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Overview
Alzheimer's disease is a brain disorder that gets worse over time. It's characterized by
changes in the brain that lead to deposits of certain proteins. Alzheimer's disease causes the
brain to shrink and brain cells to eventually die. Alzheimer's disease is the most common
cause of dementia — a gradual decline in memory, thinking, behavior and social skills. These
changes affect a person's ability to function.
About 6.5 million people in the United States age 65 and older live with Alzheimer's disease.
Among them, more than 70% are 75 years old and older. Of the about 55 million people
worldwide with dementia, 60% to 70% are estimated to have Alzheimer's disease.
The early signs of the disease include forgetting recent events or conversations. Over time, it
progresses to serious memory problems and loss of the ability to perform everyday tasks.
Medicines may improve or slow the progression of symptoms. Programs and services can
help support people with the disease and their caregivers.
There is no treatment that cures Alzheimer's disease. In advanced stages, severe loss of
brain function can cause dehydration, malnutrition or infection. These complications can
result in death.
Alzheimer's disease is a
gradual and progressive
neurodegenerative disease
caused by neuronal cell
death. It typically starts in
the entorhinal cortex in the
hippocampus. There is a
genetic role identified for
both early and late-
onset Alzheimer's disease.
Trisomy 21 is a risk factor
for early-onset dementia.
Several risk factors have
been associated
with Alzheimer's disease.
Increasing age is the most
important risk factor
for Alzheimer's disease.
Symptoms
of Alzheimer's
disease depend on
the stage of the
disease. Alzheimer's
disease is classified
into preclinical or
presymptomatic,
mild, and dementia-
stage depending on
the degree of
cognitive
impairment. These
stages are different
from the DSM-5
classification of
Alzheimer's disease.
The initial and most
common presenting
symptom is episodic short-term memory loss with relative sparing of long-term memory and can be
elicited in most patients even when not the presenting symptom.
Symptoms
Memory loss is the key symptom of Alzheimer's disease. Early signs include difficulty
remembering recent events or conversations. But memory gets worse and other symptoms
develop as the disease progresses. At first, someone with the disease may be aware of
having trouble remembering things and thinking clearly. As symptoms get worse, a family
member or friend may be more likely to notice the issues.
Brain changes associated with Alzheimer's disease lead to growing trouble with:
Memory
Everyone has memory lapses at times, but the memory loss associated with Alzheimer's
disease persists and gets worse. Over time, memory loss affects the ability to function at
work or at home.
People with Alzheimer's disease may:
Repeat statements and questions over and over.
Forget conversations, appointments or events.
Misplace items, often putting them in places that don't make sense.
Get lost in places they used to know well.
Eventually forget the names of family members and everyday objects.
Have trouble finding the right words for objects, expressing thoughts or taking part in
conversations.
Thinking and reasoning
Alzheimer's disease causes difficulty concentrating and thinking, especially about abstract
concepts such as numbers. Doing more than one task at once is especially difficult. It may be
challenging to manage finances, balance checkbooks and pay bills on time. Eventually, a
person with Alzheimer's disease may be unable to recognize and deal with numbers.
Alzheimer's disease causes a decline in the ability to make sensible decisions and judgments
in everyday situations. For example, a person may make poor choices in social settings or
wear clothes for the wrong type of weather. It may become harder for someone to respond
to everyday problems. For example, the person may not know how to handle food burning
on the stove or decisions when driving.
Routine activities that require completing steps in order become a struggle. This may
include planning and cooking a meal or playing a favorite game. Eventually, people with
advanced Alzheimer's disease forget how to do basic tasks such as dressing and bathing.
Preserved skills
Despite major changes to memory and skills, people with Alzheimer's disease are able to
hold on to some skills even as symptoms get worse. Preserved skills may include reading or
listening to books, telling stories, sharing memories, singing, listening to music, dancing,
drawing, or doing crafts. These skills may be preserved longer because they're controlled by
parts of the brain affected later in the course of the disease.
Changes in personality and behavior
Brain changes that occur in Alzheimer's disease can affect moods and behaviors. Problems
may include the following:
Depression.
