To date, researchers do not know the precise cause of Alzheimer disease (AD).  They do not fully understand all the factors that start the disease process or what makes it progress.  However, scientists have been able to separate the disease into two distinct forms:  sporadic Alzheimer disease and familial Alzheimer disease (FAD).  
Both forms of AD are associated with the same structural, chemical, and clinical abnormalities exhibited with the disease. The two structures in the brain that signal the presence of AD are amyloid plaques, found between neurons in the brain, and neurofibrillary tangles, found within neurons in the brain. Both are clusters of proteins and can form as part of the usual process of aging.  

However, in AD these proteins accumulate in greater quantities in two specific brain regions:  the hippocampus and the cerebral cortex. Amyloid plaques consist of beta-amyloid, a protein fragment of another larger protein called amyloid precursor protein (APP). APP is found in most cell membranes in our bodies and is approximately 765 amino acids long. The exact spot where the APP molecule is cut in nerve cells influences whether or not the beta-amyloid protein fragment is formed.  If it is first cut just outside the cell membrane, by an enzyme called alpha-secretase, the plaque-causing beta-amyloid fragment is not formed. But if APP is first cut a bit farther away from the cell membrane by an enzyme called beta-secretase, the beta-amyloid fragment is formed.  

The beta-amyloid fragment is either 40 or 42 amino acids long.  (The version most toxic to neurons seems to be A-beta 42.)  Once formed, beta-amyloid is either degraded and cleared from the brain, or it remains in the brain, accumulating in clumps between neurons to become plaques.  The accumulation of these amyloid plaques seems to trigger the onset of AD, but researchers are still unsure if the plaques are the cause of the disease or simply a by-product of AD.  Neurofibrillary tangles, the other abnormal cluster of proteins associated with AD, occur within neurons. These intracellular tangles consist of twisted threads of a protein called tau.  Normally the tau protein has a clear-cut function in the human nervous system — it regulates the assembly of a neuron’s internal structure and its nutrient transport system. But in AD, the tau protein is chemically changed (extra phosphate groups are added to the protein) and this causes tau to become “sticky.”  When this happens, tau proteins pair up and twist around one another, forming a helical shape.  Clumps of this helical tau form the neurofibrillary tangles seen in AD.  Researchers are not sure exactly what triggers this change in the tau protein, but once it occurs the transport system of affected nerve cells collapses.  This leads to miscommunication between nerve cells and eventually cell death from lack of nutrition. When enough neurons in an AD brain are damaged or destroyed, chemical imbalances begin to happen. The most significant chemical change is a loss of the neurotransmitter acetylcholine, which serves to transmit messages from one neuron to another.   In AD, as damage to neurons in the brain increases, the ability to produce acetylcholine decreases.  This chemical loss means important messages are not transmitted in regions of the affected brain.  The end result of the structural (plaques and tangles) and chemical (decreased amount of neurotransmitter available to nerve cells) changes in the AD brain is progressive cell death and an overall shrinkage of brain tissue.  This culminates in the progressive clinical symptoms of AD such as mental decline, agitation, and delusions. An absolute diagnosis of Alzheimer disease can only be made after the death of the patient.  At that time, an autopsy is performed and brain tissue is examined by a pathologist who looks for the plaques and tangles in the regions of the brain that are characteristic of AD.  However, trained doctors are able to correctly diagnose AD in living patients up to 90% of the time.  This is done in a two-step process: In the ruling-out phase (“possible” AD), doctors look at several possible causes of a patient’s mental symptoms.  Things such as drug reactions, brain tumors, strokes, thyroid problems, or chronic infections can all mimic the symptoms of AD.  When all other causes of a patient’s symptoms are ruled out, a diagnosis of “probable” AD is made.  Currently there is no test that marks the presence of AD in the living patient, but brain images taken by magnetic resonance imaging (MRI) may show shrinkage of the hippocampus in AD patients.   Also, there is new evidence to suggest that MRI images of another area of the brain — the entorhinal cortex — may be able to predict who will develop mild cognitive impairment and then AD later in life. The entorhinal cortex is a pre-processing center for memory formation and cups the hippocampus like a baseball mitt holds a ball.   