion just for
those diagnosed with AD, illustrating that AD is a huge public
health issue.
The psychopathology of AD is understood solely by the phys-
iological changes that define the neuropathological changes
associated with manifest clinical symptoms. Since the 1990s,
Address correspondence to Ezra C. Holston, University of
Tennessee—Knoxville, School of Nursing, 1200 Volunteer Blvd,
Knoxville, TN 37996, USA. E-mail: eholston@utk.edu
603
physiological changes observed in those with AD have been the
abnormal beta amyloid (Aβ) production that develops into neu-
rofibrillary tangles and neuritic plaques (Bobinski et al., 1998; de
Leon et al., 1993; Förstl et al., 1996; Meyer, Muramatsu, Mortel,
Obara, & Shirai, 1995; Reisberg, 1995; Reisberg, Kenowsky,
Franssen, Auer, & Souren, 1999; Reisberg & Kluger, 1998).
These neuropathological changes lead to cortical atrophy, neu-
ronal and volume loss, white matter changes, and disruption of
neuronal pathways (Bobinski et al., 1998; Carrasquillo et al.,
2014; de Leon et al., 1993; Förstl et al., 1996; Horesh, Katsel,
Haroutunian, & Domany, 2011; Solodkin et al., 2013). These
changes are associated with abnormal metabolic rates or changes
in the glucose utilization and blood circulation to perfuse the
brain (Bergman et al., 1997; Desgranges et al., 1998; Read et al.,
1995) and altered neurochemical levels or changes in the levels
of acetylcholinesterase, cholinesterase, and choline acetyltrans-
ferase (Davis et al., 1999; Förstl, Besthorn, Geiger-Kabisch,
Sattel, & Schreiter-Gasser, 1993; Qizilbash et al., 1998) that
are reported in AD. Neuropathological changes, neurochemical
changes, and metabolic changes are also associated with ab-
normal electrophysiological brain changes or altered brain ac-
tivity: slow brain activity recorded as delta activity (δ-activity;
1.5–3.5 Hz) and theta activity (θ -activity; 3.5–7.5 Hz); fast brain
activity recorded as alpha activity (α-activity; 7.5–12.5 Hz) and
beta activity (β-activity; 12.5–25 Hz) (Förstl et al., 1996; Davis
et al., 1999; Förstl et al., 1993; Fox, Cousens, Scahill, Har-
vey, & Rossor, 2000; Geddes et al., 1997; Larson et al., 1998;
Samuel et al., 2000; Szelies, Mielke, Herholz, & Heiss, 1994;
Valladares-Neto et al., 1995; Wszolek, Herkes, Lagerlund, &
Kokmen, 1992). As a result, the psychopathology of AD is un-
derstood by the neuropathological changes reaching a specific
level or threshold based on an amyloid burden from abnormal
Aβ production, which has the potential to affect the functioning
of the brain that can lead to clinical symptoms.
The assessment and treatment of AD is established on this
premise of a specific level of neuropathological changes for
the objective observation of changes to physiological functions
and manifested symptoms. This approach suggests that a neu-
ropathological threshold must be achieved in order to measure
a change in a person’s quality of life, level of impulsivity,
604 E. C. HOLSTON
impaired cognition, and/or depressive symptoms, as well as
link the symptoms to possible genetic markers (Bidzan et al.,
2008; Bosboom, Alfonso, & Almeida, 2013; Carrasquillo et al.,
2014; Horesh et al., 2011; Luque-Contreras, Carvajal, Toral-
Rios, Franco-Bocanegra, & Campos-Pena, 2014; Rochat et al.,
2013; Teng, Lu, & Cummings, 2007; Tractenberg, Weiner, Cum-
mings, Patterson, & Thal, 2005; Velasques et al., 2011; Zahodne,
Devanand, & Stern, 2013; Zahodne, Ornstein, Cosentino, De-
vanand, & Stern, 2013; Zdanys et al., 2007). This dependency on
a neuropathological threshold can potentially restrict the treat-
ment of the symptoms across all stages of AD and the effec-
tiveness of the healthcare delivery. However, it is possible, even
likely, that the electrophysiological brain changes may provide
a more expansive understanding of the phenomenon of AD.
Numerous electrophysiological studies have characterized
the onset and progression of AD as well as associated the
psychopathology from prodromal to severe stages with certain
electrophysiological brain changes. An abnormal increase in
θ -activity or slow brain activity is associated with the transi-
tion of impaired cognition from subjective complaints to mea-
surable and objective cognitive deficits (Brassen et al., 2004;
Prichep et al., 2006). This transition represents the hallmark
sign of normal-functioning elders converting to mild cogni-
tive impairment (MCI). An increase in θ -activity is observed in
normal-functioning elders who developed AD as well as their
progression from the mild to moderate stages of AD (Coben,
Danziger, & Storandt, 1985; Holston, 2003). In the late stages of
AD, a decrease in both α-activity and β-activity (fast brain ac-
tivity) is observed along with the increasing θ -activity (Prichep
et al., 1994). Manifested symptoms, such as impaired cognition,
functional decline, and behavioral problems are correlated to ab-
normal electrophysiological brain changes (Reinikainen et al.,
1988; Soininen et al., 1992). As a result, a description of AD and
its psychopathology emerge without being solely dependent on
a neuropathological threshold.
Hence, the objective of this systematic review of the lit-
erature is to propose a theory about the electrophysiological
phenomenon of AD (EPAD), provide the theoretical rationale,
and discuss the interactions or relationship of four concepts
(neuropathological changes, neurochemical changes, metabolic
changes, and electrophysiological brain changes) related to the
pathology of AD (the Aβ and τ pathology). This theory may
facilitate a richer understanding of AD and the psychopathol-
ogy, promoting pre-screening measures, proactive assessments,
earlier diagnosing, and individualized treatment of symptoms.
SEARCH HISTORY
PubMed and MEDLINE database searches were per-
formed using MESH terms: brain activity, quantitative EEG,
Alzheimer’s disease, dementia, physiology, pathology, clinical
symptoms, cognition, functioning, and behavior. The searches
limitations were: written in English, subject’s age, human sub-
jects, and published between 1940 and 2014. The search pro-
gression was initiated with 1-term searches that transitioned to
combinations of 2-term, 3-term, and 4-term searches (e.g., quan-
titative EEG + Alzheimer’s disease + cognition + pathology).
This approach was used to ensure a comprehensive and ex-
haustive review of studies related to AD. This search approach
yielded 700 possible articles. All abstracts were reviewed to
determine if articles provided information to delineate concepts
related to the electrophysiology of Alzheimer’s disease. Articles
were eliminated from further consideration because of weak
and/or subjective methodology, collapsing of data, using unreli-
able and/or invalid instruments, and other sub-topics detracting
from information about electrophysiology of AD. Additionally,
frequently cited articles found in the reference lists were re-
viewed for appropriateness. Ultimately, a total of 100 articles
were purposively selected. These articles, seminal and interna-
tional articles, were used for a foundational understanding of
concepts potentially establishing the theory of the electrophys-
iological phenomenon of AD (EPAD).
THEORY OF EPAD
The theory of the electrophysiological phenomenon of
Alzheimer’s disease (EPAD) describes how the association or
interaction of four concepts (neuropathological changes, neuro-
chemical changes, metabolic changes, and electrophysiological
changes) characterize the psychopathology of AD (Figure 1).
This theory provides an understanding of AD without being
dependent on the neuropathological threshold or amyloid bur-
den defined by the Aβ and τ pathology. In addition, this theory
provides the possibility for a non-invasive and objective assess-
ment of AD. Therefore, the theory of EPAD provides a basis
for further assessment of the association or interaction between
the abnormal electrophysiological brain changes and the psy-
chopathology indicative of AD.
The relational statements are:
• Alteration in the brain’s bioelectrical activity leads to
electrophysiological brain changes and neuropatholog-
ical changes of AD
• A bi-directional relationship exists between electro-
physiological brain changes and neuropathological
changes
• Neuropathological changes moderate the degree of the
association among electrophysiological brain changes,
neurochemical changes, and metabolic changes. Both
neurochemical and metabolic changes impact the neu-
ropathology of the brain. The degree of this combined
impact is associated with electrophysiological brain
changes, synchronized with the intensity of the com-
bined impact
• Electrophysiological brain changes directly relate to
the symptoms of AD:
• Increased θ -activity inversely associates with im-
paired cognition, from the pre-AD stage
 THE ELECTROPHYSIOLOGICAL PHENOMENON OF ALZHEIMER’S DISEASE
FIGURE 1. Theory of the Electrophysiological Phenomenon of Alzheimer’s disease (EPAD).