Loss of interest in activities.
Social withdrawal.
Mood swings.
Distrust in others.
Anger or aggression.
Changes in sleeping habits.
Wandering.
Loss of inhibitions.
Delusions, such as believing something has been stolen.
Most people in the mild stage of AD have no problem recognizing familiar faces and can
usually travel to familiar places.
Symptoms of the moderate stage of Alzheimer’s
Moderate Alzheimer’s is typically the longest stage and can last many years. People in the
moderate stage of Alzheimer’s often require care and assistance.
Have increased memory loss and confusion, often forgetting events or details about
their life, such as their telephone number or where they went to school.
Have growing confusion about which day of the week it is, which season they’re in
and where they are.
Need help with self-care, such as bathing, grooming, showering and using the
bathroom.
Experience more personality changes, including being agitated or acting out. They
may show depression, apathy or anxiety as the disease progresses.
In the final stage of Alzheimer’s, dementia symptoms are severe. People in this stage need
extensive care. In the severe stage of Alzheimer’s disease, the person often:
Needs help with all basic activities of everyday living, such as eating, sitting up and
walking.
Loses their ability to communicate. Their speech becomes limited to a few words or
phrases.
An abnormal build-up of proteins in your brain causes Alzheimer’s disease. The build-up of these
proteins — amyloid protein and tau protein — causes brain cells to die.
The human brain contains over 100 billion nerve cells and other cells. The nerve cells work together
to fulfill all the communications needed to perform functions such as thinking, learning,
remembering and planning.
Scientists believe that amyloid protein builds up in your brain cells, forming larger masses called
plaques. Twisted fibers of another protein called tau form into tangles. These plaques and tangles
block the communication between nerve cells, which prevents them from carrying out their
processes.
The slow and ongoing death of the nerve cells results in the symptoms of Alzheimer’s disease. Nerve
cell death starts in one area of your brain (usually in the area of your brain that controls memory —
the hippocampus) and then spreads to other areas.
Despite ongoing research, scientists still don’t know what exactly causes these proteins to build up.
So far, they believe that a genetic mutation may cause early-onset Alzheimer’s. They think that late-
onset Alzheimer’s happens due to a complex series of brain changes that may occur over decades. A
combination of genetic, environmental and lifestyle factors likely contribute to the cause.
Is Alzheimer’s hereditary
Researchers don’t know why some people get Alzheimer’s disease and others don’t. But
they’ve identified several factors that increase your risk for Alzheimer’s, including genetic
(hereditary) factors.
Having a form of the apolipoprotein E (APOE) gene increases your risk. This gene has several
forms, and one of those, APOE ε4, increases your risk of developing Alzheimer’s and is also
associated with an earlier age of disease onset.
However, having the APOE ε4 form of the gene doesn’t guarantee that you’ll develop the
condition. Some people with no APOE ε4 may also develop Alzheimer’s.
If you have a first-degree relative (biological parent or sibling) with Alzheimer’s disease, your
risk of developing the condition increases by 10% to 30%. People with two or more siblings
with late-onset Alzheimer’s disease are three times more likely to develop the condition
than the general population.
Having trisomy 21 (Down syndrome) also increases your risk for early-onset Alzheimer’s.
DIAGNOSIS
AND TESTS
How is
Alzheimer’s
disease
diagnosed?
Healthcare
providers use
several methods
to determine if a person with memory issues has Alzheimer’s disease. This is because many
other conditions, especially neurological conditions, can cause dementia and other
symptoms of Alzheimer’s.
In the beginning steps of an Alzheimer’s diagnosis, a provider will ask questions to better
understand your health and daily living. Your provider may also ask someone close to you,
like a family member or caregiver, for insight into your symptoms. They’ll ask about:
Overall health.
Current medications.
Medical history.
Ability to carry out daily activities.
Changes in mood, behavior and personality.
A provider will also:
Perform a physical exam and a neurological exam.
Perform a mental status exam, which includes tests to assess memory, problem-
solving, attention, basic math and language.
Order standard medical tests, such as blood and urine tests, to rule out other
possible causes of the symptoms.
