Alzheimer’s disease is a neurodegenerative disease—
or a disease that causes progressive damage to brain cells leading to slow but relentless mental decline.
Causes/Risk
Factors
Progression
Neurobiology
& pathology
Diagnosis
Treatment
Practical
tips for living with AD
Introduction
Alzheimer’s
disease (AD) is a neurodegenerative disease—or a disease that causes
progressive damage to brain cells leading to slow but relentless mental
decline. The most common early symptoms
with AD are difficulty learning and remembering new information, problems
navigating familiar routes, difficulty with finding words, and deficits in
multi-tasking (doing several things at once). As AD progresses, memory and
spatial problems worsen and new cognitive problems arise, including deficits in
understanding and expressing ideas, loss of the ability to calculate, read and
write, and severe difficulties with problem-solving. Usually patients maintain
their social graces but as the illness progresses behavioral symptoms including
apathy, agitation, anxiety, and delusions (false beliefs) emerge. Eventually,
the cognitive and behavioral problems associated with AD cause “dementia,”
defined as cognitive impairment severe enough to interfere with daily life
activities such as work, social interactions, hobbies, or self-care. There are
many diseases that cause dementia, although AD is the most common cause of
dementia in older adults.
Causes/Risk Factors
The direct changes
that are seen microscopically in the AD brain are described in the section,
“Neurobiology and Pathology” below. But what are the factors that cause people
to develop those neurobiological changes? Without a doubt, the most important
risk is aging. Incidence, or new cases
of AD, approximately double every five years after the age of 65 years
[2]. In the very old, (above 90), the number
of people who manifest AD-like changes is extremely high, leading some to
believe that if we all lived long enough we would all get AD. How aging leads to these changes remains
unknown.
For some, genetic
factors contribute to, or even cause development of the disease. This risk is
greatest for those with a strong family history of AD, and for individuals
whose family members were diagnosed with AD before age 65. Familial AD, which
is inherited in an autosomal dominant pattern, is caused by mutations in the
amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 gene on
chromosome 14, or the presenilin 2 gene on chromosome 1 [5]. These mutations
all lead to excessive production of a protein called beta amyloid (Aβ). With
this genetic form of AD, if the gene is carried there is near 100% likelihood
that the person will develop AD if they live beyond 60 years. Less than 5% of AD cases are transmitted in
this fashion. A more common genetic risk is associated with the apolipoprotein
gene on chromosome 19 [6]. This gene has three common variants or alleles,
called APOE-e2, APOE-e3, and APOE-e4. Individuals with 1 or 2 copies of the
APOE-e4 allele have a substantially increased risk for AD, whereas individuals
with 1 or 2 copies of the APOE-e2 allele have decreased risk. Unlike the
familial genes that cause AD, having APOE-e4 does not guarantee that you will
get AD, but increases your risk substantially [5]. In addition, having Down’s
syndrome, or a family history of other dementias or Parkinson’s disease, also
appears to increase risk [4].
The remaining risks
for developing AD appears to come from environmental factors, although the
precise mechanisms by which these risk factors contribute to AD is not entirely
known. Head injury is one of the most preventable environmental risk factors.
Typically, head injuries are only considered risks when there is a loss of
consciousness, which indicates brain trauma. Other potentially modifiable
environmental risk factors include high blood pressure, high cholesterol, and
diabetes, which can be reduced through diet and exercise. Diets rich in
antioxidants, Vitamin E, and omega-3 fatty acids may reduce risk for AD, while
diets high in fat and calories increase risk. In addition, exercise may reduce
risk for AD by improving cerebrovascular health and promoting the growth of new
neurons in brain regions responsible for memory[7].
Education is
commonly considered to be a preventive factor, but the relationship between
education level and AD is complex. Individuals with very high levels of
education are typically diagnosed with AD less frequently and at older ages
than similar individuals with less education. However, autopsy examinations
show greater brain shrinkage in individuals with high education levels, which
is an indication of greater progression of AD. Many researchers now believe
that education and the associated intellectual strengths that come with it
cannot prevent AD, but delay the diagnosis through what is referred to as
“cognitive reserve,” or a cognitive cushion that buffers one against showing
symptoms of AD [8].
Depression, and
particularly depression that occurs first in older adulthood, has been
suggested to be a risk factor. Whether or not late-life depression is a risk,
or rather just an an early sign of AD is still unknown [9]. Having depression
at younger ages does not appear to be a risk factor for AD.
Female gender is
associated with a slightly increased risk of developing AD. It is unclear,
however, whether that risk stems primarily from the tendency of women to live
longer than men, which puts them at increased risk simply by virtue of their
older age.