In AD, shrinkage of this area occurs prior to changes in the hippocampus. Another imaging technique used in the living brain is called positron emission tomography (PET).  Researches have found that people in the earliest stages of AD have decreased levels of sugar uptake in certain brain regions.  A PET test can show glucose uptake changes in the brain before symptoms appear, thus this and other tests in the pipeline may lead to earlier diagnosis of AD.  While no current treatment can stop the inexorable progression of AD, early diagnosis may be important to slowing the progression of the disease.  New research indicates that when drug therapy to maintain levels of the important message-sending neurotransmitter acetylcholine is started early and given consistentLY, patients with AD fared better than those who only received this drug therapy intermittently. The sporadic form of AD is by far the more common, and it is associated with a later onset of the disease, usually after age 65.  While sporadic AD is not linked to an obvious pattern of inheritance, there is an associated risk of developing this form of AD tied to a version of the APOE gene on chromosome 19.   Different versions of the same gene are called alleles.  An example of this can be found in eye color — different versions of the gene that code for eye color account for variations in eye hues.  The APOE gene has three main alleles, e2, e3, and e4.  Having one version, or allele, of a gene can lead to an increased susceptibility to developing a disorder.  People with the e4 allele of APOE are more likely to develop AD, but not everyone with APOE e4 will develop AD.   The APOE gene we have is passed to us from our parents.  Each parent contributes one allele of the APOE gene to his or her offspring. People who inherit two copies of the e4 allele of the APOE gene are at greater risk of developing sporadic AD than those with a single e4 allele.  Researchers know that the APOE gene codes for a protein that helps to transport cholesterol in the body, but they do not understand why the e4 allele increases the risk of AD.  One theory is that APOE e4 does not allow the plaque-causing beta-amyloid proteins to be cleared from the brain.   Familial AD (FAD) is rare, accounting for less than 10% of all cases.  This form of AD is also referred to as early-onset AD because those affected show symptoms between the ages of 30 and 65.  FAD is an autosomal dominant form of the disease; a person need only inherit one copy of the mutated gene to develop FAD.  At present, researchers have identified three separate gene mutations on three different chromosomes that cause FAD.   A person will develop FAD if they inherit any single one of these gene mutations.   There seems to be strong evidence that mutations in the presenilin 1 and 2 genes lead to an increased amount of beta-amyloid (the plaque-causing protein), possibly by an upsurge in gamma-secretase cutting of the APP protein.  Mutations in the APP gene on chromosome 21 can produce mutated APP protein that is no longer cut properly.  This can lead to increased amounts of beta-amyloid.  While significant headway is being made in the effort to unlock the genes responsible for FAD, it is important to note that mutations in the APP and presenilin genes account for only 50% of all FAD cases.  Genetic sleuths still have plenty of investigating to do! A child whose parent has a mutation in either of the presenilin genes or the APP gene has a 50% chance of inheriting the mutated gene and developing AD.  (Remember, inheriting any single one of these genes will cause FAD.)  For purposes of simplicity, we will refer to the presenilin genes and the APP gene as "Alzheimer" gene in our example below.  In this couple, the father has the Alzheimer mutation (A) and the normal gene, while the mother has two copies of the normal gene.  A Punnett square illustrates their possible children; let's calculate the chance each child has of inheriting the disorder.  First, we arrange each parent's genes on the outer edges of the square. Each parent donates one of their "Alzheimer" genes to the child, so we place one of the father's genes and one of the mother's genes into each box.  Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations.  Next, we count the boxes that contain an Alzheimer-causing genotype, the Aa combination.  Two of the four boxes contain this combination, or genotype.  So the chance of this couple's child inheriting FAD is two out
of four, or 50%.  The same chance applies in the opposite situation when the woman has the Alzheimer's mutation and the man does not. Two out of the four boxes contain the Alzheimer-causing combination (Aa), so the chance of this couple's child inheriting FAD is also two out of four, or 50%.The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel:  Each child is a separate "spin of the wheel," so each child has a 50% chance of receiving the mutation. In this family, one in four children has inherited FAD. Other couples with the Alzheimer's mutation may have two, three, four,
or even no children with FAD.