• Decreased α-activity positively associates with im-
paired cognition, from the early stage
• Increased θ -activity positively associates with be-
havioral dysfunction, hallucinations, and impaired
functioning, from the early stage
• Increased δ-activity with decreased α-activity posi-
tively associates with behavioral dysfunction, hallu-
cinations, and impaired functioning, from the mod-
erate stage
• Electrophysiological brain changes directly relate to
the stages of AD
• Increased θ -activity positively associates with the
pre-AD stage and subsequent stages
• Decreased α-activity associates with the prodromal
stage
• Decreased α-activity positively associates with the
moderate stage and subsequent stages
• Increased δ-activity positively associated with the
moderate stage and subsequent stages
• Symptoms of AD can moderate electrophysiological
brain changes association with the stages of AD. As
the symptoms of AD progress, they are associated with
certain electrophysiological brain changes occurring
in specific cortical areas. These electrophysiological
brain changes are associated with the stages of AD in
which the symptoms are manifested
• Electrophysiological brain changes increase with
the severity of the symptoms across the stages
of AD.
THEORETICAL RATIONALE FOR EPAD
Berger’s Psychophysical Model
The theory of EPAD can be supported by relating it to
Berger’s theoretical model used to conceptualize a person’s
605
existence, as measured by the brain activity or electrophys-
iology with an electroencephalogram (EEG). Hans Berger
(1873–1941), a German psychiatrist and father of the EEG,
produced the first recording of human brain activity using the
non-invasive EEG (Millett, 2001). His psychophysiological re-
search focused on the relationship between the physiological and
mental existence of man, the mind–body connection. Through a
series of psychophysiological experiments, Berger recorded sev-
eral forms of brain activity and identified their association with
physical activity and/or sensory stimuli (Berger, 1969; Millett,
2001). These findings supported his theory of the relationship
between mind and body or the Psychophysical Model, which
could answer questions related to health. By understanding this
relationship, healthcare providers can offer optimal health care
by using ‘observable and measureable physical or physicochem-
ical phenomena’ related to a person’s brain activity (Gloor,
1969). Berger’s Psychophysical Model has been relegated to
scientific history and not tested in current research. However,
his psychophysiological research continues to be foundational
in ‘the clinical and research applications of EEG’ (Millett,
2001).
Briefly, Berger’s Psychophysical Model (Gloor, 1969) uses
four concepts to show how brain activity represents a person.
The concepts are dualism (two perspectives of a person: phys-
ical and non-physical); mutual interaction (communication be-
tween the two perspectives); psychophysical parallelism (syn-
chronicity in development of two perspectives); and energy
conservation (energy or bioelectrical energy is neither created
nor destroyed but transformed between and across the two per-
spectives). Specific levels or frequencies of energy from the
brain can be attributed to the two perspectives as well as a re-
flection of their interaction and/or parallelism. Since energy is
neither created nor destroyed, any electrophysiological changes
in the recorded brain activity are just the transformed energy of
the two perspectives.
606 E. C. HOLSTON
Expanding the Psychophysical Model
Building on the Psychophysical Model, the theory of EPAD
conceptualizes how the abnormal electrophysiological brain
changes of a person with AD contribute to the psychopathology
of AD-manifested symptoms (i.e., impaired cognition, behav-
ioral dysfunction, and impaired functioning). The two perspec-
tives of a person can be identified with the theory of EPAD.
A person has several aspects of a physical perspective (neu-
rochemical, metabolic, neuropathologic, and electrophysiologi-
cal) and of a non-physical perspective (cognition, behavior, and
functioning). These perspectives will be altered and their rela-
tionships will be disrupted when there are internal and external
stressors, specifically AD. As a result, there will be alterations
in the aspects of both the physical perspective and non-physical
perspective. These alterations can be identified with electro-
physiological brain changes that are associated with AD.
Mutual interaction occurs when the physical and non-
physical perspectives interface or communicate. With synchro-
nized communication, the perspectives exist in equilibrium with
no discernible change in brain activity. This equilibrium and
synchronized communication between the two perspectives are
disrupted for a person with AD. An electrophysiological brain
change occurs when the physical perspective influences or over-
shadows the non-physical perspective by emphasizing stim-
ulation from events or persons in the physical environment.
From repeated physical influences on the non-physical, this
electrophysiological brain change persists and is transformed
into behavioral changes. Further impairment or behavioral dys-
function results from the increasing electrophysiological brain
changes caused by the continuous physical perspective influ-
ence. Functional changes are generated when the electrophysi-
ological brain changes occur from the non-physical perspective
influencing the physical via stimulation from attitudes, feelings,
and/or thoughts from the events or persons. Transformation of
functional changes into impaired functioning occurs as the in-
tensity and frequency of the electrophysiological brain changes
increase from the chronic non-physical perspective’s influence.
Psychophysical parallelism represents the synchronized de-
velopment, growth, and/or existence of the two perspectives.
The synchronicity occurs throughout the life of a person; and,
any imbalance in the synchronicity is addressed to regain paral-
lelism. For a person with AD, there is unparalleled development
that proceeds and is not adjusted. This means that one perspec-
tive stimulates the growth, development, and/or existence of the
other one. This disrupted synchronicity produces electrophysi-
ological brain changes with manifestations that align with the
stimulating perspective. A physical perspective orientation re-
sults when the physical perspective stimulates the growth of the
non-physical perspective, resulting in limited awareness or con-
sciousness of the physical aspects: electrophysiological brain
change related to impaired cognition. This physical orienta-
tion is manifest as cognitive changes that can be transformed
into specific impairment in memory, concentration, and/or ori-
entation from chronic activation of this type of stimulation. A
non-physical perspective orientation results when the growth of
the physical perspective is stimulated by the non-physical per-
spective. The outcome is diminished development of the phys-
ical attributes, which will produce neurological changes. These
changes can transform into abnormal brain electrophysiological
changes with chronic non-physical stimulation over the physical
perspective.
Energy conservation represents energy transformation from
the synchronized communication of the physical and non-
physical perspectives. The electrical energy (from neurochem-
ical signaling) is transformed into thermal energy (for cortical
processing), which is transformed to psychic or mental energy
(from mental activity or conscious awareness). Mental energy
is transformed to electrical energy as the non-physical perspec-
tive communicates with the physical. Therefore, energy is con-
served through transformation. For a person with AD, the altered
synchronized communication of the physical and non-physical
perspectives produce electrophysiological brain changes from
the impaired energy transformation and limited conservation.
Repeated activation of these electrophysiological brain changes
are manifested as impaired cognition, behavioral dysfunction,
and impaired functioning. Specifically, the electrophysiolog-
ical brain change of a physical perspective orientation asso-
ciates with the linear transformation of electrical-to-thermal-
to-chemical-to-mental energy. From a non-physical perspec-
tive orientation, the electrophysiological brain change asso-
ciates with the linear transformation from mental-to-chemical-
to-thermal-to-electrical energy. Energy is not conserved in per-
sons with AD since one type of transformed energy persists
and increases in intensity for specific electrophysiological brain
changes that align with changes in behavior, cognition, and func-
tioning. As noted previously, Berger used four concepts to define
the physical and non-physical perspectives of a person and how
these perspectives communicate and are parallel (Berger, 1969).
With the theory of EPAD, the synchronized communication of
the perspectives are disrupted, so that the processes are observ-
able and measurable electrophysiological brain changes of a
person with AD (John, 1980).
DISCUSSION
Concepts for the Theory of EPAD
The concepts for the theory of EPAD can be identified from
the various studies examining the association between the phys-
iological changes and psychopathology of AD. Neuropatho-
logical changes, such as neurofibrillary tangles and neuritic
plaques are observed in the cortical areas of persons with AD
(Reinikainen et al., 1988; Perez et al., 2014; Prescott et al.,
2014). Changes in neurochemicals (i.e., acetylcholinesterase,
cholinesterase, and choline acetyltransferase) and metabolism
(from altered glucose utilization and altered delivery of circu-
lating blood and glucose for neuronal activity) are associated
with neuropathological changes in the brain of persons with AD
(Bergman et al., 1997; Davis et al., 1999; Desgranges et al.,
 THE ELECTROPHYSIOLOGICAL PHENOMENON OF ALZHEIMER’S DISEASE
1998; Förstl et al., 1993; Förstl et al., 1996; Meyer et al., 1995;
Qizilbash et al., 1998; Read et al., 1995; Soininen et al., 1992).
Specific electrophysiological brain changes are characteristic of
the brain activity of persons with AD (Besthorn et al., 1997;
Coben et al., 1985; Hooijer, Jonker, Posthuma, & Visser, 1990).