Progression of Alzheimer's Disease
Alzheimer’s disease is known
for its insidious onset and slow progression. It is preceded by a stage where
cognitive functioning is diminished relative to peers of a similar age and
education level, but which is not sufficiently severe to merit a diagnosis of
AD. This stage is sometimes called mild cognitive impairment (MCI) or mild AD;
however, not everyone diagnosed with MCI will go on to develop AD. Although
there are no true distinctions between different stages of the disease, these
stages may be helpful in describing the disease progression. It typically takes
years for a person with AD to progress from 1 stage to another, and because
there are no clear demarcations between stages, there is often overlap.
On imaging, the medial temporal and parietal areas of the brain are
typically the first areas to appear shrunken as neurons die. Shrinkage is
particularly early and prominent in the hippocampi, structures that are needed for
making new memories, and in the posterior parietal lobes, which are involved in
spatial skills, navigation, and calculation. Later, nearly the entire brain
appears shrunken, and the spaces within the brain, called ventricles, grow
larger. Image:
coronal slices (planes parallel to the face) of the brain.
The left slice shows a brain with a normal hippocampus traced in
yellow, and the right slice shows a brain with a shrunken AD
hippocampus traced in yellow. Images courtesy of Dr. Howard Rosen.
Memory and spatial problems are usually the first symptoms seen and are
disproportionate to problems with attention, organizing, and multi-tasking.
About half of people with AD have one or more psychiatric symptoms[10] such as
depression, apathy, or insomnia in the early to moderate stages. Agitation and
insomnia become more common in the moderate stages of the disease, while behavioral
disturbances are most likely to emerge in the moderate to severe stages. Of
note, although people with AD have pronounced cognitive problems, they
typically retain social skills until they are in the moderate to severe stages.
These characteristics can help differentiate between AD and other types of
dementia.
Impairments in activities of daily living, or basic living skills such as
bathing and dressing one’s self, frequently do not occur until the moderate to
severe stages of the disease. Difficulties with bathing and dressing may be the
first observed difficulties that occur in the moderate stage, while
difficulties eating and toileting occurring more frequently in the severe stage
[10]. In addition, memory and judgment problems can impair safe self-care in
the moderate to severe stages of the disease. Because AD tends to spare the
motor systems until the latest stages of the disease, people with AD typically
do not need wheelchairs or other movement aids as a result of the disease,
although, of course, other medical problems common to aging may necessitate
such devices.
In the last stage of the disease, which is sometimes called the terminal
stage, people are frequently cared for in institutions due to increased care
demands. At this stage, people may have difficulty swallowing whole foods and
thin liquids, and consequently may need to drink thickened liquids for
nutrition [11]. Tube feeding is sometimes implemented in institutions if a
patient has difficulty swallowing even thickened liquids or refuses nutrition.
However, tube feeding tends to be very uncomfortable and may not improve
survival or reduce the risk of aspiration pneumonia [11], and so its use should
be carefully considered. Reduced mobility, often leading patients to be
bed-bound, increases risk for infections and bedsores. Because people with
terminal stage AD have very reduced ability to make decisions and communicate,
family members should be actively involved in making treatment decisions and
ensuring care that is consistent with the patient’s desires and values.Neurobiology
& pathology
Naturally occurring
proteins in the brain called beta amyloid (Aβ) and tau are believed to cause
the symptoms of AD by preventing brain cells from functioning normally. The amyloid hypothesis suggests that the
symptoms and neuropathological changes of AD stem primarily from an
overabundance of Aβ [12]. Aβ is a peptide, or protein segment, formed from the amyloid
precursor protein (APP). Enzymes called β-secretase and γ-secretase cause APP
to be cut in different places, creating Aβ [13]. Aβ then aggregates into small
clusters, called oligomers, and eventually into larger aggregates called
neuritic plaques (shown in A & C of
below). These oligomers in particular appear to disrupt communication
between neurons. In addition, Aβ oligomers are neurotoxic and when their
concentration becomes sufficiently high they cause neuronal death [13].
The second of the
commonly identified culprits is a neuronal protein called tau [14]. When
functioning normally, tau helps to give the neuron its unique shape and
transports oxygen and vital proteins and sugars along the neuron. In AD, enzymes attach phosphates to the tau
protein until the sites that can receive phosphates are completely saturated,
which is called hyperphosphorylation.
Hyperphosphorylation causes the tau protein to form tangles (also known
as neurofibrillary tangles; shown in B & D of below), which prevent microtubules from
performing their typical functions of distributing nutrients throughout the
cell. This is one mechanism by which
hyperphosphorylated tau leads to neuronal death. These neurofibrillary tangles
first emerge in the medial temporal lobe [15], in regions heavily involved in
verbal and visual memory formation, and are believed to contribute to the
memory problems characteristic of AD.
: Alzheimer’s disease. (A) Senile plaques
(SPs) and neuron loss in entorhinal cortex. SPs show dense cores and radially
oriented dystrophic neurites. (B) A typical neurofibrillary tangle in CA3.
