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ACT on Alzheimer’s
Alzheimer’s Disease Curriculum
Module I – Disease Description
GUIDELINES AND RESTRICTIONS ON USE OF DEMENTIA CURRICULUM MODULES
This curriculum was created for faculty across multiple disciplines to use in existing coursework
and/or to develop as a stand-alone course in dementia. Because not all module topics will be
used within all disciplines, each of the ten modules can be used alone or in combination with
other modules. Users may reproduce, combine, and/or customize any module text and
accompanying slides to meet their course needs.
Use restriction: The ACT on Alzheimer's®-developed dementia curriculum cannot be sold in its
original form or in a modified/adapted form.
NOTE: Recognizing that not all modules will be used with all potential audiences, there is some
duplication across the modules to ensure that key information is fully represented (e.g., the
screening module appears in total within the diagnosis module because the diagnosis module will
not be used for all audiences).
© 2016
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Acknowledgement
We gratefully acknowledge the funding organizations that made this curriculum development
possible: the Alzheimer’s Association MN/ND and the Minnesota Area Geriatric Education
Center (MAGEC), which is housed in the University of MN School of Public Health and is
funded by the Health Resources and Services Administration (HRSA).
We specifically acknowledge the principal drafters of one or more curriculum modules,
including Mike Rosenbloom, MD; Olivia Mastry, MPH, JD; Gregg Colburn, MBA; and the
Alzheimer’s Association.
In addition, we would like to thank the following contributors and peer review team:
Michelle Barclay, MA
Terry Barclay, PhD
Marsha Berry, MA, CAEd
Erin Hussey, DPT, MS, NCS
Sue Field, DNP, RN, CNE
Julie Fields, PhD, LP
Jane Foote EdD, MSN, RN
Helen Kivnik, PhD
Kenndy Lewis, MS
Riley McCarten, MD
Teresa McCarthy, MD, MS
Lynne Morishita, GNP, MSN
Becky Olson-Kellogg, PT, DPT, GCS
Jim Pacala, MD, MS
Patricia Schaber, PhD, OTR/L
John Selstad
Ericka Tung, MD, MPH
Jean Wyman, PhD., RN, GNP-BC, FAAN, FGSA
This project is/was supported by funds from the Bureau of Health Professions (BHPr), Health
Resources and Services Administration (HRSA), Department of Health and Human Services
(DHHS) under Grant Number UB4HP19196 to the Minnesota Area Geriatric Education Center
(MAGEC) for $2,192,192 (7/1/2010—6/30/2015). This information or content and conclusions are
those of the author and should not be construed as the official position or policy of, nor should any
endorsements be inferred by the BHPr, HRSA, DHHS or the U.S. Government.
Minnesota Area Geriatric Education Center (MAGEC)
Grant #UB4HP19196
Director: Robert L. Kane, MD
Associate Director: Patricia A. Schommer, MA
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Overview of Alzheimer’s Disease Curriculum
This is a module within the Dementia Curriculum developed by ACT on Alzheimer’s. ACT on
Alzheimer’s is a statewide, volunteer-driven collaboration seeking large-scale social change and
community capacity-building to transform Minnesota’s response to Alzheimer’s disease. An
overarching focus is health care practice change to ensure quality dementia care for all.
All of the dementia curriculum modules can be found online at www.ACTonALZ.org.
Module I:
Disease Description
Module II:
Demographics
Module III:
Societal Impact
Module IV:
Effective Interactions
Module V:
Cognitive Assessment and the Value of Early Detection
Module VI:
Screening
Module VII: Disease Diagnosis
Module VIII: Dementia as an Organizing Principle of Care
Module IX:
Quality Interventions
Module X:
Caregiver Support
Module XI:
Alzheimer’s Disease Research
Module XII: Glossary
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ACT on Alzheimer's has developed a number of practice tools and resources to assist providers
in their work with patients and clients who have memory concerns and to support their care
partners. Among these tools are a protocol practice tool for cognitive impairment, a decision
support tool for dementia care, a protocol practice tool for mid- to late-stage dementia, care
coordination practice tools, and tips and action steps to share with a person diagnosed with
Alzheimer's. These best practice tools incorporate the expertise of multiple community
stakeholders, including clinical and community-based service providers:
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Clinical Provider Practice Tool
Electronic Medical Record (EMR) Decision Support Tool
Managing Dementia Across the Continuum
Care Coordination Practice Tool
Community Based Service Provider Practice Tool
After A Diagnosis
While the recommended practices in these tools are not location-specific, many of the resources
referenced are specific to Minnesota. The resource sections can be adapted to reflect resources
specific to your geographic area.
To access ACT practice tools and resources, as well as video tutorials on screening, assessment,
diagnosis, and care coordination, visit: http://actonalz.org/provider-practice-tools
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Module 1: Learning Objectives
Upon completion of this module the student should:
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Gain understanding of normal aging and cognitive functioning.
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List potential causes of dementia and memory loss.
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Identify the impact that Alzheimer’s disease and other dementias have on the human
brain and functioning.
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Demonstrate knowledge of Alzheimer’s disease including: stages and categories,
symptoms, diagnosis, risk factors, and disease duration.
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Module I
Disease Description
Case Study:
Mr. Johnson, a 71 year-old man with a history of diabetes who currently lives alone, is
brought into the clinic by his son, Dave. Mr. Johnson does not believe he has any
significant memory problems, yet Dave describes 2.5 years of progressive memory
deficits characterized by increasing late fees while paying bills and difficulty maintaining
the household. Over the past three months, Dave has received repeated phone calls from
his father in which he complains repeatedly about losing items around the household. At
one point, he wondered whether somebody was stealing his keys and reading glasses.
