Genetic Disorders - Alzheimer's Disease

Alzheimer's disease (AD) is a progressive, degenerative disease that affects the brain and results in severely impaired memory, thinking, and behavior. It is the fourth leading cause of death in adults, and the incidence of the disease rises with age. AD affects an estimated four million American adults and is the most common form of dementia, or loss of intellectual function. The U.S. Department of Health and Human Services (DHHS) estimates that 4.5 million Americans suffered from AD in 2004, and in 2002 it was the eighth-leading cause of death in the United States. AD also contributes to many more deaths that are attributed to other causes, such as heart and respiratory failure. (See Table 5.1.)

The disease was first described by the German physician Alois Alzheimer (1864–1915) in 1907 after he had cared for a patient with an unusual mental illness. Alzheimer observed anatomical changes in his patient's brain and described them as abnormal clumps and tangled bundles of fibers. Nearly a century later, these abnormal findings, now described as amyloid plaques and neurofibrillary tangles, along with abnormal clusters of proteins in the brain, are the characteristic markers of AD.

The disease knows no social or economic boundaries and affects men and women almost equally. While 90% of AD victims are over age sixty-five, AD can strike as early as the thirties, forties, and fifties. Most patients are cared for at home as long as possible, a situation that can be emotionally and physically devastating for the affected individuals and their families.

AD has become a disease of particular concern in the United States because the nation's older adult population is growing rapidly. Approximately 10% of the population over age sixty-five is afflicted with AD. This percentage rises to more than 47% in those over age eighty-five, the fastest-growing segment of our society. By 2050 the United States will have approximately 86.7 million people over age sixty-five, according to projections released by the U.S. Census Bureau in March 2004 (http://www.census.gov/ipc/www/usinterimproj/). According to the Census Bureau, the numbers of cases of AD are expected to increase by more than 12% every five years through 2015. Prevalence (the number of people with a disease at a given time) is partially determined by the length of time people with AD survive. While average survival is eight years after diagnosis, some AD patients have lived longer than twenty years with the disease. Therefore, improvements in AD care, as well as increased length of life of the older adult population in general, will increase the numbers of AD patients.

In November 1994 former president Ronald Reagan, at age eighty-three, announced that he had been diagnosed with AD and wanted to make Americans more aware of the disease. Some observers believe that it is theoretically possible that AD had affected Reagan before he left the White House in January 1989. In 2004 former president Reagan died as a result of the disease. In August 2002 another American legend, actor and activist Charlton Heston, announced that he, too, had been diagnosed with AD.

Genetic Causes of AD

AD is not a normal consequence of growing older, and scientists are continuing to seek its cause. Researchers have found some promising genetic clues to the disease. Table 5.2 shows the different patterns of inheritance, ages of onset (when symptoms begin), genes, chromosomes, and proteins linked to the development of AD. Mutations in four genes, situated on chromosomes 1, 14, 19, and 21, are thought to be involved in the disease, and the best described are PS1 (or AD3) on chromosome 14 and PS2 (or AD4) on chromosome 1. (See Figure 5.5 and Figure 5.6.)

The formation of lesions made of fragmented brain cells surrounded by amyloid-family proteins is characteristic of the disease. Interestingly, these lesions and their associated proteins are closely related to similar structures found in Down's syndrome. Tangles of filaments largely made up of a protein associated with the cytoskeleton have also been observed in samples taken from AD brain tissue.

The first genetic breakthrough was reported in the February 1991 issue of the British journal Nature. Investigators reported that they had discovered that a mutation in a single gene could cause this progressive neurological illness. Scientists found the defect in the gene that directs cells to produce a substance called amyloid protein. Researchers at the Massachusetts Institute of Technology found that low levels of the brain chemical acetylcholine contribute to the formation of hard deposits of amyloid protein that accumulate in the brain tissue of AD patients. In normal people the protein fragments are broken down and excreted by the body. Amyloid protein is found in cells throughout the body. Researchers do not know how it becomes a deadly substance in the brain cells of some people and not others.