Order brain imaging tests, such as a brain CT, brain MRI or positron emission
tomography, to support an Alzheimer’s diagnosis or to rule out other possible
conditions.
There’s no cure for Alzheimer’s disease, but certain medications can temporarily slow the
worsening of dementia symptoms. Medications and other interventions can also help with
behavioral symptoms.
Beginning treatment as early as possible for Alzheimer’s could help maintain daily
functioning for a while. However, current medications won’t stop or reverse AD.
The U.S. Food and Drug Administration (FDA) has approved two types of drugs to treat the
symptoms of Alzheimer’s disease:
Cholinesterase inhibitors.
NMDA antagonists.
The FDA has given accelerated approval for aducanumab (Aduhelm™), the first disease-
modifying therapy for Alzheimer’s disease. The medication helps to reduce amyloid deposits
in your brain.
Aducanumab is a new medication, and researchers studied its effects in people living with
early Alzheimer’s disease. Because of this, it may only help people in the early stage.
Cholinesterase inhibitors
The following cholinesterase inhibitors can help treat the symptoms of mild to moderate
Alzheimer’s disease:
These drugs work by blocking the action of acetylcholinesterase, the enzyme responsible for
destroying acetylcholine. Acetylcholine is one of the chemicals that help nerve cells
communicate. Researchers believe that reduced levels of acetylcholine cause some of the
symptoms of Alzheimer’s disease.
These drugs can improve some memory problems and reduce some behavioral symptoms of
Alzheimer’s disease.
These medications don’t cure Alzheimer’s disease or stop the progression of the disease.
NMDA antagonists
Studies have shown that people with Alzheimer’s who take memantine perform better in
common activities of daily living such as eating, walking, toileting, bathing and dressing.
Pathophysiology
Alzheimer's disease is characterized by an accumulation of abnormal neuritic plaques and
neurofibrillary tangles.
Plaques are spherical microscopic lesions that have a core of extracellular amyloid beta-
peptide surrounded by enlarged axonal endings. Beta-amyloid peptide is derived from a
transmembrane protein known as an amyloid precursor protein (APP). The beta-amyloid
peptide is cleaved from APP by the action of proteases named alpha, beta, and gamma-
secretase. Usually, APP is cleaved by either alpha or beta-secretase and the tiny fragments
formed by them are not toxic to neurons. However, sequential cleavage by beta and then
gamma-secretase results in 42 amino acid peptides (beta-amyloid 42). Elevation in levels of
beta-amyloid 42 leads to aggregation of amyloid that causes neuronal toxicity. Beta-amyloid
42 favors the formation of aggregated fibrillary amyloid protein over normal APP
degradation. APP gene is located on chromosome 21, one of the regions linked to familial
Alzheimer's disease. Amyloid deposition occurs around meningeal and cerebral vessels and
gray matter in Alzheimer's disease. Gray matter deposits are multifocal and coalesce to form
milliary structures called plaques. However, brain scans have noted amyloid plaques in some
persons without dementia and then other persons had dementia but brain scans did not find
any plaques.
Neurofibrillary tangles are fibrillary intracytoplasmic structures in neurons formed by a
protein called tau. The primary function of the tau protein is to stabilize axonal
microtubules. Microtubules run along neuronal axons and are essential for intracellular
transport. Microtubule assembly is held together by tau protein. In Alzheimer's disease, due
to aggregation of extracellular beta-amyloid, there is hyperphosphorylation of tau which
then causes the formation of tau aggregates. Tau aggregates form twisted paired helical
filaments known as neurofibrillary tangles. They occur first in the hippocampus and then
may be seen throughout the cerebral cortex. Tau-aggregates are deposited within the
neurons. There is a staging system developed by Braak and Braak based on the
topographical staging of neurofibrillary tangles into 6 stages, and this Braak staging is an
integral part of the National Institute on Aging and Reagan Institute neuropathological
criteria for the diagnosis of Alzheimer disease. Tangles are more strongly correlated to
Alzheimer's than the plaques are.