Bielschowsky silver stain. (C) Amyloid beta protein immunohistochemistry
demonstrates frequent plaques in posterior cingulate cortex, accompanied by
cerebral amyloid angiopathy (inset). Hematoxylin counterstain. (D)
Immunohistochemical stains for hyperphosphorylated tau show aggregation in NFTs
and cortical dystrophic neurites. CP-13 antibody, hematoxylin counterstain.
Scale bars indicate 50 microns. Images courtesy of William Seeley and Stephen
DeArmond (Images from [16]; reproduced with permission from Cambridge
University Press).
As the disease
progresses, neuritic plaques and neurofibrillary tangles spread across the
brain in wider regions, disrupting additional cognitive abilities. While the
medial temporal and parietal lobes are usually affected early in AD, the
frontal lobes are affected later in the disease, with the basic sensory and
motor areas of the brain typically unaffected until very last stages of the disease. The spread of AD into the brain’s “lower
centers,” which are involved with movement and swallowing, eventually leads to
death.
In addition to
accumulation of Aβ plaques and oligomers and tau tangles, AD is associated with
changes in the brain’s neurotransmitters—the chemicals that allow neurons to
communicate. In particular, the neurotransmitter acetylcholine is severely
depleted in people with AD, and it is believed to contribute to the learning
and memory problems that are so characteristic of the disease [17]. This deficiency, only one of many
neurotransmitter deficiencies in AD, can be treated, but only partially
alleviates symptoms (see below).
Practical tips for living with Alzheimer's Disease
People may feel
overwhelmed after being diagnosed with AD. Some find it helpful to read about
the disease, so that they understand their diagnosis and know better what to
expect as the disease progresses. Understanding the disease and prognosis can
help you plan for your future and make important decisions, such as creating an
advance health care directive, and making decisions about how and where you
want to live. It is also helpful to have a trusted friend or family member with
you at your medical appointments. This person can help you in a number of ways.
He or she can ask your doctor important questions, help you remember the
information your doctor provides you, help plan future appointments or make
other relevant plans, provide emotional support, and help you get to and from
your appointments.
In addition, AD
affects more people than those diagnosed with it—it affects family members and
other loved ones. Behavioral problems are typically more difficult for
caregivers and other loved ones than are memory problems. Here are several
behavioral issues that frequently arise with AD, and ways that may help deal
with them.
• Suspicion or paranoia: People with AD
sometimes become suspicious of others. If you are the subject of that
suspicion, it can be hurtful and confusing. It is helpful to understand that
people with AD frequently become suspicious because they cannot keep track of
things as well as they used to; when they move something, they often cannot
remember that they have done so. It therefore seems to them that their
environment, and the valuable things in it, changes inexplicably, and so they
make sense of these changes by thinking that other people must be stealing from
them. This thought typically has nothing to do with how trustworthy a loved one
has been, and it is usually the person or people closest to the AD patient who
is blamed. Rather than defending yourself, or getting emotional if this
happens, you can help the person look for whatever has been misplaced. Or, if
possible, you can replace it.
• Forgotten bills: People with AD can have a
difficult time paying bills, keeping track of their finances, and otherwise
managing their money. They can also be at risk for elder financial abuse.
Caregivers often find their lives improve dramatically when they take over
handling the finances, and no longer have to worry about whether or not the
bills are being paid. Being involved with finances also can help prevent elder
financial abuse, or enable any scams or fraud to be quickly recognized and
remedied.
• Personality changes: Although personality
change is typically not as striking in AD as it is in some other types of
dementias, it is not uncommon. People with AD can become agitated, confused,
depressed, anxious, stubborn, or needy. Some personality or emotional changes,
such as depression, can be treated pharmacologically. Sometimes, it is helpful
to recognize that personality changes can be the result of poorer cognitive
skills—that when people cannot communicate their thoughts and feelings well
verbally, they communicate through actions. Identifying “triggers,” or the
preceding events or circumstances, of unwanted behavior can help you understand
what may be distressing to the person. Once you understand this, you can modify
the environment appropriately. In addition, blame the disease for the
distressing behavior or personality changes, rather than blaming the person.
• Fluctuating symptoms: One of the most
confusing things to many caregivers is that a loved one with AD can sometimes
seem to remember things, or be able to perform certain tasks, and other times
cannot. This is normal, and it is part of the disease process. Although it may
seem that a person is “faking” when their symptoms are worse, or that they
should be able to do something all the time if they can do it some of the time,
neither of these ideas are true. People with AD truly do have fluctuating
abilities. Blaming the disease for these frustrating and confusing moments,
rather than blaming the person with AD for not always being able to do things,
is very helpful. It is also helpful to simply recognize that symptoms,
including cognitive abilities, fluctuate over the course of the day and change
over time.