Scientists have known a lot about what happens in the brain once Alzheimer's disease (AD) takes hold and about the physical and mental changes that occur over time. The time from diagnosis to death varies - as little as 3 years if the patient is over 80 when diagnosed, as long as 10 or more years if the patient is younger. Although the course of AD is not the same in every patient, symptoms seem to develop over the same general stages.

PET Scan of Normal Brain	PET Scan of AD Brain

Preclinical AD

Alzheimer's disease (AD) begins in the entorhinal cortex, which is near the hippocampus and has direct connections to it. It then proceeds to the hippocampus, the brain region that plays a major role in learning and is involved in converting short-term memories to long-term memories. Affected regions begin to atrophy (shrink). Ventricles, the fluid-filled spaces inside the brain, begin to enlarge as the process continues.

Scientists believe that these brain changes begin 10 to 20 years before any visible signs and symptoms appear. Memory loss, the first visible sign, is the main feature of mild cognitive impairment (MCI) which does not have other cognitive problems that characterize AD. MCI has several subtypes. The type most associated with memory loss is called amnestic MCI. About 8 of every 10 people who fit the definition of amnestic MCI go on to develop AD within 7 years.

Mild AD

As the disease begins to affect the cerebral cortex, memory loss continues and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include:

• Memory loss
• Confusion about the location of familiar places (getting lost begins to occur)
• Taking longer to accomplish normal daily tasks
• Trouble handling money and paying bills
• Poor judgment leading to bad decisions
• Loss of spontaneity and sense of initiative
• Mood and personality changes, increased anxiety

The growing number of plaques and tangles first damage areas of brain that control memory, language, and reasoning. It is not until later in the disease that physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy, but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging. Accepting these signs and deciding to go for diagnostic tests can be a big hurdle for patients and families to cross.

Moderate AD

By this stage, AD damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families. The symptoms of this stage can include:

• Increasing memory loss and confusion
• Shortened attention span
• Problems recognizing friends and family members
• Difficulty with language; problems with reading, writing, working with numbers
• Difficulty organizing thoughts and thinking logically
• Inability to learn new things or to cope with new or unexpected situations
• Restlessness, agitation, anxiety, tearfulness, wandering - especially in the late afternoon or at night
• Repetitive statements or movement, occasional muscle twitches
• Hallucinations, delusions, suspiciousness or paranoia
• Loss of impulse control (shown through sloppy table manners, undressing at inappropriate times or places, or vulgar language)
• Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, a person may angrily refuse to take a bath or get dressed because he does not understand what his caregiver has asked him to do. If he does understand, he may not remember how to do it. The anger is a mask for his confusion and anxiety. Or, a person with AD may constantly follow her husband or caregiver and fret when the person is out of sight. To a person who cannot remember the past or anticipate the future, the world around her can be strange and frightening. Sticking close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. Taking off clothes may seem reasonable to a person with AD who feels hot and doesn't understand or remember that undressing in public is not acceptable.

Severe AD

In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Other symptoms can include:

• Weight loss
• Seizures, skin infections, difficulty swallowing
• Groaning, moaning, or grunting
• Increased sleeping
• Lack of bladder and bowel control

At the end, patients may be in bed much or all of the time. Most people with AD die from other illnesses, frequently aspiration pneumonia. This type of pneumonia happens when a person is not able to swallow properly and breathes food or liquids into the lungs.

The following figure shows the spread of neurofibrillary tangles (in blue) throughout the brain as Alzheimer's disease progresses. Plaques also spread throughout the brain, starting in the entorhinal cortex.