When people exhibit symptoms consistent with AD, doctors perform tests to exclude other causes of dementia or cognitive problems.  If no other reason is found, a tentative diagnosis is made — a conclusive diagnosis of AD can only be made by direct examination of the patient’s brain for characteristic plaques and tangles after death in an autopsy.   Alzheimer disease (AD) is characterized by progressive destruction and death of nerve cells in the brain.  This leads to shrinkage or “atrophy” in certain regions of the brain and a decrease in chemicals called neurotransmitters that ferry important messages between nerve cells.  The result of these cell and chemical losses is a steady decline in mental function. Currently, there is no treatment that will stop or reverse the symptoms of Alzheimer disease.  However, the Food and Drug Administration has approved the use of three drugs that attempt to slow the progression of the disease.  These drugs work to maintain levels of critical message-sending chemicals in the brain called neurotransmitters.  The brains of people with Alzheimer disease (AD) exhibit two significantly different structures:  amyloid plaques and neurofibrillary tangles.  Both the plaques and tangles consist mostly of protein and are thought to interfere with brain function and contribute to the dementia that is a hallmark of AD.  People with Alzheimer disease have two distinct sets of symptoms:  cognitive and behavioral.  The severity of the symptoms increases over time. Cognitive symptoms: Memory lossDisorientation ConfusionDifficulty with reasoned thought Behavioral symptoms: Agitation / Anxiety Delusions / Hallucinations Depression Insomnia Wandering Age is the major risk factor for Alzheimer disease (AD).  It is the most common cause of dementia in people over 65.  As many as 4 million Americans currently suffer from AD, and as the U.S. population ages that number is expected to rise significantly.  Some 10% of people over age 65 are afflicted with AD; of those age 85 or older the incidence increases to 50%. Frequency: Dr. Shelanski talks about the frequency of Alzheimer disease in populations of 60. Aluminum & Alzheimer: Dr. Shelanski speaks about whether aluminum is a factor associated with Alzheimer disease. Head injuries & Alzheimer: Dr. Shelanski talks about certain types of head injuries and how some of the symptoms are similar to Alzheimer. Preventing Alzheimer Disease: Dr. Shelanski discusses the relationship between anti-inflammatory drugs and Alzheimer disease. Identifying Gamma Secretase: Dr. Shelanski describes the link between gamma secretase – and important enzyme in the plaque formation in patients with Alzheimer – and mutations of the presenilin genes. Diagnostic Challenges: Dr. Shelanski talks about determining the risks for developing AD and the pros and cons of “predictive” diasgnostics. Drug Therapy: Dr. Wisniewski, Associate Professor of nerology, pathology, and psychiatry at New York University School of Medicine, talks about drug therapy to treat memory loss in Alzheimer patients. Mild cognitive Impairment (MCI): Dr. Wisniewski talks about the connection between mild cognitive impairment and Alzheimer disease as well as early identification of those with MCI. MCI and forgetfulness: Dr. Wisniewski differentiates between MCI and normal forgetfulness associated with aging.  Diagnosis: Dr. Wisniewski talks about the process of “ruling out” other causes of dementia in patients with cognitive decline. Alzheimer & Cell Death: Dr. Wisniewski explaines why “cell suicide may lead to the symptoms seen in Alzheimer disease. Cholesterol and Alzheimer Disease: Dr. Wisniewski explains why keeping your cholesterol levels low may be important in preventing Alzheimer disease. Behavior Changes: Ro Johnson’s mother suffers from Alzheimer disease. Ms. Johnson recalls when she first noticed something amiss in her mother’s behavior. Modifying Lifestyle: Ro Johnson describes how she undertook the initial steps to assist in her mother’s care. Deterioration: Ms Johnson struggles with her emotions as she describes her mother’s decline and how she copes with the losses. Financial struggles: Ms Johnson discusses the financial strains infolved in coping with Alzheimer disease. Testing: Ms Johnson talks about the progressive memory testing her mother underwent, and whether she, herself, will undergo testing to determine her genetic risk for Alzheimer disease. Safe Return: Ms Johnson describes the “safe return” program for Alzheimer patients and their caregivers. The diagnosis: Julie Zale was diagnosed with Alzheimer disease in 1998. She explains what led her to seek a diagnosis for her ongoing mental changes and lists some of the testing involved. Coming to Terms: Ms Zale explains why being diagnosed with Alzheimer disease brought her a strange sense of relief – the relief of finally knowing! Adapting: Ms Xale talks about how she sought to gain knowledge about her disease and support for herself. Building a team: Ms. Zale explains how she went about assigning people to handle her affairs as her health declines and the sense of empowerment that brought her. Family: Ms Zale discusses why she does not wish to burden her daughter with her future care. Last Days: Ms Zale anticipates the end stages of her disease and talks about the people who will make decisions for her at that point, including when to place her in a care facility.