Alzheimer disease (AD) is an irreversible form of dementia characterized by memory loss, a progressive decline in intellectual ability, deteriorating language and speech skills, and personality and behavioral changes that eventually interfere with daily living. Currently, Alzheimer disease has been estimated to affect more than 5.5 million Americans over the age of 65 and about 200,000 under the age of 65.
Although some aspects of AD mimic changes found in the brain as we age, AD is not a normal part of the aging process. Nerve cell injury and death occur due to the build-up of abnormal protein structures in the brain called amyloid plaques, also known as senile plaques, and neurofibrillary tangles. The destruction of nerve cells also results in decreased levels of substances called neurotransmitters (the most important being acetylcholine) that help transmit brain signals. Over time, AD results in decreased interaction between different areas of the brain.
Relationship with Aging
The risk of having AD and other forms of dementia increases greatly with age. About 10% to 12% of the population will have dementia by the time they are 65 years old, with the risk increasing to 50% for those who reach the age of 100. According to the Alzheimer's Association, with the U.S. population aging and living longer, it is estimated that the number of those living with AD may be up to 16 million by 2050.
In general, "late onset" AD begins after the age of 65 and is not thought to be inherited. "Early onset" AD, starting before the age of 65, accounts for about 5% to 10% of all AD cases and is more likely to be caused by inherited mutations (disease-causing variants) in one of several genes.
While the more common, late onset Alzheimer disease appears to be caused by a variety of factors that are still not well understood, three genes have been identified in association with a certain form of early-onset familial Alzheimer (also known as Alzheimer disease type 3) disease: PSEN1, PSEN2, and APP. A mutation in any one of these genes can lead to abnormal protein production, which contributes to the senile plaques that cause progressive dementia. Only one copy of one of these genes needs to be altered for it to cause AD, which means that there is a 50% chance of inheriting this mutation from an affected parent. Genetic testing of these genes may be recommended when a person has several generations of individuals who are all diagnosed with AD prior to age 65.
No causative genes have been identified for late onset AD. However, a few genes have been found to be associated with the disorder, meaning that people who have variants in these genes aren't guaranteed to develop late onset AD, but their risk is increased compared to others in the general population who do not have these variants. These "susceptibility" genes may explain why there is an increased risk of developing late onset AD in individuals who have other affected family members.
The APOE gene is the most clearly established susceptibility gene for late onset AD. This gene directs the production of apolipoprotein E, a protein that helps transport lipids (fats and cholesterol) in the blood. The APOE gene exists in three different forms (alleles): e2, e3, and e4. Everyone inherits a pair of APOE genes that contains some combination of these three alleles. The e3 allele is the most common. It is present in approximately 60% of the general population. The e4 allele has been established as a risk factor (particularly in familial versus sporadic) for AD.
Most individuals with Down syndrome (DS), caused by the abnormal trisomy of chromosome 21, will eventually show some of the mental changes associated with AD, usually by the time they are in their 40's or 50's. The pathology found in the brains of these adults with DS is very similar to that found in AD. The extra copy of chromosome 21 causes an increased production of the protein that accumulates and forms senile plaques similar to that seen in AD. Relatives of individuals with DS do not have an increased risk of AD since they do not have the extra copy of chromosome 21.
Other Risk Factors
The risk of AD appears to vary by ethnicity. Compared to Caucasians, individuals of African American ancestry have a risk for AD that is approximately four times greater and individuals of Hispanic ancestry have a risk approximately two times greater. In addition to ethnic background, other risk factors that are associated with AD include: type 2 diabetes and milder forms of insulin resistance, obesity, high blood pressure, unhealthy lipid levels, and high levels of inflammatory markers such as C-reactive protein (CRP).
In 2011, new criteria and guidelines for the diagnosis of Alzheimer disease were released by three expert workgroups spearheaded by the Alzheimer's Association and the National Institute on Aging (NIA) of the National Institutes of Health (NIH).
Their articles expand the definition of Alzheimer disease to include three stages:
- Preclinical Alzheimer disease – measurable changes in biomarkers, including brain imaging and certain proteins in the cerebrospinal fluid, but no outward symptoms; the purpose of defining a preclinical stage is to help guide research.
- Mild cognitive impairment (MCI) – mild changes in memory and thinking abilities that do not compromise day to day activities; people with MCI may or may not progress to AD-related dementia.
- Dementia due to Alzheimer disease – memory, thinking and behavioral symptoms that impair a person's ability to function independently in daily life
These guidelines are intended to provide more information about the current understanding of Alzheimer disease, provide a framework for future research, and to propose a stronger role for biomarker use in the future.