To better understand this debilitating disease, which affects millions of Americans and their families, one needs to begin with a working knowledge of the brain, and its basic building block, the neuron. Charged with the ability to communicate with each other through electrical and chemical processes, there are over 10 billion neurons in the brain. Each neuron has its own job, which serves the greater task of working to control important human functions, including cognition, behavior, movement and sensation.

Thanks to traditional neuroanatomy and emerging neuroimaging techniques, we now know that neurons in specific regions of the brain control specific functions. For instance, it has been proven that certain neurons in the large anterior part of the brain called the frontal lobe are responsible for personality, judgment, movement and speech, whereas neurons on the side of the brain called the temporal lobe integrate hearing, form memory and regulate emotion. This linkage is shared by all people, and the complex communication circuits formed with other parts of the brain and the spinal cord relate in perfect harmony to carry out the brain’s work.

Critical Mass
A normal brain sits dense and healthy inside the skull, actually looking like it will burst at the seams in its desire to grow. When viewing the brain of an individual with Alzheimer’s, it appears as if the brain is shrinking. A comparatively large space exists between the brain and the skull, while the outer part of the brain, called the cerebral cortex – where we do most of our higher levels of thinking – is significantly smaller than in the healthy brain. The ventricles – small holes deep inside the brain which secrete and circulate cerebral spinal fluid may appear larger, as a result of less brain tissue.

Areas of Vulnerability
In Alzheimer’s disease, some areas of the brain appear to be more susceptible to damage than others, leaving hallmark changes in specific behaviors. For example, areas of the cerebral cortex are involved in cognitive processes related to the perception and understanding of the environment, language and judgment. Components of the limbic system (the brain circuitry which regulates emotions) are often affected by Alzheimer’s, leaving the person with behavioral problems such as aggression, anxiety or depression. A limbic structure called the hippocampus, which is responsible for the formation of memories, is also affected, creating the memory deficits prevalent in Alzheimer’s patients.

Each of these structures receives chemical messages from a cluster of neurons deep in the brain called the basal nucleus, which is responsible for supplying the brain’s neurotransmitter acetylcholine, the chemical messenger crucial to cognition, behavior and memory. These neurons degenerate in Alzheimer’s disease, resulting in debilitating communication breakdowns in affected areas.

Under the Microscope
From a microscopic view (histopathology), there are two major deficits identified during the onset of Alzheimer’s disease. Neurofibrillary tangles are made from proteins called microtubules found inside the neuron. Microtubules have many important functions, including skeletal support of the complex neuronal processes and serving as a transport system.

In the normal brain, microtubules run parallel to each other and form highways throughout the neuron where various substances travel. These highways have cross bridges connecting them made from the protein Tau. In Alzheimer’s disease, these Tau proteins twist and cluster inside the cell, forming a major component of the neurofibrillary tangle. The microtubules can no longer function properly, resulting in cell death. Although the presence of such tangles is actually common to a minimal extent in the normal, aging brain, it is in the brains of Alzheimer’s patients where they appear in larger concentrations in areas of vulnerability associated with the disease.

Senile (Amyloid) plaques are large deposits of the protein amyloid just outside of the neuron. These plaques also increase in the normal aging brain, but in Alzheimer’s disease it appears that the number of plaques, as well as the density of the plaques, increases in proportion to the individual’s cognitive degeneration. They are found in brain regions vulnerable to Alzheimer’s especially those that regulate memory. It is not yet known if these plaques are the cause or result of the Alzheimer’s disease.

The Origins of Alzheimer’s
Current research into the causes of Alzheimer’s disease has concentrated on two distinct areas, genetics and the environment. Regardless of the cause, what is known is that overall incidents increase as one ages, to the point where an 80-year-old has up to a 30 percent chance of developing Alzheimer’s disease.

Scientists have identified Apolipoprotein E (ApoE) as a major genetic risk factor in Alzheimer’s disease. ApoE is a normal protein, which transports cholesterol in the circulatory system (www.alzheimers.org). There are three versions of the ApoE gene: ApoE2, ApoE3 and ApoE4. Every person inherits one version of the gene from each parent, and ApoE3 is the most common gene of the three.

ApoE4 gene is associated with late onset of Alzheimer’s disease (occurring after age 65). The ApoE protein is found in neurofibrillary tangles and amyloid plaques and may be involved in the collapse of the microtublules, resulting in the formation of the neurofibrillary tangles. ApoE4 gene is present in two-thirds of people with late onset and is found in both genetic and sporadic forms (www.alzheimers.org). In fact, individuals who receive the ApoE4 gene from both parents have a 95 percent chance of Alzheimer’s onset by age 80 (Munoz & Feldman, 2002).