Originally, Dave suspected that his father was fixated on this topic but, over time, it
became clear that he had forgotten about the original conversations. His cognitive
review of systems is remarkable for forgetting appointments and becoming lost while
driving in familiar neighborhoods. Dave mentions that he is worried about his dad’s
driving as well. He denied any specific symptoms for depression.
The past medical history includes diabetes and hypertension. He was previously on a
more complicated medication regimen aiming for “tighter” blood sugar control. He is
now taking metformin, which is taken two times a day, lisinopril, and a baby aspirin,
which can be taken once a day. He will occasionally take Tylenol PM (with
diphenhydramine) at night for sleep. The primary provider is hoping that simplifying the
medication regimen will make it easier for Mr. Johnson to follow instructions accurately.
Mr. Johnson is a retired janitor with a high school education. No active smoking or
drinking. There is a family history of Alzheimer’s disease in his father who developed
symptoms at age 81.
Neurological exam was non focal. Neuropsychological screening showed a MoCA=21
(losing points for cube copy, 1/5 words after 5 minutes [could not recognize when given a
list], orientation to date, clock draw).
Laboratory studies showed normal complete blood count, electrolytes, LFTs, glucose,
thyroid stimulating hormone, and B12 levels. A referral was made for
neuropsychological testing: Mr. Johnson showed severe deficits in learning and memory,
moderate deficits in visuospatial function, and mild executive impairments. The Geriatric
Depression Scale score was 2 and within normal limits. Brain MRI was positive for
bilateral hippocampal and parietal atrophy, but no evidence for stroke or focal lesions.
Mr. Johnson was diagnosed by his primary provider with probable Alzheimer’s disease.
Dave inquired about any interventions that can possibly slow or treat the disease
process. It is clear that Dave is distressed about his father’s new diagnosis. He has many
questions about his father’s safety and how he can proactively take steps to ensure his
dad’s well-being.
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Normal Aging
One of the greatest challenges for care providers is distinguishing normal aging from a
neurodegenerative disorder. An individual who complains of memory loss does not necessarily
have dementia and may very well be experiencing symptoms associated with normal aging.
Typically, normal aging is characterized by the following cognitive changes:
• General slowing of cognitive performance
• Decrease in mental flexibility
• Mild word finding difficulties
• Mild decrease in working memory (Karlawish & Clark, 2003).
A thorough medical history and cognitive evaluation will usually reveal the following
characteristics that would be inconsistent with neurodegenerative disease and reassuring for
healthy aging:
• Independence in instrumental activities of daily living (managing finances, administering
own medications, using technology)
• Highly detailed complaints about memory
• Level of concern that exceeds that of family and friends
• Memory intact for current events
• Normal performance on mental status exam and formal cognitive testing
Description of Dementia
Dementia is a chronic and persistent disorder caused by a brain disease or injury that produces a
decline in memory and one other cognitive domain from a previously higher level of functioning
severe enough to interfere with everyday life (McKhann, et al., 1984). Dementia is not part of
normal aging and the term is used to refer to a variety of diseases and conditions that develop
when nerve cells in the brain die or fail to function normally. The death or malfunction of these
nerve cells (neurons) causes changes in one’s memory, behavior, and cognition. For more
information, please refer to the following clips:
http://www.youtube.com/watch?v=BXnZt5VMjZY
http://www.youtube.com/watch?v=Ca4MwySbi5w
There are a number of types of dementia each with its own specific characteristics. The
following table lists the more common types of dementia and their associated characteristics:
Type of Dementia
Characteristics
Alzheimer’s disease
Most common type of dementia; accounts for an estimated 60 to 80% of cases
(Alzheimer’s Association, 2012).
Difficulty remembering names and recent events is often an early clinical symptom.
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Patients may further experience deficits impacting language, visuospatial function,
and behavior where apathy and depression are often early symptoms. Later
symptoms include impaired judgment, disorientation, confusion, behavior changes,
and difficulty speaking, swallowing, and walking.
New criteria and guidelines for diagnosing Alzheimer’s were proposed and
published in 2011 (Sperling, et al., 2011). They recommend that Alzheimer’s
disease be considered a disease that begins well before the development of
symptoms. Studies have shown that AD-related changes in the brain may occur 1520 years prior to symptom onset (Jack Radiology, May 2012).
Hallmark abnormalities are deposits of the protein fragment beta-amyloid (plaques)
and twisted strands of the protein tau (tangles) as well as evidence of nerve cell
damage and death in the brain (Braak & Braak, 1991).
Vascular dementia
Previously known as multi-infarct or post-stroke dementia, vascular dementia (VD)
is rarely the primary cause of dementia (5-10% of cases) and frequently overlaps
with Alzheimer’s disease (AD).
The clinical manifestations of VD are diverse and may be divided into cortical and
subcortical syndromes (Staekenborg, et al., 2008). In general, patients with vascular
dementia present with a stepwise rather than a gradual decline (Desmond DW
Alzheimer’s Dis Assoc Disord, 1999). For cortical syndromes, the presenting
symptoms vary according to the original stroke location (e.g. left
frontalexpressive aphasia; right parietalhemineglect syndrome). Patients with
subcortical syndromes generally present with focal motor signs, gait disturbance,
personality/mood changes, and a cognitive syndrome characterized by mild memory
deficit, psychomotor retardation, and abnormal executive function (Jokinen, et al.,
2006) Neuroimaging and neuropsychological testing are both helpful in
distinguishing VD from AD.
In the past, evidence of vascular dementia was used to exclude a diagnosis of
Alzheimer’s disease (and vice versa). That practice is no longer considered
consistent with pathologic evidence, which shows that the brain changes of both
types of dementia can be present simultaneously. When any two or more types of
dementia are present at the same time, the individual is considered to have “mixed
dementia.”