These electrophysiological brain changes are also associated
with the psychopathology of AD, before onset and across the
stages of AD (pre-clinical or prodromal, mild, moderate, or se-
vere) in the progression of AD (Gianotti et al., 2007; Knott,
Mohr, Mahoney, & Ilivitsky, 2001). Therefore, these interact-
ing concepts support the relational statements of the theory of
EPAD (Figure 1).
Neuropathological Changes
The Aβ and τ pathology is the accepted organic basis for
a diagnosis of AD, which results in neuritic plaques and neu-
rofibrillary tangles. The production and accumulation of the
amyloid-β peptide lead to neuritic plaques and neurofibrillary
tangles occur from the accumulation of aggregated phosphory-
lated τ oligomers in cortical areas (Alexopoulos et al., 2013;
Grutzendler et al., 2007; Ito et al., 2014; Luque-Contreras et al.,
2014; Prescott et al., 2014). From the continued accumulation,
there is increased amyloid-β and -τ proteins burden in the cor-
tical areas, leading to neuropathological changes (Grutzendler
et al., 2007; Ito et al., 2014; Leroy et al., 2000; Luque-Contreras
et al., 2014; Prescott et al., 2014). Their occurrence are observed
post-mortemly in the cortical areas of persons with a diagnosis
of AD (Prescott et al., 2014; Solodkin et al., 2013). The po-
tential for these changes to contribute to the onset of AD is re-
lated to the observed abnormal Aβ production and metabolism
in persons with MCI (Ito et al., 2014; Wu et al., 2012). Per-
sons with MCI had elevated levels of amyloid-β deposits with
low metabolism. However, this potentiality is not reached until
the Aβ production achieves a specific threshold that indicates
abnormal production, which is often at the moderate and/or
moderate-to-severe stage of AD (Ito et al., 2014; Perez et al.,
2014). This approach indicates that a diagnosis is made well
in the disease process and currently cannot be definitely made
before. Neuropathological changes are not consistently associ-
ated with the pre-onset, pre-clinical symptoms, weakening their
possible association with the psychopathology at these stages.
However, neuropathological changes, such as neuritic plaques
and neurofibrillary tangles directly relate to electrophysiological
brain changes (Reinikainen et al., 1988; Soininen et al., 1992).
Disruption of the neuronal activity contributes to the amyloid-β
and phosphorylated τ accumulation in cortical areas such as
the ventral tegmental area (especially the limbic region) and
thalamus. The altered neuronal activity is manifested as electro-
physiological brain changes (John, 2002). They create a neuro-
environment conducive to the continued increasing amyloid-β
and -τ , leading to a specific threshold or amyloid burden for the
production of neuropathological changes (Moretti, Paternico,
Binetti, Zanetti, & Frisoni, 2014; Prescott et al., 2014). These
607
neuropathological changes are associated with cognitive deficits
in persons with mild cognitive impairment (MCI) and AD; and,
both the neuropathological changes and cognitive deficits are
correlated to observed electrophysiological brain changes such
as increased activity in θ - and δ- as well as decreased α-activity
depending on the stage of AD (Moretti et al., 2014; Prichep
et al., 1994). It is evident that the abnormal electrophysiologi-
cal brain changes correlate with the neuropathological changes
and link to the psychopathology of AD. In addition, this asso-
ciation has been reported in various neuroimaging techniques
(i.e., the BEAM: brain electrical activity mapping; the SPECT:
single photo emission computed tomography; the LORETA:
low resolution electromagnetic tomography; the PET: positron
emission tomography, and the fMRI: functional magnetic reso-
nance imaging), which are used to display the association among
neuropathological changes, altered levels of neurochemicals, al-
tered metabolic rates, and/or electrophysiological brain changes
(Bergman et al., 1997; Bobinski et al., 1998; Brenner et al., 1986;
Chen, Hsu, Chiu, Hu, & Lee, 2013; Desgranges et al., 1998;
Duffy, Albert, & McAnulty, 1984; Förstl et al., 1993; Förstl
et al., 1996; Gianotti et al., 2007; Szelies, Mielke, Herholz, &
Heiss, 1994; Wszolek et al., 1992).
Based on these findings, it is evident that electrophysiologi-
cal brain changes are directly related to the Aβ and τ pathology
and occurring prior to the amyloid burden or a neuropatholog-
ical threshold. The organic basis of AD is stimulated from the
disrupted neuronal activity that is manifested as electrophysi-
ological brain changes. It is this abnormality that contributes
to the neuropathological changes and psychopathology of AD.
Therefore, understanding the interaction between the electro-
physiological brain changes and neuropathological changes fa-
cilitates an understanding of the onset and progression of AD.
Neurochemical Changes
Neurochemical changes are directly related to the develop-
ment of neuritic plaques and tangles. Decreased levels of
choline acetyltransferase and acetylcholinesterase disrupt the
cholinergic neurons of the nucleus basalis, promoting amyloid-
β deposits and over time lead to neuropathological changes
(Grutzendler, Helmin, Tsai, & Gan, 2007; Reinikainen et al.,
1988). These decreased levels of acetylcholinesterase and
choline acetyltransferase as well as increased levels of choline-
sterase are observed in the blood plasma and post-mortemly
identified in persons with AD (Davis et al., 1999; Qizilbash et al.,
1998). Elevated levels of cholinesterase and decreased acetyl-
choline synthesis have been associated with cognitive deficits
(impaired concentration and decreased stimuli detection), be-
havioral disturbances, and altered functioning (Miller, 2007;
Qizilbash et al., 1998; Reinikainen et al., 1988). The altered lev-
els of the neurochemicals continue with the increasing severity
of AD (Davis et al., 1999; Qizilbash et al., 1998). In some in-
stances, the decreased levels of acetylcholinesterase and choline
acetyltransferase in blood plasma seemed to provide a measure
608 E. C. HOLSTON
of the onset of AD; however, the decreased levels failed to con-
sistently reflect the psychopathology across the mild, moderate,
or severe stages of AD (Davis et al., 1999; Qizilbash et al.,
1998). Importantly, low levels of choline acetyltransferase are
associated with increased θ -activity (Soininen et al., 1992). As
a result, neurochemical changes relate to the neuropathological
abnormalities of AD; and, both are linked to electrophysiolog-
ical brain changes. Consequently, neurochemical changes have
a positive indirect relationship to the electrophysiological brain
changes that are moderated by neuropathological changes, sup-
porting the theory of EPAD.
Metabolic Changes
Using neuroimaging techniques (i.e., CT, PET, and SPECT),
metabolic changes (i.e., decreased glucose utilization in the
brain and/or impaired delivery of circulating blood to brain are
directly associated with the neuropathological changes observed
in persons with AD (Bergman et al., 1997; Desgranges et al.,
1998; Förstl et al., 1996; Meyer et al., 1995; Read et al., 1995;
Wu et al., 2012). These metabolic changes or hypometabolism
disrupts the neuronal activity (i.e., neuron firing, synaptic trans-
mission, inhibition/excitation of neurons), causing a change in
protein production in cortical areas such as the precuneus, hip-
pocampus, entorhinal cortex, cingulate gyrus, and inferior pari-
etal cortex (Desgranges et al., 1998; Larson et al., 1998; Wu
et al., 2012). Overproduction and deposition of amyloid-β and -
τ proteins lead to the development of neuropathological changes
associated with AD (Alexopoulos et al., 2013; Desgranges et al.,
1998; Larson et al., 1998; Wu et al., 2012). Interestingly, altered
metabolism has been useful in detecting impaired cognition
and memory deficits as they are manifested in persons with
MCI and those with AD (Alexopoulos et al., 2013; Desgranges
et al., 1998; Wu et al., 2012). In addition, the amyloid deposits
from hypometabolism seemed to increase with the progression
of AD (Wu et al., 2012). However, metabolic changes were
not sensitive or specific enough to support a diagnosis of AD
by measuring amyloid-β deposits from hypometabolism or to
characterize the clinically-observed behavioral and functional
changes (Alexopoulos et al., 2013; Bergman et al., 1997; Meyer
et al., 1995). Metabolic changes are also associated with electro-
physiological brain changes, such as an increase in slow brain
activity (θ -activity and δ-activity) in persons with MCI and
those with AD. An increased θ -activity occurred in the left hip-
pocampus and temporal region for persons with MCI who have
a high risk for developing AD (Moretti et al., 2014) and pre-
dominantly in the parietotemporal strip for persons with AD
(Szelies et al., 1994). An increased δ-activity occurred in the
temporal region, specifically the left amygdala, for persons with
AD (Valladares-Neto et al., 1995). Through the altered neuronal
activity, abnormal metabolic changes are correlated to neuro-
chemical changes and neuropathological changes observed in
persons with AD (Bergman et al., 1997; Davis et al., 1999;
Förstl et al., 1993; Förstl et al., 1996; Meyer et al., 1995; Qizil-
bash et al., 1998; Read et al., 1995). Moreover, it is through
this electrophysiological commonality that neuropathological
changes moderate the impact of both metabolic changes and
neurochemical changes on electrophysiological brain changes
throughout the progression of AD. As a result, they contribute
to the understanding of how electrophysiological brain changes
relate to the psychopathology of AD, providing a way to under-
stand and examine EPAD.