Early onset of Alzheimer’s (prior to age 65) has been associated with changes (mutations) in the gene encoding for B-amyloid. These mutations involve increases in amyloid production (found in senile plaques) or produce longer chains of amyloid that is easier to cluster.

Since Alzheimer’s disease is not completely genetic, significant research is focused on determining what environmental factors are involved in the development of this disease. Despite early research suggesting aluminum as a risk factor, reliable studies conducted recently do not confirm this.

Research has shown that Alzheimer’s brains have inflammation, and the immune responses associated with it. Evidence supporting this theory includes the fact that people who take anti-inflammatory drugs are less inclined to develop Alzheimer’s. (Munoz & Feldman, 2002). The exact relationship between inflammation and the cell degeneration associated with Alzheimer’s has not yet been established, nor has the long-term effectiveness of anti-inflammatory drugs in battling the disease, but studies continue in this potentially promising area of research.

Fighting Back
Since Alzheimer’s disease results in a decrease in neurons, many of which release the neurotransmitter acetylcholine, several prescription drugs called "cholinesterase inhibitors" have been approved by the FDA. These inhibitors block the breakdown of acetylcholine, increasing the efficacy of the precious little acetylcholine that remains. None of the current drugs block the progression of the disease, but may slow down the behavioral symptoms caused by a loss of acetylcholine. Unfortunately, as more and more acetylcholine neurons degenerate, the effects of these drugs decrease. Currently, cholinesterase inhibitors are effective on approximately half the Alzheimer’s population, (www.alzheimers.org).

A normal neuron produces small amounts of a byproduct called oxygen-free radicals. Some research indicates that when amyloid proteins break apart they release these radicals. High concentrations of oxygen-free radicals building in the neuron result in cell death. Vitamin E is an antioxidant that fights to prevent free radicals from damaging the cell’s membrane and DNA. Since free radicals may play a role in Alzheimer’s disease, it is possible that Vitamin E, as well as other antioxidants, may help prevent the progress of the disease.

Through the Looking Glass
Alzheimer’s is a degenerative disease, meaning it will continue to kill more and more neurons until it achieves death. To date, there is no cure for this disease. Since the number of victims afflicted with Alzheimer’s is growing at alarming rates, significant research is focusing on trying to slow down or stop the degeneration. Recent advances in neuroimaging technology allowing us to visualize the living brain — such as functional magnetic resonance imaging (MRI) or the positron emission tomography (PET) with fluorodoexyglucose (FDG) — may allow us to view the brain’s dysfunction prior to the decline in the person’s behavior, which could lead to further advances in prevention and treatment.

Since each individual brain differs, these imaging techniques are not currently used as the primary diagnostic tool. Furthermore, genetic testing is being developed, but is not a common diagnostic tool for early detection, since some people may have the genes associated with Alzheimer’s, but may never get the disease.

One significant breakthrough in the study of Alzheimer’s is the progress in understanding its common acceptance as a neuropathological disease, instead of being passed off as senility or old age. Having been identified as a dementia disease of the brain, as opposed to a series of "senior moments," Alzheimer’s is now a focus of intense research with particular interest in molecular and chemical changes in the brain.

The challenge now is to find out why or how Alzheimer’s manifests itself, and then apply that knowledge to a working mechanism which can change the neuron’s fate, and subsequently the fate of the patient. Once we understand the environmental and genetic factors which trigger neuronal degeneration in specific regions of the brain, we can move forward in the treatment and prevention of this disease that threatens the premature death of millions.

• Munoz, D. & Feldman, H. Causes of Alzheimer’s Disease. CMAJ, 2002; 162(1); 65-72.

• Richie, K. & Lovestone, S. The dementias. Lancet, 2002:360; 1759-66.

• www.alzheimers.org/pubs/adpr95.html. Progress report on Alzheimer’s disease, 1995.

Dr. Kristie Reilly is the associate dean of the Nathan Weiss College of Graduate Studies. She also teaches neuroscience and anatomy for the Kean University/UMDNJ joint doctoral program in physical therapy.

A Kean alum from the class of 1991, Reilly earned her Ph.D. in neuroscience at the University of Medicine and Dentistry of New Jersey. She also studied at Yale University as part of her research dissertation with UMDNJ.