Lewy Body Dementia (LBD)
People with LBD have some of the symptoms commonly in Alzheimer’s, but are
more likely than people with Alzheimer’s to have initial or early symptoms such as
sleep disturbances, cognitive fluctuations, well-formed visual hallucinations, and
muscle rigidity or other parkinsonian movement features.
Lewy bodies are abnormal aggregations (or clumps) of the protein alpha-synuclein
and represent the pathological hallmark of this disease. When they develop in a part
of the brain called the cortex, dementia can result. Alpha-synuclein also aggregates
in the brains of people with Parkinson’s disease and multiple system atrophy, but the
aggregates may appear in a pattern that is different from LBD. Typically, LBD is a
consideration if dementia onset occurs within 1 year of parkinsonism whereas
Parkinson’s disease with dementia results from cognitive symptoms developing ≥1
year from onset of the movement disorder (Miller & Boeve, 2009).
Mixed dementia
Characterized by the characteristic abnormalities of Alzheimer’s and another type of
dementia — most commonly, vascular dementia, but also other types, such as LBD.
Recent studies suggest that mixed dementia is more common than previously
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thought. Many patients with AD have underlying vascular disease and likewise,
patients with a “vascular dementia” may also be discovered to have AD-related
brain abnormalities at autopsy.
Parkinson’s disease dementia
As Parkinson’s disease progresses, it often results in a severe dementia similar to
LBD.
Early in the disease, hallmark symptoms are primarily associated with a movement
disorder with symptoms that include bradykinesia, rigidity, tremor, and/or postural
instability. On cognitive testing, patients show slowed processing speed, decreased
attention, and executive dysfunction with relative sparing of memory, which is
primarily affected in Alzheimer’s disease (Galvin, Alzheimer’s Disease and
Associated Disorders, 2006).
Alpha-synuclein aggregates are likely to begin in an area deep in the brain called the
substantia nigra and spread to other brain areas. The aggregates are thought to cause
degeneration of the nerve cells that produce dopamine.
The incidence of Parkinson’s disease is about one-tenth that of Alzheimer’s disease.
Frontotemporal lobar
degeneration (FTLD)
Includes dementias such as behavioral variant frontotemporal degeneration (bvFTD), primary progressive aphasia (PPA), corticobasal degeneration (CBD), and
progressive supranuclear palsy (PSP).
Typical symptoms associated with bv-FTD include behavioral disinhibition; apathy
or inertia; loss of sympathy or empathy; perseverative, stereotyped, or
compulsive/ritualistic behavior; and hyperorality or dietary changes (Rascovsky, et
al., 2007). Primary progressive aphasia is characterized by either a nonfluent or
agrammatical subtype or a fluent aphasia with semantic memory loss (semantic
dementia). CBD and PSP may present with either behavioral or language symptoms
accompanied by motor and extrapyramidal dysfunction (Miller & Boeve, 2009).
People with behavioral variant FTD generally develop symptoms at a younger age
(at about age 60) and survive for fewer years than those with Alzheimer’s.
Disease process impacts frontotemporal brain structures with relative sparing of
memory networks associated with Alzheimer’s disease. Neuropathological
diagnosis may show tau (Pick bodies), TDP43, or the most recently described FUS
inclusions (Mackenzie, et al., 2011).
Creutzfeldt-Jakob
disease
Rapidly progressive fatal disorder that impairs cognition and coordination, and
causes behavior changes, resulting in a 1 year mortality in 85% of individuals
(Geschwind, et al., 2008).
Results from an infectious misfolded protein (prion) that causes other proteins
throughout the brain to misfold and thus malfunction.
Variant Creutzfeldt-Jakob disease is caused by consumption of products from cattle
affected by mad cow disease. There is also a familial or inherited form caused by a
genetic mutation.
Normal pressure
hydrocephalus
Symptoms include difficulty walking, memory loss, and inability to control
urination (Adams, et al., 1965). Diagnosis is dependent upon improvement of gait
following large-volume spinal tap.
Characterized by enlarged ventricular size in the setting of normal opening pressure
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on spinal tap.
Represents a reversible type of dementia that may be responsive to placement of a
ventriculoperitoneal (VP) shunt (shunts fluid from ventricles to the peritoneum).
Memory loss can result from a variety of potential causes in addition to the conditions listed
above. Furthermore, approximately 9% of dementia cases are potentially reversible, and
therefore, the health care provider should also be familiar with the broad differential diagnoses
associated with memory loss (Clarfield, 2003). Below is a list of potential disease etiologies that
may result in memory loss with common diagnoses.
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Autoimmune: Central nervous system vasculitis, paraneoplastic disease, Hashimoto’s (or
steroid-responsive) encephalopathy, NMDA receptor antibody encephalitis, voltage-gated
potassium channel (VGKC) complex antibody encephalitis (non-paraneoplastic variant)
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Endocrine: Hypothyroidism
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Episodic: Seizure disorder, migraine, transient global amnesia
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Infectious: Herpes simplex virus (HSV) encephalitis, Human Immunodeficiency Virus
(HIV) Dementia, Neurosyphilis, Lyme Disease, Whipple's Disease of the Central
Nervous System (CNS), tuberculosis of the CNS.
•
Metabolic: B12 deficiency, Wernicke-Korsakoff syndrome (thiamine deficiency),
electrolyte imbalance, hyper- or hypo-glycemia, obstructive sleep apnea (related to
hypercapnia), hepatic encephalopathy
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Neoplastic: Brain tumor (e.g. CNS lymphoma, glioblastoma multiforme)
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Neurodegenerative: Huntington’s disease (HD), spinocerebellar atrophy, multiple
system atrophy
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Toxic: Alcoholism, medication overdose or misuse, lead exposure
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Traumatic: Traumatic brain injury, chronic traumatic encephalopathy
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Vascular: Ischemic or hemorrhagic stroke, posterior reversible encephalopathy syndrome
(PRES), hypoxic injury after cardiac arrest
Finally, the provider frequently must distinguish between a dementing illness and a delirium. A
delirium frequently occurs in patients with toxic-metabolic disturbance and is characterized by
transient, fluctuating disturbances in consciousness. The medical history, exam, and
neuropsychological testing can all be helpful in distinguishing a primary memory disorder from a
delirium.
