What Causes Alzheimer’s Disease?


Scientists believe that many factors influence when Alzheimer’s disease begins and how it progresses.

Increasing age is the most important known risk factor for Alzheimer’s. The number of people with the disease doubles every 5 years beyond age 65. About one-third of all people age 85 and older may have Alzheimer’s disease.

The causes of late-onset Alzheimer’s, the most common form of the disease, probably include a combination of genetic, lifestyle, and environmental factors. The importance of any one of these factors in increasing or decreasing the risk of development Alzheimer’s may differ from person to person.

Scientists are learning how age-related changes in the brain may harm nerve cells and contribute to Alzheimer’s damage. These age-related changes include atrophy (shrinking) of certain parts of the brain, inflammation, production of unstable molecules called free radicals, and breakdown of energy production within cells.

As scientists learn more about this devastating disease, they realize that genes also play an important role.

Genetics 101

Each human cell contains the instructions a cell needs to do its job. These instructions are made up of DNA, which is packed tightly into structures called chromosomes. Each chromosome has thousands of segments called genes.

Genes are passed down from a person’s birth parents. They carry information that defines traits such as eye color and height. Genes also play a role in keeping the body’s cells healthy. Problems with genes—even small changes to a gene—can cause diseases like Alzheimer’s disease.

The Genetics of Disease

Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. If a person inherits from a parent a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer’s disease are examples of inherited genetic disorders.

In other diseases, a genetic variant may occur. A single gene can have many variants. Sometimes, this difference in a gene can cause a disease directly. More often, a variant plays a role in increasing or decreasing a person’s risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.

Alzheimer’s Disease Genetics

There are two types of Alzheimer’s—early-onset and late-onset. Both types have a genetic component.

Some Differences Between Late-Onset and Early-Onset Alzheimer’s Disease
Late-Onset Alzheimer’s Early-Onset Alzheimer’s
Signs first appear in a person’s mid-60s Signs first appear between a person’s 30s and mid-60s
Most common type Very rare
May involve a gene called APOE e4 Usually caused by gene changes passed down from parent to child

Late-Onset Alzheimer’s Disease

Researchers have not found a specific gene that directly causes the late-onset form of the disease. However, one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19—does increase a person’s risk. APOE comes in several different forms, or alleles:

  • APOE e2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE e4 gene.
  • APOE e3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
  • APOE e4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. A person has zero, one, or two APOE e4 alleles. Having more APOE e4 alleles increases the risk of developing Alzheimer’s.

APOE e4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE e4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE e4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE e4 alleles.

Early-Onset Alzheimer’s Disease

Early-onset Alzheimer’s disease occurs between a person’s 30s to mid-60s and represents less than 10 percent of all people with Alzheimer’s. Some cases are caused by an inherited change in one of three genes, resulting in a type known as early-onset familial Alzheimer’s disease, or FAD. For other cases of early-onset Alzheimer’s, research suggests there may be a genetic component related to factors other than these three genes.

A child whose biological mother or father carries a genetic mutation for early-onset FAD has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset FAD.

Early-onset FAD is caused by any one of a number of different single gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.

Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer’s disease.

Health, Environmental, and Lifestyle Factors

Research suggests that a host of factors beyond genetics may play a role in the development and course of Alzheimer’s disease. There is a great deal of interest, for example, in the relationship between cognitive decline and vascular conditions such as heart disease, stroke, and high blood pressure, as well as metabolic conditions such as diabetes and obesity. Ongoing research will help us understand whether and how reducing risk factors for these conditions may also reduce the risk of Alzheimer’s.

A nutritious diet, physical activity, social engagement, and mentally stimulating pursuits have all been associated with helping people stay healthy as they age. These factors might also help reduce the risk of cognitive decline and Alzheimer’s disease. Clinical trials are testing some of these possibilities.