Electrophysiological Brain Changes
Electrophysiological brain changes result from the alteration
of the bioelectrical activity of the brain (the electrophysiology of
the brain). They can be recorded with a quantitative electroen-
cephalogram (qEEG), which is a non-invasive way to produce
a detailed and accurate representation or image for assessment
purposes (Jelic & Kowalski, 2009; Knott et al., 2001; Moretti
et al., 2014; Niedermeyer & Da Silva, 1999). The qEEG is
separated into slow brain activity (δ-activity = 1.5–3.5 Hz;
θ -activity = 3.5–7.5 Hz) and fast brain activity (α-activity =
7.5–12.5 Hz; β-activity = 12.5–25 Hz). The reliability and
validity of the qEEG has been extensively demonstrated (Jelic
& Kowalski, 2009; Jeong, Kim, & Han, 1998; John, Prichep,
Fridman, & Easton, 1988; Pozzi et al., 1995; Prichep & John,
1992; Prichep et al., 1994; Valdés et al., 1992).
Since the mid-1980s, abnormal electrophysiological brain
changes have been reported in persons with AD, such as in-
creased or excessive slow brain activity (δ-activity and θ -
activity) and/or decreased α-activity (Breslau, Starr, Sicotte,
Higa, & Buchsbaum, 1989; Coben, Danziger, & Storandt, 1985;
Duffy, Albert, & McAnulty, 1984; Duffy, Albert, McAnulty,
& Garvey, 1984). The electrophysiological brain changes are
recorded as abnormal because they are significantly beyond
the normal range when compared with the brain activity of
a control group or a population-based normative database of
normal-functioning older adults. As a result, the abnormal elec-
trophysiological brain changes significantly differentiate per-
sons with AD from normal-functioning older adults (Besthorn
et al., 1997; Claus et al., 1999; Fonseca, Tedrus, Fondello, Reis,
& Fontoura, 2011; Lee, Park, Kim, & Im, 2010; Prichep et al.,
1994; Knott et al., 2001; Mody, McIntyre, Miller, Altman, &
Read, 1991). These changes are reported as potentially objective
ways to differentiate the stages of AD from the diagnosis of AD
as well as discern AD from other dementias (Fonseca, Tedrus,
Fondello et al., 2011; Fonseca, Tedrus, Prandi, & de Andrade,
2011; Gawel, Zalewska, Szmidt-Salkowska, & Kowalski, 2009;
Signorino et al., 1996). Specifically, an increase in θ -activity
alone is often recorded in any of the stages of AD from pro-
dromal to severe and an increase in θ -activity with a decrease
in α-activity is often recorded in the moderate to severe stages
of AD (Anghinah et al., 2011; Fonseca, Tedrus, Fondello et al.,
2011; Fonseca, Tedrus, Prandi et al., 2011; Moretti et al., 2014).
An increase in δ-activity is recorded as early as the moderate
stage of AD (Gawel et al., 2009). These electrophysiological
 THE ELECTROPHYSIOLOGICAL PHENOMENON OF ALZHEIMER’S DISEASE
brain changes are associated with altered metabolism and pro-
duction of neuropathological changes in specific cortical areas
(ventricles, intracranial cerebral fluid space, superior tempo-
ral gyrus, transverse temporal gyrus, postcentral gyrus, cuneus,
lingual gyrus, inferior parietal lobule, parietotemporal strip, and
brain regions: left temporo-parietal, frontal, temporal, parietal,
and/or occipital), as well as any disruption in the synchronicity
between the hemispheres (Anghinah et al., 2011; Förstl et al.,
1993; Förstl et al., 1996; Fonseca, Tedrus, Prandi et al., 2011;
Gianotti et al., 2007; Kim et al., 2012; Jung, Lee, Kim, Lee, &
Chung, 2007; Wszolek et al., 1992). In addition, electrophysio-
logical brain changes can differentiate AD from other dementias.
Vascular dementia (subcortical and general) has temporal lobe
lateralization of abnormal δ-activity and decreased θ -activity;
frontotemporal dementia has increased δ- and θ -activity only in
anterior regions with no abnormality in the posterior regions;
and dementia with Lewy bodies has predominantly decreased
α-activity with increased δ- and θ -activity in temporal regions
(Micanovic & Pal, 2014).
Electrophysiological brain changes are correlated with spe-
cific symptoms of AD that comprise the psychopathology of
AD (i.e., psychotic features, impaired cognition, and behavioral
disturbances) (D’Onofrio et al., 1996; Gianotti et al., 2007;
Jung et al., 2007; Kim et al., 2012; Knott et al., 2001; Lopez
et al., 1997). In the early stages of AD, an increased θ -activity
is associated with the onset of impaired cognition and its in-
creasing severity, paralleling the diminishing cognition in the
psychopathology (Gianotti et al., 2007; Jung et al., 2007; Kim
et al., 2012; Knott et al., 2001). Throughout the progression of
AD, impaired cognition is associated with early-stage increased
θ -activity and late-stage increased δ-activity with decreased α-
activity (Breslau et al., 1989; Chen, Hsu, Chiu, Hu, & Lee, 2013;
Duffy, Albert, McAnulty, & Garvey, 1984; Lopez et al., 1997;
Robinson et al., 1994). This association is also occurring with
the increasing severity of the impaired cognition. The electro-
physiological brain changes parallel the diminishing cognition
across the stages of AD, providing an objective way to psycho-
metrically measure the clinically manifested impaired cognition
(Brenner et al., 1986; Chiaramonti et al., 1997; Dierks, Perisic,
Frölich, Ihl, & Maurer, 1992; Duffy, Albert, & McAnulty, 1984;
Duffy, Albert, McAnulty, & Garvey, 1984; Förstl et al., 1993;
Förstl et al., 1996; Garn et al., 2014; Ihl, Dierks, Martin, Frölich,
& Maurer, 1996; Pozzi et al., 1995). As the illness progressed,
the correlation became stronger. The electrophysiological brain
changes reported in the moderate stages of AD are associated
with behavioral disturbances, hallucinations, declining func-
tioning or limited activities of daily living, and incontinence
(Brenner et al., 1986; Dierks et al., 1992; D’Onofrio et al.,
1996; Förstl et al., 1993; Nobili et al., 1999). Equally important,
abnormal electrophysiological brain changes are observed and
measured before the onset of mild cognitive impairment (MCI),
indicating an objective marker(s) for the onset of the AD dis-
ease process (Holston, 2003; Prichep et al., 2006; Prichep et al.,
1994).
609
Electrophysiological brain changes are associated with the
neuropathological changes and psychopathology of AD, which
is based on the electrophysiological brain changes’ impact on
the Aβ and τ pathology. As previously discussed, disruption
of the neuronal activity at certain nuclei (i.e., nucleus basalis,
nucleus reticularis, or nucleus supramammillaris) is manifested
as electrophysiological brain changes and contributes to the Aβ
and τ pathology. Continuation of the disruption promotes ab-
normal electrophysiological brain changes, changing the neuro-
environment for the accumulation of the Aβ and τ proteins.
Over time, a threshold or amyloid burden is reached to gen-
erate neuropathological changes. A bi-directional association
results as the electrophysiological brain changes lead to the al-
tered Aβ and τ pathology and the neuropathological changes
from the amyloid burden contribute to the abnormality of the
electrophysiological brain changes. The theory of EPAD ex-
plains this association between the abnormal electrophysiolog-
ical brain changes and the symptoms occurring throughout the
stages and during the progression of AD. Therefore, EPAD
links electrophysiological brain changes to Aβ and τ pathology
throughout the progression of AD.
Aging might be a possible concept of EPAD given the occur-
rence of AD in the elderly population. Aging and AD both have
similar changes related to impaired cognition and functioning.