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Neuroanatomy of Memory Loss
Memory has traditionally been divided into the following memory systems: episodic, working,
semantic, and procedural; separate brain structures are responsible for each memory type
(Budson & Price, 2005).
Episodic memory: lasts minutes to years and localizes to the hippocampus and limbic circuits.
This type of memory is most commonly impaired in AD (Budson & Price, 2005).
Working memory: a type of memory lasting seconds and involving active rehearsal of
information; relies on the integrity of the prefrontal cortex and the echoic memory in the angular
gyrus. This type of memory may be affected in vascular dementia (Budson & Price, 2005).
Semantic memory: typically consists of factual information (e.g., knowing what a certain object
is and what it is used for, knowing who was the first president of the U.S.), and localizes to the
anterior and inferolateral temporal lobes. Patients with the semantic dementia subtype of
frontotemporal dementia suffer from semantic memory problems (Budson & Price, 2005).
Procedural memory: pertains to playing the piano or riding a bike, and involves the basal
ganglia, cerebellum, and supplementary motor area. This type of memory impairment is
infrequently found in the clinical setting, but could potentially develop in patients with disease
confined to basal ganglia and cerebellar structures (Budson & Price, 2005).
Alzheimer’s Disease
The most common type of dementia is dementia caused by Alzheimer’s disease. Alzheimer’s
disease was first identified more than 100 years ago (Alzheimer, 1907), but research into its
symptoms, causes, risk factors, and treatment has gained momentum only in the last 30 years.
Although scientific inquiry has revealed a great deal about Alzheimer’s, the precise physiologic
changes that trigger the development of Alzheimer’s disease remain largely unknown except in
the case of the autosomal dominantly inherited forms of the disease, which account for <5% of
AD cases.
Symptoms of Alzheimer’s Disease
Alzheimer’s disease affects people in different ways, but the most common symptom pattern
begins with gradual worsening ability to remember new information. This occurs because
disruption of brain cell function usually begins in brain regions involved in forming new
memories (e.g., hippocampal and limbic structures). As damage spreads, individuals experience
other difficulties. The following are 10 warning signs of Alzheimer’s:
• Memory loss that disrupts daily life
• Challenges in planning or solving problems
• Difficulty completing familiar tasks at home, at work, or at leisure
• Confusion with time or place
• Trouble understanding visual images and spatial relationships
• New problems with words in speaking or writing
• Misplacing things and losing the ability to retrace steps
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• Decreased or poor judgment
• Withdrawal from work or social activities
• Changes in mood and personality
Mild Cognitive Impairment (MCI)
MCI is a condition characterized by mild but measurable changes in thinking abilities on
cognitive screening or formal neuropsychological testing that are noticeable to the person
affected and/or family members and friends. MCI is distinguished from dementia in that there is
preservation of an individual’s ability to carry out everyday activities (Petersen, et al., 1999).
The most common form of MCI is amnestic MCI, in which memory is the primary problem.
However, MCI can occur in cognitive domains other than memory, including language,
visuospatial, and frontal executive function (e.g., problems organizing, planning, multi-tasking).
About 50% of patients diagnosed with amnestic MCI will progress to dementia within five years.
The rate of progression to dementia is about 12% per year (Petersen, et al., 1999). Whereas
previously, MCI was understood as a condition distinct from Alzheimer’s disease, in 2011, the
National Institute on Aging (NIA) suggested that in some cases MCI is a precursor to AD,
representing the midpoint on a continuum between normal function and dementia.
Defining Alzheimer’s Disease through Biomarkers
The original National Institute for Communicable Disorders and Stroke-Alzheimer’s Disease and
Related Disorders (NINCDS-ADRDA) criteria for the diagnosis of Alzheimer’s disease were
published in 1984 (McKhann, et al., 1984) to provide physicians and researchers guidance in AD
diagnosis. The criteria divided Alzheimer’s disease into definite, probable, and possible. A
diagnosis of “definite AD” required the combination of both “probable AD” and an autopsy
confirmation of the diagnosis. ‘‘Probable AD’’ required deficits in two or more areas of
cognition, including memory, that were progressively worsening, confirmed by clinical and
neuropsychological evaluations, and not associated with either delirium or other brain or
systemic illnesses that could be the cause of the dementia. The diagnosis was further supported
by impaired function in activities of daily living (ADLs) and presence of behavioral dysfunction,
and family history (particularly if supported by previous neuropathology). A diagnosis of
‘‘possible AD’’ included cases where there is a single progressively more severe cognitive
deficit, a second brain or systemic cause for dementia, and atypical onset (early or with unusual
symptoms and course [rapid or stuttering]).
In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association recommended
new diagnostic criteria and guidelines for Alzheimer’s disease to better represent the
pathophysiological processes associated with the various stages of Alzheimer’s disease
(Sperling, et al., 2011). The new criteria and guidelines update, refine, and broaden guidelines
published in 1984 by the NINCDS-ADRDA and were a result of the collaborative work between
40 Alzheimer’s researchers from around the world.
It is important to note that these are recommended criteria and guidelines. More research is
needed, especially biomarker research, before the new criteria and guidelines can be used in
clinical settings, such as in a doctor’s office.
