The Three Stages of Alzheimer’s Disease

Patients, families and clinicians all want to know how far Alzheimer’s disease has progressed and what the future is likely to hold. Learn about the symptoms associated with the three stages of the disease.

Dr. Alois Alzheimer described the disease that was later given his name more than 100 years ago, but not until 1984 did health care providers and researchers agree on a standard approach to the diagnosis of Alzheimer’s disease. In 1984, workgroups from the National Institutes of Health and other organizations published a set of diagnostic criteria that later became the gold standard for diagnosis.¹ Their guideline emphasized that in order for a person to be diagnosed with probable Alzheimer’s disease, they must show difficulties in two or more areas of cognitive functioning, progressive worsening of memory, onset of symptoms between ages of 40 and 90, and no delirium or other likely cause for cognitive decline. Definite Alzheimer’s disease, according to their criteria, was only diagnosed after confirmation by brain biopsy or autopsy.

The International Classification of Diseases (ICD) and psychiatry’s Diagnostic and Statistical Manual (DSM) adopted similar standards for assigning an AD diagnosis, and this approach is commonly used now throughout the world.

Arthur’s question is one that clinicians hear very often. Beyond simply making a diagnosis, patients, families and clinicians all want to know how far a disease has progressed and what the future is likely to hold. This is why various systems have developed for describing the stages of AD. One of the simplest and most useful of these is the “three-stage” model that defines early/mild, middle/moderate, and late/severe Alzheimer’s disease.² This three-stage model claims to describe “Alzheimer’s disease,” but I will explain later why it actually only describes “Alzheimer’s dementia,” the final chapter of a long process of brain disease. The three stages of dementia typically run their course from diagnosis to death in 4 to 8 years, but they may take as long as 20 years for a specific individual.

The Three-Phase Model

Since 1984, fortunately, clinicians and researchers have learned a huge amount about how the brain changes of Alzheimer’s “disease” lead to the clinical picture of “Alzheimer’s dementia.” Much of our progress has resulted from the use of blood tests, cerebrospinal fluid tests, and neuroimaging (CT, MRI, SPECT, PET scans), which have revealed that Alzheimer’s dementia is preceded by decades of disease progression.

Together, these tests create key indicators referred to as “biomarkers.” These biomarkers have shown that the accumulation of brain cell damage that eventually results in dementia occurs at first silently, so a person could be said to have “Alzheimer’s disease” without yet showing the clinical symptoms of “Alzheimer’s dementia.” In 2009, the National Institute on Aging (NIA) and the Alzheimer’s Association sponsored a series of meetings during which a group of AD experts reconsidered the former diagnostic criteria. By 2011, they were ready to publish their recommendations for a different approach to diagnosing Alzheimer’s disease. Their influential articles included a “three-phase” model that was different from the “three-stage” system previously used to describe Alzheimer’s dementia.³

Phase I (Pre-Clinical Alzheimer’s Disease)

The first phase of the 2011 model is called “preclinical Alzheimer’s disease” and is primarily useful to researchers. People in the earlier part of this phase of the disease have no symptoms and appear normal and unaffected. A research examination of their blood, CSF, or brain, however, reveals the beginning of a neurodegenerative process or the early signs of that amyloid plaque and hyperphosphorylated tau protein are accumulating. In the later stage of this “presymptomatic phase” there can be awareness of mild cognitive symptoms (sometimes called “subjective cognitive decline” and very subtle cognitive changes that are detectable with more sophisticated testing).  People in this stage are considered ideal subjects for new therapies aimed at preventing progression from preclinical to clinical disease.

Phase II (Mild Cognitive Impairment)

The second phase of this model describes what we’ve called “Mild Cognitive Impairment” or “Mild Neurocognitive Disorder.” That’s the phase during which a person or those who know them have become concerned that there may be changes in memory, executive function, language, or other cognitive abilities, but independence and general functioning remain intact.

Phase III (Probable Dementia Due to Alzheimer’s Disease)

During this phase, we see the familiar clinical syndrome of dementia, which follows the three stages discussed below. The use of this broader classification for understanding Alzheimer’s disease has been very helpful in stimulating research efforts aimed at developing new treatment approaches.

• Stage I (Mild Symptoms)

In the mild or early stage, people have trouble with complex tasks, and they may lose interest in hobbies. They have more trouble planning or organizing tasks. The hobbies that had been fun become more difficult. Social withdrawal becomes more common as the challenge of relating to others is more challenging and stressful. A person with mild Alzheimer’s dementia can make more mistakes, misplace objects, or lose track of the date. Mr. G, who was later diagnosed with Alzheimer’s dementia, was at this mild stage when first evaluated.

• Stage II (Moderate Symptoms)
  
  The moderate or middle stage of Alzheimer’s dementia includes more advanced symptoms. People in this stage forget details about their own histories. They need more help with the basic activities of daily living, such as dressing properly and maintaining good personal hygiene. Their personalities may show disturbing changes such as more anxiety, suspiciousness, or irritability. Sometimes, in this stage, a person often has trouble recognizing their grandchildren or even children, and less commonly their spouse. They may get confused about where they are. Wandering can become a problem, and bladder and bowel control are often affected.

• Stage III (Severe Symptoms)
  
  In the severe or late stage of Alzheimer’s dementia, a person is totally dependent on others for basic functions such as feeding and toileting. Twenty-four-hour care is usually necessary. Familiar people are no longer recognized as such. This severe stage often includes problems with basic communication skills, interfering with a person’s ability to understand others or express their needs. It is in this severe stage that a fall or infection may lead to life-threatening complications and death.

Our research understanding of the pathology of AD and has been greatly improved since the adoption of this three-stage classification system that understands AD as progressing through an asymptomatic phase and a mild cognitive impairment phase before reaching the clinical stage of dementia. Researchers now describe the progression of disease using a classification system that reflects the severity of biomarker-associated pathology. This AT(N) classification system describes the presence or absence of:

• A - amyloid pathology as detected through cerebrospinal fluid measurement or amyloid PET scanning
• T - phosphorylated Tau protein as measured with newly available PET scan tau ligands
• N - neurodegenerative changes measured through structural neuroimaging with CT or MRI scans.⁴

Scientists can use the AT(N) system to measure the deleterious effects of risk factors or the beneficial effects of proposed therapies on these co-occurring but distinct facets of disease progression. In the future, this classification system and highly accurate new biomarker blood tests⁵ may also help clinicians choose which individuals are most likely to benefit from new therapies in development which are hoped to have disease modifying properties.