However, aging may have a precursory association with EPAD,
since the similar changes in AD have a more rapid and severe
progression than normal aging. Also, genetic markers may be
indicative of a genetic concept of AD such as Apolipoprotein E
(APOE), which has been linked to clinical manifestations (Car-
rasquillo et al., 2014; Lehtovirta et al., 2000; Leroy et al., 2000;
Liu et al., 2014; Luque-Contreras et al., 2014; Rodriguez et al.,
2014). However, this relation to EPAD remains unclear given
the limited extent of research examining the relationship among
genes, electrophysiological changes, and AD.
Implications of the Theory of EPAD
Using the theory of EPAD, it is possible to describe the psy-
chopathology of AD via the electrophysiology of the brain. Elec-
trophysiological activity is defined as either diffused desynchro-
nized bioelectrical activity or diffused, synchronized bioelectri-
cal activity in the brain. Electrophysiological activity falls within
four types of brain activity or frequencies (δ = 1.5–3.5 Hz;
θ = 3.5–7.5 Hz; α = 7.5–12.5 Hz; β = 12.5–25 Hz).
Due to the onset and progression of AD, the normal electro-
physiological activity becomes altered, producing electrophysi-
ological brain changes. The brain normally maintains a diffused
synchrony during inattentiveness or unfocused conscious states
(Berger, 1969). However, the onset and/or progression of AD
(a stimulus) alters the diffused synchrony in specific cortical
areas, generating a structured, discernible electrophysiological
change in the bioelectrical activity or electrophysiological brain
change. There is an imbalance between the bioelectrical activity
in the entire cerebral cortex and in the specific cortical area. As
610 E. C. HOLSTON
the stimulus intensifies, the electrophysiological brain change
increases, enhancing its predictability (John, 1980; 2002).
With that understanding, the influence of the electrophysio-
logical brain change on the symptom of AD can be described
by the dominating perspective orientation. From a non-physical
perspective orientation, the altered bioelectrical activity pro-
duces electrophysiological brain changes manifested as func-
tional changes and/or neurological changes. The electrophysi-
ological brain change can be measured as increased θ -activity,
linking the functional changes to the altered electrophysiolog-
ical activity. With a physical perspective orientation, the al-
tered bioelectrical activity produces electrophysiological brain
changes manifested as cognitive changes and/or behavioral
changes. The electrophysiological brain changes for cognitive
changes are increased θ -activity and/or decreased α-activity. For
behavioral changes, the electrophysiological brain changes are
an increased θ -activity and/or increased δ-activity. Again, the
change associated with AD is linked to the altered electrophys-
iological activity. Thus, measurable changes in the bioelectrical
activity potentiate the ability to identify the electrophysiological
brain changes of AD.
The theory of EPAD can be tested using quantitative re-
search methods so that the empirical measures or variables are
the electrophysiological brain changes and quantified clinical
symptoms. Using the theory of EPAD, the relationship between
brain activity and depressive symptoms was described in 14
participants with AD (Holston, 2014). A discernible electro-
physiological brain change occurred in each participant’s brain
activity due to the physical perspective overshadowing the non-
physical perspective. This orientation produced an increased
θ -activity in the brain activity, impaired cognition, and depres-
sive symptoms. The increased θ -activity was associated with
both impaired cognition and depressive symptoms. The elec-
trophysiological brain change increased with the severity of the
symptoms. In addition, this increased θ -activity was associated
with the mild stage of AD. In a longitudinal study, the theory of
EPAD was used to examine the relationship between the brain
activity and manifested clinical symptoms for 96 participants
that were classified across the stages of AD (pre-clinical or pro-
dromal, mild, moderate, or severe) (Holston, 2003). At baseline,
an increased θ -activity was the only discernible electrophysio-
logical brain change recorded in participants in the mild stages
of AD. This is indicative of the physical perspective overshad-
owing the non-physical perspective. The increased θ -activity
was associated with changes in overall behavior and cognition.
At the 2-year follow-up evaluation, the continued influence from
the physical perspective orientation produced a greater degree of
an increased θ -activity. It was associated with the stages (pre-
clinical or prodromal, mild, moderate, and severe) of AD to
which the participants had converted. The increased θ -activity
was also inversely associated with impaired cognition and pos-
itively associated with behavioral changes, providing an objec-
tive measure of the clinical symptoms. Therefore, the theory of
EPAD provides a theoretical foundation to understand AD from
its conceptualization to quantifiable measurements.
CONCLUSION
Unquestionably, AD is escalating (AA, 2014). It is decimat-
ing the ability for self-care, and creating challenges for familial
caregiving (AA, 2014; Reisberg et al., 1999). Care is based on
assessing the neuropathological changes, the organic basis of the
psychopathology, which is often at the mild-to-moderate stage
of AD (Bosboom et al., 2013; Rochat et al., 2013; Tracten-
berg et al., 2005; Zahodne, Devanand et al., 2013; Zahodne,
Ornstein et al., 2013; Zdanys et al., 2007). Although some stud-
ies are examining the psychopathology at the prodromal stage
(Bidzan et al., 2008; Holtzer et al., 2003; Teng et al., 2007), the
current neuropathological approach persists, limiting the assess-
ment and treatment of the early stages of AD’s psychopathology
(Courtney et al., 2004; Holtzer et al., 2003; Miller, 2007). It also
fosters a retrograde understanding of the psychopathology in
the early stages, restricting the ability to address any fluctua-
tions or variances in symptoms. However, the theory of EPAD
could facilitate an anterograde understanding where proactive
and aggressive efforts can be used to slow the potential for AD
and its psychopathology.
The theory of EPAD facilitates the potential of addressing
the psychopathology at its earliest occurrence and potential for
progressing to AD. If the theory is supported by subsequent
research, healthcare providers can objectively assess the insid-
ious progression and develop more effective treatment modali-
ties. The confusion about cognitive deficits being normal aging
or AD can be addressed by monitoring the electrophysiologi-
cal brain changes and using this information to develop proac-
tive interventions to address the deficits. Healthcare providers
can transition their reactionary care of the psychopathology to
proactive care and enhance their ability to implement health
promotion measures. The theory of EPAD holds promise for an
objective way for early recognition of AD’s psychopathology,
which is paramount if healthcare providers are going to address
the psychopathology of AD with support and patient education
(Grusendorf, 1994). Importantly, the theory of EPAD facilitates
teaching family members how to care for a person with AD,
which is significant in their ability to cope with the stress asso-
ciated with the caring of a loved one (Gélinas, Gauthier, McIn-
tyre, & Gauthier, 1999; Lim et al., 1999; Reisberg et al., 1999;
Reisberg & Kluger, 1998). In addition, family members could
learn how to lessen feelings of helplessness that they experience
with AD (Gélinas et al., 1999; Lim et al., 1999). Through the
EPAD, the psychopathology can be assessed as early as pre-
AD. Therefore, the EPAD may provide a more comprehensive
understanding of the psychopathology, facilitating healthcare
providers’ capacity for implementing early interventions, antic-
ipatory guidance, and health education.
 THE ELECTROPHYSIOLOGICAL PHENOMENON OF ALZHEIMER’S DISEASE
Declaration of Interest: The author reports no conflicts of
interest. The author alone is responsible for the content and
writing of the paper.
REFERENCES
Anghinah, R., Kanda, A. M., Lopes, H. F., Basile, L. F. H., Machado, S.,
Ribeiro, P., et al. (2011). Alzheimer’s disease qEEG: Spectral analysis versus
coherence: Which is the best measurement? Arquivos De Neuro-Psiquiatria,
69(6), 871–874.
Alexopoulos, P., Guo, L. H., Jiang, M., Bujo, H., Grimmer, T., Förster, S.,
et al. (2013). Amyloid cascade and tau pathology cerebrospinal fluid markers
in mild cognitive impairment with regards to Alzheimer’s disease cerebral
metabolic signature. Journal of Alzheimer’s Disease, 36(2), 401–408.
Alzheimer’s Association (AA). (2014). 2014 Alzheimer’s disease: Facts and
figures. Includes a special report on women and Alzheimer’s disease.
Alzheimer’s & Dementia, 10(2), e47-e92.
Berger, H. (1969). On the electroencephalogram of man. The fourteen origi-
nal reports on the human electroencephalogram. Supplements to Electroen-
cephalography and Clinical Neurophysiology 28. Amsterdam, NY: Elsevier.
Bergman, H., Chertkow H., Wolfson, C., Stern, J., Rush, C., Whitehead, V.,
et al. (1997). HM-PAO (CERETEC) SPECT brain scanning in the diagnosis
of Alzheimer’s disease. Journal of American Geriatrics Society, 45, 15–20.