In 1995 three more genes linked to AD were identified. One gene appears to be related to the most devastating form of AD, which can strike people in their thirties. When defective, the gene may prevent brain cells from correctly processing a substance called beta amyloid precursor protein. The second gene is linked to another early-onset form of AD that strikes before age sixty-five. This gene also appears to be involved in producing beta amyloid. Researchers believe that the discovery of these two genes will allow them to narrow their search for the proteins responsible for early-onset AD and give them clues to the causes of AD in older people. (See Table 5.2.)

TABLE 5.1
Ten leading causes of death in the United States, 2002
[Data are based on a continuous file of records received from the states. Rates are per 100,000 population specified group. Figures are based on weighted data rounded to the nearestindividual, so categories may not add to totals or subtotals.]

Ranka	Cause of death and age	Number	Rate
All agesb
…	All causes	2,447,862	848.9
1	Diseases of heart	695,754	241.3
2	Malignant neoplasms	558,847	193.8
3	Cerebrovascular diseases	163,010	56.5
4	Chronic lower respiratory diseases	125,500	43.5
5	Accidents (unintentional injuries)         Motor vehicle accidents	102,303	35.5
…		44,572	15.5
	All other accidents
…		57,731	20.0
6	Diabetes mellitus	73,119	25.4
7	Influenza and pneumonia	65,984	22.9
8	Alzheimer's disease	58,785	20.4
9	Nephritis, nephritic syndrome and nephrosis	41,018	14.2
10	Septicemia	33,881	11.7
…	All other causes	529,661	183.7
1–4 years
…	All causes	4,838	31.1
1	Accidents (unintentional injuries)         Motor vehicle accidents	1,609	10.3
…		602	3.9
	All other accidents
…		1,007	6.5
2	Congenital malformations, deformations and chromosomal abnormalities	521	3.3
3	Malignant neoplasms	401	2.6
4	Assault (homicide)	384	2.5
5	Diseases of heart	164	1.1
6	Influenza and pneumonia	107	0.7
7	Septicemia	82	0.5
8	Certain conditions originating in the perinatal period	63	0.4
9	Chronic lower respiratory diseases	62	0.4
10	In situ neoplasms, benign neoplasms and neoplasms of uncertain or unknown behavior	58	0.4
…	All other causes	1,387	8.9
5–14 years
…	All causes	7,152	17.4
1	Accidents (unintentional injuries)         Motor vehicle accidents	2,692	6.6
…		1,603	3.9
	All other accidents
…		1,089	2.7
2	Malignant neoplasms	1,061	2.6
3	Congenital malformations, deformations and chromosomal abnormalities	395	1.0
4	Assault (homicide)	342	0.8
5	Intentional self-harm (suicide)	259	0.6
6	Diseases of heart	237	0.6
7	Chronic lower respiratory diseases	118	0.3
8	Septicemia	100	0.2
9	Influenza and pneumonia	92	0.2
10	In situ neoplasms, benign neoplasms and neoplasms of uncertain or unknown behavior	86	0.2
…	All other causes	1,770	4.3
15–24 years
…	All causes	33,009	81.3
1	Accidents (unintentional injuries)          Motor vehicle accidents	15,026	37.0
…		11,303	27.8
	All other accidents
…		3,722	9.2
2	Assault (homicide)	5,070	12.5
3	Intentional self-harm (suicide)	3,932	9.7
4	Malignant neoplasms	1,728	4.3
5	Diseases of heart	948	2.3
6	Congenital malformations, deformations and chromosomal abnormalities	472	1.2
7	Human immunodeficiency virus (HIV) disease	175	0.4
8	Chronic lower respiratory diseases	172	0.4
9	Cerebrovascular diseases	163	0.4
9	Diabetes mellitus	163	0.4
…	All other causes	5,160	12.7

TABLE 5.1
Ten leading causes of death in the United States, 2002 [CONTINUED]
[Data are based on a continuous file of records received from the states. Rates are per 100,000 population specified group. Figures are based on weighted data rounded to the nearestindividual, so categories may not add to totals or subtotals.]
SOURCE: K.D. Kochanek and B.L. Smith, "Death and Death Rates for the 10 Leading Causes of Death in Specific Age Groups: United States, Preliminary2002," in "Deaths: Preliminary Data for 2002,"National Vital Statistics Reports, vol. 52, no. 13, February 11, 2004, http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_13.pdf (accessed February 7, 2005)