Differences Between the Original and New Criteria
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The 1984 criteria were based chiefly on the provider’s clinical judgment about the cause of a
patient’s symptoms, taking into account reports from the patient, family members, and friends;
results of cognitive testing; and general neurological assessment. The new diagnostic criteria and
guidelines incorporate two notable changes to add measures considered likely to become key
markers for early diagnosis:
(1) Biomarker tests. A biomarker is something in the body that can be measured and that
accurately indicates the presence or absence of disease, or the risk of later developing a
disease. For example, blood glucose level is a biomarker of diabetes, and cholesterol
level is a biomarker of heart disease risk. Levels of certain proteins in fluid (levels of
beta-amyloid and tau in the cerebrospinal fluid and blood) are among several factors
being studied as possible biomarkers for Alzheimer’s.
(2) Identification of preclinical stages of AD in addition to MCI and AD: a) preclinical
AD is characterized by the presence of AD-related biomarkers and absence of cognitive
symptoms such as memory impairment; b) MCI due to AD represents a state where there
are subjective and objective findings suggestive of cognitive impairment with relative
preservation of ADLs and IADLs; c) Dementia due to AD where there is impairment in
both ADLs and IADLs in the setting of objective/subjective cognitive impairment.
Biomarker Tests
The new criteria and guidelines identify two biomarker categories: (1) biomarkers showing the
level of beta-amyloid accumulation in the brain (e.g. amyloid imaging with PET technology as
well as decreased CSF levels of Abeta 42); and (2) biomarkers showing neuronal damage (e.g.
elevated CSF tau, brain atrophy on structural MRI imaging, or decreased cerebral glucose update
on FDG-PET imaging).
Researchers believe that future treatments will be more effective in slowing or halting the
progression of Alzheimer’s disease (referred to as “disease modifying” treatments) when
administered during the preclinical and MCI stages of the disease.
In the future, biomarker tests may be helpful for the following 1) identifying individuals within
the earliest AD stages; 2) distinguishing AD from other types of dementia; 3) deciding upon the
point at which to initiate medications; 4) assessing response to FDA approved and exploratory
compounds through clinical trials; and 5) providing objective information to guide prognosis
(Jack Jr., et al., 2011;(Wallin, et al., 2010).
The Three Stages of Alzheimer’s Disease Proposed by the New Criteria
The three stages of Alzheimer’s disease identified in the new criteria and guidelines are
preclinical Alzheimer’s disease, mild cognitive impairment (MCI) due to Alzheimer’s disease,
and dementia due to Alzheimer’s disease. The stages of Alzheimer’s are often described as
mild/early-stage, moderate/mid-stage or severe/late-stage. The new criteria propose that
Alzheimer’s disease begins before the mild/early-stage and that new technologies have the
potential to identify Alzheimer’s-related brain changes that occur before mild/early stage disease.
When these very early changes in the brain are identified, an asymptomatic individual diagnosed
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using the new criteria would be said to have preclinical Alzheimer’s disease or MCI due to
Alzheimer’s if there is memory impairment. The third stage of the new criteria, dementia due to
Alzheimer’s disease, encompasses all stages of Alzheimer’s disease as described today, from
mild/early-stage to severe/late-stage.
Preclinical Alzheimer’s Disease
In this stage, individuals have measurable changes in the brain, cerebrospinal fluid and/or blood
(biomarkers) that indicate the earliest signs of disease, but they have not yet developed
symptoms such as memory loss. This preclinical or pre-symptomatic stage reflects current
thinking that Alzheimer’s begins creating changes in the brain as many as 20 years before
symptoms occur. Although the new criteria and guidelines identify preclinical disease as a stage
of Alzheimer’s, they do not establish diagnostic criteria that doctors can use now. This category
will require further development through further research and evaluation.
Large clinical trials such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4)
study (http://www.adcs.org/) are identifying asymptomatic individuals with characteristic AD
brain abnormalities and starting them on drugs with the intention of possibly preventing the
anticipated development of MCI/AD. Other studies performed through Washington University,
the Dominantly Inherited Autosomal Dominant Network (DIAN) (http://www.dian-info.org/)
and Alzheimer’s Prevention Initiative (API) through the Banner Institute
(http://banneralz.org/research-clinical-trials/types-of-research-studies/alzheimer%E2%80%99sprevention-initiative.aspx) are targeting preclinical Alzheimer’s disease in persons with
genetically-inherited forms of AD.
MCI due to Alzheimer’s Disease
Individuals with MCI have mild but measurable changes in thinking abilities that are noticeable
to the person affected and to family members and friends, but do not significantly affect the
individual’s ability to carry out everyday activities. Studies indicate that as many as 10 -20% of
people age 65 and older have MCI. Further cognitive decline is more likely among individuals
whose MCI involves memory problems than in those whose MCI does not involve memory
problems. Over one year, most individuals with MCI who are identified through community
sampling remain cognitively stable. Some, primarily those without memory problems,
experience an improvement in cognition or revert to normal cognitive status. It is unclear why
some people with MCI develop dementia and others do not. When an individual with MCI goes
on to develop dementia, many scientists believe the MCI is actually an early stage of the
particular form of dementia, rather than a separate condition. The new criteria and guidelines
suggest the role of biomarker testing in supporting a diagnosis of MCI, but these tests do not
need to be part of the routine diagnostic work-up. If it can be shown that changes in the brain,
cerebrospinal fluid, and/or blood are caused by physiologic processes associated with
Alzheimer’s, the new criteria and guidelines recommend a diagnosis of MCI due to Alzheimer’s
disease. Before doctors can make such a diagnosis, however, researchers must prove that the
biomarker tests accurately indicate risk.
Dementia due to Alzheimer’s Disease
This stage is characterized by memory, cognitive, and behavioral symptoms that impair a
person’s ability to function in daily life and that are caused by Alzheimer’s disease-related
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processes. As in MCI, the biomarkers may can support, but are not essential for securing a
diagnosis of Alzheimer's disease in routine practice.