Besthorn, C. Zerfass, R., Geiger-Kabisch, C., Sattel, H., Daniel, S., Schreiter-
Gasser, U., et al. (1997). Discrimination of Alzheimer’s disease and normal
aging by EEG data. Electroencephalography and Clinical Neurophysiology,
103, 241–248.
Bidzan, L., Pachalska, M., Grochmal-Bach, B., Bidzan, M., Cieslukowska,
A., & Pufal, A. (2008). Behavioral and psychological symptoms in the
preclinical stage of Alzheimer’s disease. Medical Science Monitor, 14(9),
CR473–CR479.
Bobinski, M., de Leon, M J., Tarnawski, M., Wegiel, J., Bobinski, M., Reisberg,
B., et al. (1998). Neuronal and volume loss in CA1 of the hippocampal
formation uniquely predicts duration and severity of Alzheimer disease. Brain
Research, 805, 267–269.
Bosboom, P. R., Alfonso, H., & Almeida, P. (2013). Determining the predictors
of change in quality of life self-ratings and carer-ratings for community-
dwelling people with Alzheimer disease. Alzheimer Disease & Associated
Disorders, 27, 363–371.
Brassen, S., Braus, D. F., Weber-Fahr, W., Tost, H., Moritz, S., & Adler, G.
(2004). Late-onset depression with mild cognitive deficits: Electrophysiolog-
ical evidences for a preclinical dementia syndrome. Dementia and Geriatric
Cognitive Disorders, 18, 271–277.
Brenner, R. P., Ulrich, R. F., Spiker, D. G., Sclabassi, R. J., Reynolds, C. F.,
Marin, R. S., et al. (1986). Computerized EEG spectral analysis in elderly nor-
mal, demented, and depressed subjects. Electroencephalography and Clinical
Neurophysiology, 64, 483–492.
Breslau, J., Starr, A., Sicotte, N., Higa, J., & Buchsbaum, M. S. (1989). Topo-
graphic EEG changes with normal aging and SDAT. Electroencephalography
and Clinical Neurophysiology, 72, 281–289.
Carrasquillo, M. M., Khan, Q., Murray, M. E., Krishnan, S., Aakre, J., Pankratz,
V. S., et al. (2014). Late-onset Alzheimer disease genetic variants in posterior
cortical atrophy and posterior AD. Neurology, 82(16), 1455–1462.
Chen, C. C., Hsu, C. Y., Chiu, H. W., Hu, C. J., & Lee, T. C. (2013). Frequency
power and coherence of electroencephalography are correlated with the sever-
ity of Alzheimer’s disease: A multicenter analysis in Taiwan. Journal of the
Formosan Medical Association, S0929–6646(13), 232–235.
Chiaramonti, R., Muscas, G. C., Paganini, M., Müller, T. J., Fallgatter, A.
J., Versari, A., et al. (1997). Correlations of topographical EEG features
with clinical severity in mild and moderate dementia of Alzheimer type.
Neuropsychobiology, 36, 153–158.
Claus, J. J., Strijers, R. L. M., Jonkman, E. J., Ongerboer de Visser, B. W.,
Jonker, C., Walstra, G. J. M., et al. (1999). The diagnostic value of electroen-
611
cephalography in mild senile Alzheimer’s disease. Clinical Neurophysiology,
110, 825–832.
Coben, L. A., Danziger, W., & Storandt, M. (1985). A longitudinal EEG study
of mild senile dementia of Alzheimer type: Changes at 1 year and at 2.5 years.
Electroencephalography and Clinical Neurophysiology, 61, 101–112.
Courtney, C., Farrell, D., Gray, R., Hills, R., Lynch, L., Sellwood, E., et al.;
AD 2000 Collaborative Group. (2004). Long-term donepezil treatment in 565
patients with Alzheimer’s disease (AD2000): Randomize double-blind trial.
Lancet, 363(9427), 2105–1225.
Davis, K. L., Mohs, R. C., Marin, D., Purohit, D. P., Perl, D. P., Lantz, M., et al.
(1999). Cholinergic markers in elderly patients with early signs of Alzheimer
disease. Journal of American Medical Association, 281, 1401–1406.
de Leon, M. J., Golomb, J., George, A. E., Convit, A., Tarshish, C. Y., McRae,
T., et al. (1993). The radiologic prediction of Alzheimer disease: The atrophic
hippocampal formation. American Journal of Neuroradiology, 14, 897–906.
Desgranges, B., Baron, J.-C., de la Sayette, V., Petit-Taboué, M.-C., Benali,
K., Landeau, B., et al. (1998). The neural substrates of memory systems
impairment in Alzheimer’s disease: A PET study of resting brain glucose
utilization. Brain, 121, 611–631.
Dierks, T., Perisic, I., Frölich, L., Ihl, R., & Maurer, K. (1992). Topography
of the quantitative electroencephalogram in dementia of the Alzheimer type:
Relation to severity of dementia. Psychiatry Research: Neuroimaging, 40,
181–194.
D’Onofrio, F., Salvia, S., Petretta, V., Bonavita, V., Rodriguez, G., & Tedeschi,
G. (1996). Quantified-EEG in normal aging and dementias. Acta Neurologica
Scandinavica, 93, 336–345.
Duffy, F. H., Albert, M. S., & McAnulty, G. (1984). Brain electrical activity in
patients with presenile and senile dementia of the Alzheimer type. Annals of
Neurology, 16, 439–448.
Duffy, F. H., Albert, M. S., McAnulty, G., & Garvey, A. J. (1984). Age-related
difference in brain electrical activity of healthy subjects. Annals of Neurology,
16, 430–438.
Fonseca, L. C., Tedrus, G. M., Fondello, M. A., Reis, I. N., & Fontoura, D. S.
(2011). EEG theta and alpha reactivity on opening the eyes in the diagnosis
of Alzheimer’s disease. Clinical EEG and Neuroscience, 42(3), 185–189.
Fonseca, L. C., Tedrus, G. M. A. S., Prandi, L. R., & de Andrade, A. C. A. (2011).
Quantitative electroencephalography power and coherence measurements in
the diagnosis of mild and moderate Alzheimer’s disease. Arquivos De Neuro-
Psiquiatria, 69(2B), 297–303.
Förstl, H., Besthorn, C., Geiger-Kabisch, C., Sattel, H., & Schreiter-Gasser,
U. (1993). Psychotic features and the course of Alzheimer’s disease: Rela-
tionship to cognitive, electroencephalographic and computerized tomography
findings. Acta Psychiatrica Scandinavica, 87, 395–399.
Förstl, H., Sattel, H. Besthorn, C., Daniel, S., Geiger-Kabisch, C., Hentschel,
F., et al. (1996). Longitudinal cognitive, electroencephalographic and mor-
phological brain changes in ageing and Alzheimer’s disease. British Journal
of Psychiatry, 168, 280–286.
Fox, N. C., Cousens, S., Scahill, R., Harvey, R. J., & Rossor, M. N. (2000).
Using serial registered brain magnetic resonance imaging to measure disease
progression in Alzheimer disease: Power calculations and estimates of sample
size to detect treatment effects. Archives of Neurology, 57, 339–344.
Garn, H., Waser, M., Deistler, M., Schmidt, R., Dal-Bianco, P., Ransmayr,
G., et al. (2014). Quantitative EEG in Alzheimer’s disease: Cognitive state,
resting state and association with disease severity. International Journal of
Psychophysiology, 93(3), 390–397.
Gawel, M., Zalewska, E., Szmidt-Salkowska, E., & Kowalski, J. (2009). The
value of quantitative EEG in differential diagnosis of Alzheimer’s disease
and subcortical vascular dementia. Journal of the Neurological Sciences,
283, 127–133.
Geddes, J. W., Tekirian, T. L., Soultanian, N. S., Ashford, J. W., Davis, D. G.,
& Markesbery, W. R. (1997). Comparison of neuropathologic criteria for the
diagnosis of Alzheimer’s disease. Neurobiology of Aging, 18, S99-S105.
Gélinas, I., Gauthier, L., McIntyre, M., & Gauthier, S. (1999). Development
of a functional measure for persons with Alzheimer’s disease: The disability
612 E. C. HOLSTON
assessment of dementia. American Journal of Occupational Therapy, 53,
471–481.
Gianotti, L. R., Kunig, G., Lehmann, D., Faber, P. L., Pascual-Marqui, R. D.,
Kochi, K., et al. (2007). Correlation between disease severity and brain elec-
tric LORETA tomography in Alzheimer’s disease. Clinical Neurophysiology,
118, 186–196.