Another feature of Alzheimer's disease is granulovacuolar degeneration of hippocampal
pyramidal cells by amyloid angiopathy. Some reports indicate that cognitive decline
correlates more with a decrease in the density of presynaptic boutons from pyramidal
neurons in laminae III and IV, rather than an increase in the number of plaques. Neuronal
loss in Nucleus Basalis of Myenert, leading to low Acetylcholine has also been noted.
Vascular contribution to the neurodegenerative process of Alzheimer's disease is not fully
determined. The risk of dementia is increased fourfold with subcortical infarcts. The
cerebrovascular disease also exaggerates the degree of dementia and its rate of progression.
Staging
Preclinical or Presymptomatic
In this stage, individuals are asymptomatic with definite laboratory evidence. Identifying the
biomarkers can help diagnosing Alzheimer disease in this stage. Low amyloid and increased
tau proteins in CSF serve as a biomarker but they are not specific for Alzheimer disease.
Another analysis has indicated that a combination of different variables– ApoE4 positivity,
scores on the the paired associates immediate recall test and digits symbol substitution test,
increased tau protein in CSF, and right entorhinal cortex thickness and right hippocampal
volume on MRI – can predict the progression to MCI.
Mild Cognitive Impairment
In this stage, patients have impairment in either memory or in nonmemory domains, such as
executive ability or language function. These individuals continue to work, socialize, and
function independently. Patients with MCI progress to dementia t rate of 10% per year. Risk
factors for progression to dementia includes the severity of impairment at the time of
diagnosis in addition to the other risk factors for Alzheimer's disease.
Dementia
In this stage, patients have incapacitating memory impairment. Language changes include
anomia, paraphasic errors, decrease in spontaneous verbal output and a tendency for
circumlocution to avoid forgotten words. Impairment of visuospatial abilities leads to
wandering in the familiar surroundings and constructional apraxia.
20-40% of patients will have delusions. Visual hallucinations are more common, although,
patients can also have auditory and olfactory hallucinations as well. Disruptive behaviors
occurs in almost 50% of the patients. Patients also lose their normal circadian sleep-wake
pattern and their sleep becomes fragmented. Motor vehicle crashes are greater in these
patients.
History and progress of hypotheses and clinical trials for Alzheimer's disease
2020 Alzheimer's disease facts and figures
2020 50.0
2021 51.6
2022 53.3
2023 55.0
2024 56.8
Research Question 1: "What are the primary genetic risk factors associated with the
development of Alzheimer's disease, and how do they contribute to disease
pathogenesis?"
Research Question 2: "What are the environmental factors that increase the risk of
Alzheimer's disease, and how do they interact with genetic factors to influence
disease onset and progression?"
Research Question 3: "What are the potential biomarkers for early detection and
diagnosis of Alzheimer's disease, and how accurate and reliable are they in clinical
settings?"
Research Question 4: "What are the current treatment options for Alzheimer's
disease, and what are their efficacy and limitations in improving cognitive function
and slowing disease progression?"
Research Question 5: "What are the emerging therapeutic strategies and
interventions being investigated for Alzheimer's disease, and what potential benefits
do they offer in terms of disease management and prevention?"
Research Question 6: "What is the impact of lifestyle factors, such as physical
exercise, diet, cognitive stimulation, and social engagement, on the prevention and
management of Alzheimer's disease?"
Research Question 7: "What are the potential mechanisms underlying the
neurodegenerative processes in Alzheimer's disease, and how can this knowledge
contribute to the development of novel therapeutic targets and interventions?"
Research Question 8: "What are the psychosocial and economic impacts of
Alzheimer's disease on individuals, caregivers, and society, and how can support
systems and policies be improved to address these challenges effectively?"
Research Question 9: "What are the implications of Alzheimer's disease on brain
health and aging, and how can a better understanding of the disease contribute to
promoting healthy brain aging and preventing cognitive decline?"
Research Question 10: "What are the future directions in Alzheimer's disease
research, including advancements in diagnostic techniques, therapeutic
interventions, and preventive strategies?"
HYPOTHESES FOR ALZHEIMER'S RESEARCH+
Article prepared by
Harun Alraei
Sabiha Pazarac