Alzheimer's Disease Causes

While a great deal of progress has been made in Alzheimer’s disease (AD) research, the exact cause or causes (etiology) still eludes researchers. However, many scientists believe that a build-up of two abnormal structures in the brain play an integral role. These structures are called amyloid plaques and neurofibrillary tangles.

These findings are not new. In 1906, a German psychiatrist/neuropathologist first described the unusual plaques and tangles within the brain of a patient who had suffered from memory loss, language problems, and unpredictable behavior. The name of this research pioneer? Alois Alzheimer.

Amyloid Plaques

Amyloid plaques (pronounced: AM-uh-loyd plaks) are dense, mostly insoluble clumps of protein fragments that deposit a highly damaging substance outside and around the brain’s nerve cells.

People with AD have an abundance of these destructive plaques in their hippocampus—a structure in the brain that plays a vital role in memory, including the transfer of immediate or short-term memories into long-term memories. Also, depending upon the extent of the damage, without a healthy hippocampus, your ability to function in the world may be greatly diminished. Why? Everything from remembering whether you’ve eaten to being able to recognize a loved one to remembering whether you turned off the stove all have to do with your ability to acquire, store, and retrieve memories.

Of note, the hippocampus is also essential to both spatial memory and spatial navigation. In fact, there is growing research to suggest that early damage to the hippocampus may be one of the factors involved in AD sufferers sometimes wandering and getting lost.

Neurofibrillary Tangles

Neurofibrillary tangles (pronounced NER-oh-FI-bri-lair-ee) are insoluble twisted up fibers that form essentially clogs up the brain works from the inside out.

Brain nerve cells (called neurons) have a specialized transport system called microtubules that act like railroad tracks, safely guiding and transporting nutrients, molecules, and information to other cells. An important fiber-like protein called tau is responsible for keeping those microtubules stable.

However, in people with AD, the tau’s chemical make-up is altered, resulting in the threads of tau getting all tangled and twisted up together—which causes the microtubules to become unstable and disintegrate, collapsing the whole neuron transport system.

Thus, it may be that this series of events results in (or at least may be associated with) the triggering of the first visible sign of AD—memory loss. That being said, the scientific jury is still out as to whether or not amyloid plaques, tangles, and tau are a cause of AD—as opposed to being symptoms of AD progression or perhaps some combination thereof.

Genetics of Alzheimer’s Disease

Researchers are certain of a genetic component to AD. In the elderly, the gene most associated with the onset of readily apparent symptoms is located on chromosome 19 and is called apolipoprotein E (APOE). 

There are several alleles (versions) of APOE. About 40 percent of all people who develop AD later in life have an APOE e4 allele, and there is a blood test to determine if a person has an APOE e4 allele. However, it’s still not possible to predict who will or will not develop AD. Some people with one or even two APOE e4 alleles never develop the disease, and others who develop AD don’t have any APOE e4 alleles.  

When it comes to developing AD later in life (as opposed to early-onset Alzheimer’s disease), having an “AD gene” does not necessarily mean you will get AD, but rather, having the genetic factors increases your risk of developing the disease.  

As of 2011, scientists have discovered five new genes—for a total of 10 genes—that appear to contribute to an increased risk of developing AD later in life. In fact, scientists now believe that the predisposition to AD may be up to 80 percent genetic, though estimates vary widely.

One of those newly identified genes, called CD33, appears to be responsible for a failure of the body to eliminate as many amyloid plaques as it should. And indeed, scientists have long believed that the amyloid plaques—and more specifically, their building up to toxic levels—likely plays a key role in the degradation of neurons in the brain.

Genetics of Early-Onset AD

Genetic studies of families with a history of early-onset AD have identified mutations in three different genes: APP (on chromosome 21), PSEN-1 (on chromosome 14), and PSEN-2 (on chromosome 1).

These genes are thought to be responsible for the rare form of AD that afflicts men and women starting in their early 30s or 40s. These defective genes are believed to be involved in the production and processing of the amyloid protein that forms the characteristic amyloid plaques (in addition to neurofibrillary tangles), which are the hallmarks of AD. These mutated genes do not play a role in the more common late-onset AD.

Of note, less than one out every 1000 cases of Alzheimer’s disease is the early-onset type. However, approximately 50 percent of the individuals who had a parent with early-onset AD will likely inherit the genetic mutation and will develop the disease. For those young individuals where neither parent had early-onset AD, research has found that usually a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had early-onset AD.