Gloor, P. (1969). Hans Berger on the electroencephalogram of man. The fourteen
original reports on the human electroencephalogram. Supplements to Elec-
troencephalography and Clinical Neurophysiology 28, 1–36. Amsterdam,
NY: Elsevier.
Grusendorf, P. (1994). EEGs in cognitive stages of Alzheimer’s-type dementia.
Journal of Neuroscience Nursing, 26, 42–46.
Grutzendler, J., Helmin, K., Tsai, J., & Gan, W.-B. (2007). Various dendritic
abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s
disease. Annals of the New York Academy of Science, 1097(1), 30–39.
Holston, E. C. (2003). The relationship between the abnormal electrophysiolog-
ical features and the degeneration in cognition, behavior, daily functioning,
and global presentation manifested by individuals with Alzheimer’s disease.
Dissertation Abstracts International, 64(08), 3743(UMI#AAT 3100793).
Holston, E. C. (2014). Describing brain activity of persons with AD and depres-
sive symptoms. Archives of Psychiatric Nursing, 28(6), 413–419.
Holtzer, R., Tang, M.-X., Devanand, D. P., Albert, S. M., Wegesin, D. J., Marder,
K., et al. (2003). Psychopathological features in Alzheimer’s disease: Course
and relationship with cognitive status. Journal of the American Geriatric
Society, 51, 953–960.
Hooijer, C., Jonker, C., Posthuma, J., & Visser, S. L. (1990). Reliability, va-
lidity and follow-up of the EEG in senile dementia: Sequelae of sequential
measurement. Electroencephalography and Clinical Neurophysiology, 76,
400–412.
Horesh, Y., Katsel, P., Haroutunian, V., & Domany, E. (2011). Gene expression
signature is shared by patients with Alzheimer’s disease and schizophrenia at
the superior temporal gyrus. European Journal of Neurology, 18, 410–424.
Ihl, R., Dierks, T., Martin, E.-M., Frölich, L., & Maurer, K. (1996). Topography
of the maximum of the amplitude of EEG frequency bands in dementia of the
Alzheimer type. Biological Psychiatry, 39, 319–325.
Ito, H., Shinotoh, H., Shimada, H., Miyoshi, M., Yanai, K., Okamura, N.,
et al. (2014). Imaging of amyloid deposition in human brain using positron
emission tomography and [18F]FACT: comparison with [11c]PIB. European
Journal of Nuclear Medicine and Molecular Imaging, 41(4), 745–754.
Jelic, V. & Kowalski, J. (2009). Evidence-based evaluation of diagnostic ac-
curacy of resting EEG in dementia and mild cognitive impairment. Clinical
EEG and Neuroscience, 40(2), 129–142.
Jeong, J., Kim, S. Y., & Han, S.-H. (1998). Non-linear dynamic analysis of the
EEG in Alzheimer’s disease with optimal embedding dimension. Electroen-
cephalography and Clinical Neurophysiology, 106, 220–228.
John, E. R. (1980). Multipotentiality: A statistical theory of brain function –
evidence and implications. In Davidson R. J. & Davidson, J. M. (Eds), The
psychobiology of consciousness (pp. 129–146). New York, NY: Plenum.
John, E. R. (2002). The neurophysics of consciousness. Brain Research Reviews,
39(1), 1–28.
John, E. R., Prichep, L. S., Fridman, J., & Easton, P. (1988). Neurometrics:
Computer-assisted differential diagnosis of brain dysfunctions. Science, 239,
162–169.
Jung, H.-T., Lee, S.-H., Kim, J.-N., Lee, K.-J., & Chung, Y.-C. (2007). Quantita-
tive electroencephalography and low resolution electromagnetic tomography
imaging of Alzheimer’s disease. Psychiatry Investigation, 4, 31–37.
Kim, J.-S., Lee, S.-H., Park, G., Kim, S., Bae, S.-M., Kim, D.-W., et al.
(2012). Clinical implications of quantitative electroencephalography and cur-
rent source density in patients with Alzheimer’s disease. Brain Topography,
25, 461–474.
Knott, V., Mohr, E., Mahoney, C., & Ilivitsky, V. (2001). Quantitative electroen-
cephalography in Alzheimer’s disease: Comparison with a control group,
population norms and mental status. Journal of Psychiatry & Neuroscience,
26(2), 106–116.
Larson, C. L., Davidson, R. J., Abercrombie, H. C., Ward, R. T., Schaefer, S.
M., Jackson, D. C., et al. (1998). Relations between PET-derived measures of
thalamic glucose metabolism and EEG alpha power. Psychophysiology, 35,
162–169.
Lee, S.-H., Park, Y.-M., Kim, D.-W., & Im, C.-H. (2010). Global synchronization
index as a biological correlate of cognitive decline in Alzheimer’s disease.
Neuroscience Research, 66, 333–339.
Lehtovirta, M., Partanen, J., Könönen, M., Hiltunen, J., Helisalmi, S., Har-
tikainen, P., et al. (2000). A longitudinal quantitative EEG study of
Alzheimer’s disease: Relation to Apolipoprotein E polymorphism. Dementia
and Geriatric Cognitive Disorders, 11, 29–35.
Leroy, K., Menu, R., Conreur, J. L., Dayanandan, R., Lovestone, S., Ander-
ton, B. H., et al. (2000). The function of the microtubule-associated protein
tau is variably modulated by graded changes in glycogen synthase kinase-
3beta activity. Federation of European Biochemical Societies: Letters, 465,
34–38.
Lim, A., Tsuang, D., Kukull, W., Nochlin, D., Leverenz, J., McCormick, W.,
et al. (1999). Clinico-neuropathological correlation of Alzheimer’s disease in
a community-based case series. Journal of American Geriatric Society, 47,
54–569.
Liu, Y., Yu, J. T., Wang, H. F., Han, P. R., Tan, C. C., Wang, C., et al. (2014).
APOE genotype and neuroimaging markers of Alzheimer’s disease: Sys-
tematic review and meta analysis. Journal of Neurology, Neurosurgery, and
Psychiatry, 86(2), 127–134.
Lopez, O. L., Brenner, R. P., Becker, J. T., Ulrich, R. F., Boller, F., & DeKosky,
S. T. (1997). EEG spectral abnormalities and psychosis as predictors of
cognitive and functional decline in probable Alzheimer’s disease. Neurology,
48, 1521–1525.
Luque-Contreras, D., Carvajal, K., Toral-Rios, D, Franco-Bocanegra, D., &
Campos-Pena, V. (2014). Oxidative stress and metabolic syndrome: Cause
or consequence of Alzheimer’s disease? Oxidative Medicine and Cellular
Longevity, DOI: 10.1155/2014/497802.
Meyer, J. S., Muramatsu, K., Mortel, K. F., Obara, K., & Shirai, T. (1995).
Prospective CT confirms differences between vascular and Alzheimer’s de-
mentia. Stroke, 26, 735–742.
Micanovic, C. & Pal, S. (2014). The diagnostic utility of EEG in early-onset de-
mentia: A systematic review of the literature with narrative analysis. Journal
of Neural Transmission, 121(1), 59–69.
Miller, L. J. (2007). The use of cognitive enhancers in behavioral disturbances
of Alzheimer’s disease. The Consultant Pharmacist, 22(9), 754–762.
Millett, D. (2001). Hans Berger: From psychic energy to the EEG. Perspectives
in Biology and Medicine, 44(4), 522–542.
Mody, C. K., McIntyre, H. G., Miller, B. L., Altman, K., & Read, S. (1991).
Computerized EEG frequency analysis and topographic brain mapping in
Alzheimer’s disease. Annals of the New York Academy of Sciences, 620,
45–55.
Moretti, D. V., Paternico, D., Binetti, G. Zanetti, O., & Frisoni, G. B. (2014).
Theta frequency is associated to morpho-structural and perfusional modifica-
tions in subjects with mild cognitive impairment. Journal of Psychology and
Psychotherapy Research, 1(1), 3–13.
Niedermeyer, E. & Da Silva, F. L. (Eds). (1999). Electroencephalography: basic
principles, clinical applications, and related fields (4th ed.). Philadelphia, PA:
Lippincott Williams & Wilkins.
Nobili, F., Copello, F., Vitali, P., Prastaro, T., Carozzo, S., Pérego, G., et al.
(1999). Timing of disease progression by quantitative EEG in Alzheimer’s
patients. Journal of Clinical Neurophysiology, 16, 566–573.
Perez, S. E., He, B., Nadeem, M., Wuu, J., Scheef, S. W., Abrahamson, E. E.,
et al. (2014). Resilience of precuneus neurotrophic signaling pathways despite
amyloid pathology in prodromal Alzheimer’s disease. Biological Psychiatry,
DOI: 10.1016/j.biopsych.2013.12.016.