Ranka	Cause of death and age	Number	Rate
25–44 years
…	All causes	132,052	155.6
1	Accidents (unintentional injuries)         Motor vehicle accidents	27,454	32.4
…		13,902	16.4
	All other accidents
…		13,552	16.0
2	Malignant neoplasms	20,008	23.6
3	Diseases of heart	16,155	19.0
4	Intentional self-harm (suicide)	11,501	13.6
5	Human immunodeficiency virus (HIV) disease	7,531	8.9
6	Assault (homicide)	7,505	8.8
7	Chronic liver disease and cirrhosis	3,476	4.1
8	Cerebrovascular diseases	2,934	3.5
9	Diabetes mellitus	2,747	3.2
10	Influenza and pneumonia	1,294	1.5
…	All other causes	31,447	37.1
45–64 years
…	All causes	425,412	637.9
1	Malignant neoplasms	143,416	215.1
2	Diseases of heart	100,378	150.5
3	Accidents (unintentional injuries)         Motor vehicle accidents	21,578	32.4
…		9,522	14.3
	All other accidents
…		12,056	18.1
4	Cerebrovascular diseases	15,869	23.8
5	Diabetes mellitus	15,452	23.2
6	Chronic lower respiratory diseases	14,720	22.1
7	Chronic liver disease and cirrhosis	13,131	19.7
8	Intentional self-harm (suicide)	9,517	14.3
9	Human immunodeficiency virus (HIV) disease	5,729	8.6
10	Septicemia	5,416	8.1
…	All other causes	80,206	120.3
	65 years and over
…	All causes	1,817,095	5,103.9
1	Diseases of heart	577,353	1,621.7
2	Malignant neoplasms	392,145	1,101.5
3	Cerebrovascular diseases	143,780	403.9
4	Chronic lower respiratory diseases	109,158	306.6
5	Influenza and pneumonia	59,235	166.4
6	Alzheimer's disease	58,205	163.5
7	Diabetes mellitus	54,717	153.7
8	Nephritis, nephritic syndrome and nephrosis	34,389	96.6
9	Accidents (unintentional injuries)          Motor vehicle accidents	32,973	92.6
…		7,479	21.0
	All other accidents
…		25,493	71.6
10	Septicemia	26,688	75.0
…	All other causes	328,452	922.6
…Category not applicable.
aRank based on number of deaths.
bIncludes deaths under 1 year of age.
Note: Data are subject to sampling and/or random variation.

The third gene, known as apolipoprotein E (apoE), was actually reported as associated with AD in 1993, but its role in the body was not known at that time. Researchers have since found that the gene plays several roles. Within the body, it regulates lipid metabolism within the organs and helps to redistribute cholesterol. In the brain apoE participates in repairing nerve tissue that has been injured. There are three forms (alleles) of the gene: apoE-2, apoE-3, and apoE-4. Until recently, people with two copies of apoE-4, one from each parent, were thought to have a greatly increased risk of developing AD before age seventy. Between one-half and one-third of all AD patients have at least one apoE-4 gene, while only 15% of the general population have an apoE-4 gene. In 1998, FIGURE 5.5
Chromosome 1 and the AD4 gene related to Alzheimer's disease
SOURCE: "The AD4 Gene Maps to Chromosome 1," in "Alzheimer's Disease," Science: The Human Gene Maps 7, National Institutes of Health, National Center for Biotechnology Information, 2004, http://www.ncbi.nlm.nih.gov/SCIENCE96/gene.cgi?AD4 (accessed February 8, 2005) FIGURE 5.6
Chromosome 14 and the AD3 gene related to Alzheimer's
disease
SOURCE: "The AD3 Gene Maps to Chromosome 14," in "Alzheimer's Disease," Science: The Human Gene Maps 7, National Institutes of Health, National Center for Biotechnology Information, 2004, http://www.ncbi.nlm.nih.gov/SCIENCE96/gene.cgi?AD3 (accessed February 8, 2005) however, researchers discovered that the apoE-4 gene seems to affect when a person may develop AD, not whether the person will develop the disease.

