Preclinical Alzheimer’s Disease In this phase, individuals have measurable brain changes that indicate the earliest signs of Alzheimer’s disease (biomarkers), but they have not yet developed symptoms such as memory loss. Examples of Alzheimer's biomarkers include abnormal levels of beta-amyloid as shown on positron emission tomography (PET) scans32 and in analysis of cerebrospinal fluid (CSF), and decreased metabolism of glucose as shown on PET scans. When the early changes of Alzheimer’s occur, the brain compensates for them, enabling individuals to continue to function normally. While research settings have the tools and expertise to identify some of the early brain changes of Alzheimer’s, additional research is needed to fine-tune the tools’ accuracy before they become available for widespread use in hospitals, doctors’ offices and other clinical settings. It is important to note that not all individuals with evidence of Alzheimer’s-related brain changes go on to develop symptoms of MCI or dementia due to Alzheimer’s.33-34 For example, some individuals have beta-amyloid plaques at death but did not have memory or thinking problems in life. MCI due to Alzheimer’s Disease People with MCI due to Alzheimer’s disease have biomarker evidence of Alzheimer’s brain changes plus subtle problems with memory and thinking. These cognitive problems may be noticeable to the individual, Symptoms interfere with most everyday activities Symptoms interfere with many everyday activities Symptoms interfere with some everyday activities Very mild symptoms that do not interfere with everyday activities No symptoms Preclinical AD Mild Cognitive Impairment due to AD Mild Moderate Severe Dementia due to AD Dementia due to AD Dementia due to AD *Although these arrows are of equal size, the components of the AD continuum are not equal in duration. Alzheimer's Disease (AD) Continuum* FIGURE 1 Alzheimer’s Disease Continuum The progression of Alzheimer’s disease from brain changes that are unnoticeable to the person affected to brain changes that cause problems with memory and eventually physical disability is called the Alzheimer’s disease continuum. On this continuum, there are three broad phases: preclinical Alzheimer’s disease, mild cognitive impairment (MCI) due to Alzheimer’s disease and dementia due to Alzheimer’s disease (see Figure 1).27-30 The Alzheimer’s dementia phase is further broken down into the stages of mild, moderate and severe, which reflect the degree to which symptoms interfere with one’s ability to carry out everyday activities. Alzheimer's Begins Before Dementia In the past, Alzheimer’s disease was often used to describe the dementia phase of the disease. Today we know that dementia is only one part of the disease. It is preceded by mild cognitive impairment (MCI), a period when individuals have subtle cognitive changes that do not interfere with everyday activities. When biomarker tests show that individuals with MCI have the brain changes of Alzheimer’s disease, they are said to have MCI due to Alzheimer’s disease, another part of the Alzheimer’s disease continuum. MCI is a key area of interest to researchers involved in drug development. Because individuals with MCI are still able to function independently, a treatment that prevents MCI from progressing to dementia would have a significant impact on quality of life, caregiver burden, and use and cost of care. Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2021;17(3). Overview 9 family members and friends, but not to others, and they do not interfere with individuals’ ability to carry out everyday activities. The mild changes in thinking abilities occur when the brain can no longer compensate for the damage and death of nerve cells caused by Alzheimer’s disease. Among those with MCI, about 15% develop dementia after two years.35 About one-third (32%) of individuals with MCI develop Alzheimer’s dementia within five years’ follow-up.36 It’s important to note that some individuals are diagnosed as having MCI several years after cognitive decline began, and these individuals are likely to develop dementia sooner than those whose cognitive decline is more recent.