Stages of Alzheimer’s Disease
The severity of Alzheimer’s disease can be divided into the mild, moderate, and severe cognitive
decline categories. http://www.alz.org/alzheimers_disease_stages_of_alzheimers.asp.
MILD
Stage 1: No impairment (normal function). The person does not experience any memory
problems. An interview with a medical professional does not show any evidence of symptoms of
dementia.
Stage 2: Very mild cognitive decline (may be normal age-related changes or earliest signs of
Alzheimer's disease). The person may feel as if he or she is having memory lapses — forgetting
familiar words or the location of everyday objects, but no symptoms of dementia can be detected
during a medical examination or by friends, family, or co-workers.
Stage 3: Mild cognitive decline (early-stage Alzheimer's can be diagnosed in some, but not all,
individuals with these symptoms). Friends, family or co-workers begin to notice difficulties.
During a detailed medical interview, doctors may be able to detect problems in memory or
concentration. Common stage 3 difficulties include: 1) noticeable problems coming up with the
right word or name; 2) trouble remembering names when introduced to new people; 3) having
noticeably greater difficulty performing tasks in social or work settings; 4) forgetting material
that one has just read; 5) losing or misplacing a valuable object; 6) experiencing increased
difficulty with planning or organizing.
MODERATE:
Stage 4: Moderate cognitive decline (mild or early-stage Alzheimer's disease). At this point, a
careful medical interview should be able to detect clear-cut symptoms in several areas: 1)
forgetfulness of recent events; 2) impaired ability to perform challenging mental arithmetic —
for example, counting backward from 100 by 7s; 3) greater difficulty performing complex tasks,
such as planning dinner for guests, paying bills, or managing finances; 4) forgetfulness about
one's own personal history; 5) becoming moody or withdrawn, especially in socially or mentally
challenging situations.
Stage 5: Moderately severe cognitive decline (moderate or mid-stage Alzheimer's disease).
Gaps in memory and thinking are noticeable and individuals begin to need help with day-to-day
activities. At this stage, those with Alzheimer's may: 1) be unable to recall their own address or
telephone number or the high school or college from which they graduated; 2) become confused
about where they are or what day it is; 3) have trouble with less challenging mental arithmetic;
such as counting backward from 40 by subtracting 4s or from 20 by 2s; 4) need help choosing
proper clothing for the season or the occasion; 5) still remember significant details about
themselves and their family; 6) still require no assistance with eating or using the toilet.
SEVERE:
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Stage 6: Severe cognitive decline (moderately severe or mid-stage Alzheimer's disease).
Memory continues to worsen, personality changes may take place and individuals need extensive
help with daily activities. At this stage, individuals may: 1) lose awareness of recent experiences
as well as of their surroundings; 2) remember their own name but have difficulty with their
personal history; 3) distinguish familiar and unfamiliar faces but have trouble remembering the
name of a spouse or caregiver; 4) need help dressing properly and may, without supervision,
make mistakes such as putting pajamas over daytime clothes or shoes on the wrong feet; 5)
experience major changes in sleep patterns — sleeping during the day and becoming restless at
night; 6) need help handling details of toileting (for example, flushing the toilet, wiping or
disposing of tissue properly); 7) have increasingly frequent trouble controlling their bladder or
bowels; 8) experience major personality and behavioral changes, including suspiciousness and
delusions (such as believing that their caregiver is an impostor) or compulsive, repetitive
behavior like hand-wringing or tissue shredding; 9) tend to wander or become lost.
Stage 7: Very severe cognitive decline (severe or late-stage Alzheimer's disease). In the final
stage of this disease, individuals lose the ability to respond to their environment, to carry on a
conversation and, eventually, to control movement. They may still say words or phrases. At this
stage, individuals need help with much of their daily personal care, including eating or using the
toilet. They may also lose the ability to smile, to sit without support and to hold their heads up.
Reflexes become abnormal. Muscles grow rigid. Swallowing impaired. In this stage, individuals
are more vulnerable to infections, including pneumonia (infection of the lungs). Alzheimer’s
disease is ultimately fatal, and Alzheimer’s-related pneumonia is often a contributing factor.
Diagnosis of Alzheimer’s Disease
A diagnosis of Alzheimer’s disease is most commonly made by an individual’s primary care
physician or neurologist. The physician obtains a medical and family history, including
psychiatric history and history of cognitive and behavioral changes. Ideally, a family member or
other individual close to the patient is available to provide input. The physician also conducts
cognitive tests and physical and neurologic examinations. Sometimes, patients will require
referral to a neuropsychologist for formal cognitive testing. In addition, the patient may undergo
brain magnetic resonance imaging (MRI) or head computed tomography (CT) scans to identify
brain changes, such as the presence of a tumor or evidence of a stroke that could cause cognitive
decline.
ACT on Alzheimer’s Tools: The Clinical Provider Practice Tool provides physicians a
streamlined protocol for managing cognitive impairment and guiding decisions for screening,
diagnosis, and disease management. This tool incorporates current best practices for efficient
and appropriate dementia care.
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Causes of Alzheimer’s Disease
The cause or causes of Alzheimer’s disease are not yet known. However, most experts agree that
AD, like other common chronic diseases, develops as a result of multiple factors rather than a
single cause.
These factors include a variety of brain changes that begin as many as 20 years before symptoms
appear. Increasingly, the time between the initial brain changes of Alzheimer’s and the
symptoms of advanced Alzheimer’s is considered by scientists to represent the “continuum” of
Alzheimer’s. At the start of the continuum, the individual is able to function normally despite
these brain changes. Further along the continuum, the brain can no longer compensate for the
increased neuronal damage caused by brain changes, and the individual shows subtle decline in
cognitive function. In some cases, physicians identify this point in the continuum as MCI.