Pozzi, D., Petracchi, M., Sabe, L., Golimstock, A., Garcia, H., & Stark-
stein, S. (1995). Quantified electroencephalographic correlates of neuropsy-
chological deficits in Alzheimer’s disease. Journal of Neuropsychiatry, 7,
61–67.
 THE ELECTROPHYSIOLOGICAL PHENOMENON OF ALZHEIMER’S DISEASE
Prescott, J. W., Guidon, A., Doraiswamy, P. M., Choudhury, K. R., Liu, C., &
Petrella, J.; The Alzheimer’s Disease Neuroimaging Initiative. (2014). The
Alzheimer structural connectome: Changes in cortical network topology with
increased amyloid plaque burden. Radiology, 273(1), 175–184.
Prichep, L. S. & John, E. R. (1992). QEEG profiles of psychiatric disorders.
Brain Topography, 4, 249–257.
Prichep, L. S., John, E. R., Ferris, H. S., Rausch, L., Fang, Z., Cancro, R., et al.
(2006). Prediction of longitudinal cognitive decline in normal elderly with
subjective complaints using electrophysiological imaging. Neurobiology of
Aging, 27, 471–481.
Prichep, L. S., John, E. R., Ferris, S. H., Reisberg, B., Almas, M., Alper, K.,
et al. (1994). Quantitative EEG correlates of cognitive deterioration in the
elderly. Neurobiology of Aging, 15, 85–90.
Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L., & Far-
low, M. (1998). Cholinesterase Inhibition for Alzheimer Disease: A meta-
analysis of the tacrine trials. Journal of American Medical Association, 280,
1777–1782.
Read, S. L., Miller, B. L., Mena, I., Kim, R., Itabashi, H., & Darby, A. (1995).
SPECT in dementia: Clinical and pathological correlation. Journal of Amer-
ican Geriatrics Society, 43, 1243–1247.
Reinikainen, K. J., Riekkinen, P. J., Paljärvi, L., Soininen, H., Helkala, E.-
L., Jolkkonen, J., et al. (1988). Cholinergic deficit in Alzheimer’s disease:
A study based on CSF and autopsy data. Neurochemical Research, 13,
135–146.
Reisberg, B. (1995). Senile dementia. In G. L. Maddox, R. C. Atchley, J. G.
Evans, C. E. Finch, D. F. Hutlsch, R. A. Kane, et al. (Eds), The encyclopedia
of aging: a comprehensive resource in gerontology and geriatrics (2nd ed.,
pp. 838–847). New York: Springer.
Reisberg, B., Kenowsky, S., Franssen, E. H., Auer, St. R., & Souren, L. E. M.
(1999). President’s report. Towards a science of Alzheimer’s disease manage-
ment: A model based upon current knowledge of retrogenesis. International
Psychogeriatrics, 11, 7–23.
Reisberg, B. & Kluger, A. (1998). Assessing the progression of dementia: Di-
agnostic considerations. In C. Salzman (Ed.), Clinical geriatric psychophar-
macology (3rd ed., pp. 432–462). Baltimore: Williams & Wilkins.
Robinson, D. J., Merskey, H., Blume, W. T., Fry, R., Williamson, P. C., &
Hachinski, V. C. (1994). Electroencephalography as an aid in the exclusion
of Alzheimer’s disease. Archives of Neurology, 51, 280–284.
Rochat, L., Billieux, J., Van der Linden, A.-C. J., Annoni, J.-M., Zekry, D.,
Gold, G., et al. (2013). A multidimensional approach to impulsivity changes
in mild Alzheimer’s disease and control participants: Cognitive correlates.
Cortex, 49(1), 90–100.
Rodriguez, R., Lopera, F., Alvarez, A., Fernandez, Y., Galan, L., Quiroz, Y., et al.
(2014). Spectral analysis of EEG in familial Alzheimer’s disease with E280A
Presenilin-1 mutation gene. International Journal of Alzheimer’s Disease,
DOI: 10.1155/2014/180741.
Samuel, W., Caligiuri, M., Galasko, D., Lacro, J., Marini, M., McClure, F. S.,
et al. (2000). Better cognitive and psychopathologic response to donepezil in
patients prospectively diagnosed as dementia with Lewy bodies: a preliminary
study. International Journal of Geriatric Psychiatry, 15, 794–802.
Signorino, M., Pucci, E., Brizioli, E., Cacchio, G., Nolfe, G., & An-
geleri, F. (1996). EEG power spectrum typical of vascular dementia in a
613
subgroup of Alzheimer patients. Archives of Gerontology and Geriatrics,
23, 139–151.
Soininen, H., Reinikainen, K. J., Partanen, J., Helkala, E.-L., Paljärvi, L., &
Riekkinen, P. J. (1992). Slowing of electroencephalogram and choline acetyl-
transferase activity in post mortem frontal cortex in definite Alzheimer’s
disease. Neuroscience, 49, 529–535.
Solodkin, A., Chen, E. E., Van Hoesen, G. W., Heimer, L., Shereen, A.,
Kruggel, F., et al. (2013). In vivo parahippocampal white matter pathol-
ogy as a biomarker of disease progression to Alzheimer’s disease. Journal of
Comparative Neurology, 521(18), 4300–4317.
Szelies, B., Mielke, R., Herholz, K., & Heiss, A. W. D. (1994). Quantitative
topographical EEG compared to FDG PET for classification of vascular and
degenerative dementia. Electroencephalography & Clinical Neurophysiol-
ogy, 91, 131–139.
Teng, E., Lu, P. H., & Cummings, J. (2007). Neuropsychiatric symptoms are
associated with progression from mild cognitive impairment to Alzheimer’s
disease. Dementia and Geriatric Cognitive Disorders, 24, 253–259.
Tejada-Vera, B. (2013). Mortality from Alzheimer’s disease in the United States:
Data for 2000 and 2010. NCHS Data Brief, No. 116. Hyattsville, MD: Na-
tional Center for Health Statistics.
Tractenberg, R. E. W., Weiner, M. F., Cummings, J. L., Patterson, M. B., &
Thal, L. J. (2005). Independence of changes in behavior from cognition and
function in community-dwelling persons with Alzheimer’s disease: A factor
analytic approach. Journal of Neuropsychiatry and Clinical Neurosciences,
17, 51–60.
Valdés, P., Valdés, M., Carballo, J. A., Alvarez, A., Dı́az, G. F., Biscay, R., et al.
(1992). QEEG in a public health system. Brain Topography, 4, 259–266.
Valladares-Neto, D. C., Buchsbaum, M. S., Evans, W. J., Nguyen, D., Nguyen,
P., Siegel, B. V., et al. (1995). EEG delta, positron emission tomography, and
memory deficits in Alzheimer’s disease. Neuropsychobiology, 31, 173–181.
Velasques, B., Machado, S., Paes, F., Cunha, M., Sanfim, A., et al. (2011).
Sensorimotor integration and psychopathology: Motor control abnormalities
related to psychiatric disorders. World Journal of Biological Psychiatry, 12,
560–573.
Wszolek, Z. K., Herkes, G. K., Lagerlund, T. D., & Kokmen, E. (1992). Com-
parison of EEG background frequency analysis, psychologic test scores, short
test of mental status, and quantitative SPECT in dementia. Journal of Geri-
atric Psychiatry and Neurology, 5, 22–30.
Wu, L., Rowley, J., Mohades, S., Leuzy, A., Dauar, M. T., Shin, M., et al.;
Alzheimer’s Disease Neuroimaging Initiative. (2012). Dissociation between
brain amyloid deposition and metabolism in early mild cognitive impairment.
Plos One, 7(10), e47905.
Zahodne, L. B., Devanand, D. P., & Stern, Y. (2013). Coupled cognitive and
functional change in Alzheimer’s disease and the influence of depressive
symptoms. Journal of Alzheimer’s Disease, 34, 851–860.
Zahodne, L. B., Ornstein, K., Cosentino, S., Devanand, D. P., & Stern, Y.
(2013). Longitudinal relationships between Alzheimer disease progression
and psychosis, depressed mood, and agitation/aggression. American Journal
of Geriatric Psychiatry, 23(2), 130–140.
Zdanys, K. F., Kleiman, T. G., MacAvoy, M. G., Black, B. T., Rightmer, T. E.,
Grey, M., et al. (2007). Apolipoprotein E E4 allele increases risk for psychotic
symptoms in Alzheimer’s disease. Neuropsychopharmacology, 32, 171–179.