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 million Americans.
Although some aspects of AD mimic changes found in the brain as we age, AD is not a normal part of the aging process. Due to the build-up of abnormal protein structures in the brain called senile plaques (SPs) and neurofibrillary tangles (NFTs), nerve cell injury and cellular death occur. 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 genetically linked.
Alzheimer disease appears to be caused by a variety of still not well understood factors. Three genes, whose normal function has yet to be determined, have been associated with rare forms of early onset familial Alzheimer disease (EOFAD, also called Alzheimer disease type 3 or AD3). Certain mutations in each of these genes (known as PSEN1, PSEN2, and APP) produce abnormal proteins that result in AD. There is a 50% chance that the gene mutation will be passed on to each of the affected person's children. So far, mutations in these three genes have only been found in a very small number of families.
At this time, testing for the presenilin 1 gene (PSEN1 on chromosome 14), presenilin II gene (PSEN2 on chromosome 1), and amyloid precursor protein gene (APP on chromosome 21) is available but not frequently ordered.
Other genes have been identified and have been linked to late onset AD yet are not thought to be a direct cause. 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 is some combination of these three. The e3 is the most common allele, found in 60% of the general population. Presence of the APOE e4 allele has been associated with the majority of familial cases and with an increased risk of AD.
The risk of AD may vary by ethnicity, with African Americans' risk as much as four times greater and Hispanics' as much as two times greater, respectively, than that of Caucasians. Other risk factors that have been associated with AD are type 2 diabetes and milder forms of insulin resistance, obesity, high blood pressure, dyslipidemia, and high levels of inflammatory markers such as C-reactive protein (CRP).
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.
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:
- Preclinical Alzheimer disease – Measurable changes in biomarkers but no outward symptoms (intended only to help guide research for now)
- Mild cognitive impairment (MCI) due to Alzheimer disease – Mild changes in memory and thinking abilities that do not compromise day to day activities
- Dementia due to Alzheimer disease – Memory, thinking and behavioral symptoms that impair a person's ability to function 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.