Toward the end of the continuum, neuronal damage and death is so significant that the individual
shows obvious cognitive decline, such as memory changes or confusion as to time or place. At
this point, physicians following the 1984 criteria for Alzheimer’s would diagnose the individual
as having Alzheimer’s disease. The new criteria and guidelines discussed above propose that the
entire continuum, not just the symptomatic points on the continuum, represents Alzheimer’s.
Researchers continue to explore why some individuals who have the brain changes associated
with the earlier points of the continuum do not go on to develop the overt symptoms of the later
points of the continuum.
Among the brain changes believed to contribute to the development of Alzheimer’s are the
accumulation of the protein beta-amyloid outside neurons in the brain and the accumulation of
the protein tau inside neurons. A healthy adult brain has 100 billion neurons, each with long,
branching extensions. These extensions enable individual neurons to form specialized
connections with other neurons. At these connections, called synapses, information flows in tiny
chemical pulses released by one neuron and detected by the receiving neuron. The brain contains
100 trillion synapses. They allow signals to travel rapidly and constantly through the brain’s
circuits, creating the cellular basis of memories, thoughts, sensations, emotions, movements, and
skills.
In Alzheimer’s disease, information transfer at synapses begins to fail, the number of synapses
declines and neurons eventually die. The amyloid hypothesis proposes that the Abeta 1-42
fragment from the larger amyloid precursor protein (APP) is abnormally cleaved by the protease
gamma-secretase (Querfurth & LaFerla, 2010). The amyloid fragment forms extracellular
polymers, resulting in an insoluble aggregate that triggers downstream inflammatory events
resulting in cell destruction. The other pathological feature of AD is the formation of tau and
neurofibrillary tangle formation within cells. Studies have shown that the severity of clinical
symptoms correlate with neurofibrillary tangles (Braak & Braak, 1991). Brains from people
with advanced Alzheimer’s show dramatic atrophy from cell loss.
One known cause of Alzheimer’s is genetic mutation. A small percentage of Alzheimer’s
disease cases, probably less than 5 percent, is caused by three known genetic mutations
https://ghr.nlm.nih.gov/condition/alzheimer-disease. These mutations involve the gene for the
amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) proteins. Inheriting
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any of these genetic mutations guarantees that an individual will develop Alzheimer’s disease.
In such individuals, the disease tends to develop before age 65, sometimes in individuals as
young as age 30.
Risk Factors for Alzheimer’s Disease
The greatest risk factor for Alzheimer’s disease is advancing age, but it should be emphasized
that Alzheimer’s is different than normal aging. Most cases of Alzheimer’s disease occur in
individuals aged 65 years or older. The prevalence of AD within the general population is 1-2%
at age 65, increasing to 15% at age 75, and approaching the 35-50% range at age 85 (Farlow,
2007). The likelihood of developing AD doubles every 5 years after the age of 65. Observations
have shown that AD presents more commonly than previously thought in persons younger than
age 65, and in such cases, is referred to as “younger-onset” (or “early-onset”) Alzheimer’s.
Advancing age is not the only risk factor for Alzheimer’s disease. The following sections
describe other risk factors.
Family History
Individuals who have a parent, brother, or sister with Alzheimer’s are more likely to develop the
disease than those who do not have a first-degree relative with Alzheimer’s. Those who have
more than one first-degree relative with Alzheimer’s are at even higher risk of developing the
disease. Approximately 20% of patients with AD have one or more siblings or parents affected
and a pattern of autosomal inheritance. When diseases run in families, heredity (genetics), shared
environmental/lifestyle factors, or both may play a role in development of the clinical phenotype.
Apolipoprotein E-ε4 (APOE-ε4)
The ApoE protein is primarily responsible for transportation of cholesterol and lipids within the
bloodstream, but is thought to play a role in amyloid clearance. APOE-ε4 is one of three
common forms (ε2, ε3 and ε4) of the APOE gene and is present in 15-20% of the population.
Everyone inherits one form of the APOE gene from each parent, and individuals with the ε4
form of the gene apolipoprotein E are at increased risk of developing Alzheimer’s disease
compared to those inheriting the ε2 or ε3 forms of the APOE gene. Individuals with two copies
of the apoE4 allele (2% of the total population) have a 50% to 90% chance of developing AD by
the age of 85, and those with one copy of apoE4 (15% of the total population) have a 45%
chance of developing the disease (Corder, et al., 1993). Unlike the known genetic mutations for
Alzheimer’s, the APOE-ε4 genotype is only a risk factor for AD and does not guarantee that an
individual will develop the disease. For this reason, screening for the APOE-ε4 genotype or any
genetic marker in an AD patient is not recommended by the American Academy of Neurology
(Knopman, et al., 2001).
Mild Cognitive Impairment (MCI)
See description above.
Cardiovascular Disease Risk Factors and Metabolic Syndrome
Growing evidence suggests that the health of the brain is closely linked to the overall health of
the heart and blood vessels. Recent studies indicate that cardiovascular disease risk factors, such
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as physical inactivity, high cholesterol (especially in midlife), hypertension, diabetes, smoking,
and obesity are associated with a higher risk of developing Alzheimer’s and other dementias.
Unlike genetic risk factors, many of these cardiovascular disease risk factors are modifiable —
that is, they can be changed to decrease the likelihood of developing cardiovascular disease and,
possibly, the cognitive decline associated with Alzheimer’s and other forms of dementia.
Various studies have also suggested a strong association between Alzheimer’s risk and premorbid diagnosis of diabetes, insulin resistance, and metabolic syndrome (Martins, et al., 2006).
Social Engagement/Cognitive Activity
People with limited social networks and low social engagement are more likely to develop
dementia compared to those living socially rich lives (Fratiglioni & Wang, 2007). Additional
studies suggest that other modifiable factors, such as remaining mentally and socially active and
consuming a diet low in saturated fats and rich in vegetables may support brain health.
However, there are fewer of these types of studies than studies of cardiovascular risk factors, and
they often involve a smaller number of participants than cardiovascular studies. As a result, their
conclusions are generally considered less convincing than those of cardiovascular studies. Thus,
compared with other risk factors, relatively little is known about how lifetime social engagement
or diet may affect Alzheimer’s risk.
Head Trauma and Traumatic Brain Injury (TBI)
Head injury, head trauma, and TBI are associated with an increased risk of Alzheimer’s disease
and other dementias (Jellinger, 2004). Moderate head injuries are associated with twice the risk
of developing Alzheimer’s compared with no head injuries, and severe head injuries are
associated with 4.5 times the risk. Moderate head injury is defined as a head injury resulting in
loss of consciousness or post-traumatic amnesia lasting more than 30 minutes; if either of these
lasts more than 24 hours, the injury is considered severe. These increased risks have not been
shown for individuals experiencing mild head injury or any number of common mishaps such as
bumping one’s head while exiting a car. Groups that experience repeated head injuries, such as
boxers, football players, and combat veterans, may be at risk for chronic traumatic
encephalopathy (CTE), a pathological diagnosis exemplified by increased risk of dementia, midlate life cognitive impairment, neuropsychiatric disturbances, and evidence of tau tangles at
autopsy (McKee, et al., 2009). Some studies suggest that APOE-ε4 carriers who experience
moderate or severe head injury are at higher risk of developing Alzheimer’s than APOE-ε4
carriers who do not have a history of moderate or severe head injury. In addition, APOE-ε4
carriers suffering head trauma have a poorer recovery compared to non-AD carriers (Jellinger,
2004). Additional research is needed to better understand the association between brain injury
and increased risk of Alzheimer’s.
Education
Several studies have shown that increased education has been associated with reduced risk for
AD and later onset of dementia. People who engage in mentally stimulating activities such as
learning, reading, or playing games at older ages are less likely to develop dementia compared
with those who do not engage in these activities (Fratiglioni & Wang, 2007). It has been
suggested that individuals with greater education have greater cognitive reserve, and therefore
require greater AD-related pathology to present with clinical symptoms.
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Disease Duration
Studies indicate that individuals with Alzheimer’s disease aged 65 and older survive a median of
3 to 8 years after a diagnosis of Alzheimer’s disease, yet some may live as long as 20 years with
Alzheimer’s (Helzner, et al., 2008), ( Larson, et al., 2004), (Wolfso, et al., 2001), thus
demonstrating the slow, insidious nature of AD progression. On average, a person with
Alzheimer’s will spend more years (40% of the total number of years with Alzheimer’s) in the
most severe stage of the disease than in any other stage (Alzheimer’s Association, 2012). Much
of this time will be spent in a nursing home, as nursing home admission by age 80 is expected for
75% of people with Alzheimer’s compared with 4% of the general population. In all, an
estimated two thirds of dementia patients die in nursing homes compared to 20% of cancer
patients and 28% of people dying from all other conditions (Alzheimer’s Association, 2012).
Thus, in addition to Alzheimer’s being the sixth-leading cause of death (and fifth leading cause
in individuals 65 and older), the cost of caring for individuals with AD in a long-term care
residence is an equally telling statistic of the public health impact of Alzheimer’s disease.
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Module I: Questions for review
1. Changes seen in the brains of patients with Alzheimer’s disease include:
a. amyloid plaques
b. neurofibrillary tangles
c. decreased neurotransmission
d. all of the above
2. The most common type of dementia is:
a. vascular
b. mixed
c. Alzheimer’s
d. Parkinson’s
3. A diagnosis of Alzheimer’s disease is most commonly made by a:
a. neuropsychologist
b. psychiatrist
c. neurologist
d. primary care provider
4. A 70 year old woman comes to clinic complaining of memory loss. She says “I have
Alzheimer’s disease like my mother.” She reports occasional difficulty with
remembering names of new acquaintances and forgetting where she put her car keys
at times. It is taking her longer than she likes to complete the New York Times crossword puzzle each week. She notes that she is often irritable with her neighbors whom
she finds “nosy”. She has insomnia which has been a problem for most of her adult
life, and she has episodes of urinary incontinence when she laughs. A brief
hospitalization for a “possible TIA” 8 years ago is noted in her records.
The patient works full-time as a social worker for a state agency and has had no
problems at work. She drives a car and has been managing her finances without
difficulties. Her family is dismissive of her memory concerns and reports that she is
“sharp as a tack”. A mini-cog screening exam shows no deficits. The patient’s
diagnosis is most likely:
a. Normal aging
b. Vascular dementia
c. Lewy Body Dementia
d. Normal pressure hydrocephalus
5. Mr. Torini is brought in by his son for evaluation of memory loss. After a thorough
work up, the patient is diagnosed with Alzheimer’s disease. He has difficulty dressing
appropriately for weather conditions, does not always remember his address, and
often becomes confused about the date. He sometimes thinks he is in his childhood
home though he has lived with his son for several months. The severity of Mr.
Torini’s Alzheimer’s disease would be considered:
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a. Mild
b. Moderate
c. Severe
6. Using the NIA (National Institute on Aging) and Alzheimer’s Association new
recommended diagnostic criteria (2011), the stage of Mr. Torini’s Alzheimer’s
disease would be:
a. Preclinical Alzheimer’s disease
b. Mild cognitive impairment (MCI) due to Alzheimer’s disease
c. Dementia due to Alzheimer’s disease
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