Another newly discovered gene, A2M-2, appears to affect whether a person will develop AD. Nearly one-third (30%) of Americans may carry A2M-2, a genetic variant that more than triples their risk of developing late-onset AD compared to siblings with the normal version of the A2M gene. The discovery of A2M-2 opens up the possibility of developing a drug that mimics the A2M gene's normal function. This has the potential to TABLE 5.2
Genes for Alzheimer's disease
SOURCE: "Genes for Alzheimer's Disease," in Genetics vol. 1, A–D, Macmillan Reference USA, Gale Group, 2002

Age at onset	Inheritance	Chromosome	Gene	Protein	% AD
Early onset	AD	14	PS1	Presenilin 1	<2
Early onset	AD	21	APP	Amyloid	<20 families*
				Precursor protein
Early onset	AD	1	PS2	Presenilin 2	3 families*
Early onset	AD	?	?	?	?
Late onset	Familial/sporadic	19	APOE	Apolipoprotein E	˜50
Late onset	Familial	12p11-q13	?	?	?
Late onset	Familial	9p22.1	?	?	?
Late onset	Familial	10q24	?	?	?
Late onset	?	?	?	?	?
Age of onset: early onset: <60 years, late onset: >60 years; inheritance: AD: autosomal dominant, familial: disease in at least one first-degree relative, sporadic: disease in no other family member; chromosome: number, arm, and region; gene: designation of identified gene; protein: name of protein coded for by the gene; % AD: percent of AD caused by or * number of families identified with AD for each gene.

protect susceptible persons against brain damage or perhaps even reverse it.

Symptoms of AD

AD begins slowly. The symptoms include difficulty with memory and a loss of cognitive function (intellectual abilities). The AD patient may also experience confusion; language problems, such as trouble finding words; impaired judgment; disorientation in place and time; and changes in mood, behavior, and personality. How quickly these changes occur varies from person to person, but eventually the disease leaves its victims unable to care for themselves. In their terminal stages AD victims require care twenty-four hours a day. They no longer recognize family members or themselves, and they need help with such daily activities as eating, dressing, bathing, and using the toilet. Eventually, they may become incontinent, blind, and unable to communicate. Finally, their bodies may "forget" how to breathe or make the heart beat. Many patients die from pneumonia.

Testing for AD

A complete physical, psychiatric, and neurological evaluation can usually produce a diagnosis of AD that is about 90% accurate. For many years, the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease—tangles of fibers (neurofibrillary tangles) and clusters of degenerated nerve endings (neuritic plaques) in areas of the brain that are crucial for memory and intellect. Also, the cortex of the brain is shrunken.

In 1996 a San Francisco biotechnology firm developed a diagnostic test for AD. The test, which involves analysis of blood and spinal fluid, produced conclusive results in 60% of older patients with dementia attributed to AD.

In 2000 researchers at Brigham and Women's Hospital in Boston found that by using magnetic resonance imaging (MRI) they could measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning, and using these measurements could accurately identify people with AD and predict who would develop AD in the future. The same year other scientists at New York University Medical Center, the Mayo Clinic, and the National Hospital for Neurology and Neurosurgery in London reported using MRI to identify parts of the brain affected by AD before symptoms appear and to measure brain atrophy to monitor the progression of AD.

In early 2005 researchers Chad Mirkin and William Klein at Northwestern University announced development of yet another diagnostic test that detects small amounts of protein in spinal fluid. The test is called a bio-barcode assay and is as much as a million times more sensitive than other tests. First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid-beta-derived diffusible ligand (ADDL). ADDLs are small soluble proteins that may be indicative of Alzheimer's disease. To detect them the researchers used nanoscale particles that had antibodies specific to ADDL. The researchers' findings were reported in the February 9, 2005, issue of the Proceedings of the National Academy of Science.

Investigators continue to look at other biological markers, such as blood tests, for AD and at neuropsychological tests, which measure memory, orientation, judgment, and problem solving, to see if they can accurately predict whether healthy, unaffected older adults will develop AD or whether those with mild cognitive impairment will go on to develop AD.

Physicians and neuroscientists have long been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes. An accurate test would allow the detection of AD early enough for the use of experimental medications to slow the progression of the disease, as well as identify those at risk of developing AD. But the availability of tests raises ethical and practical questions: Do patients really want to know their risks of developing AD? Will health insurers use genetic or other diagnostic test results to deny insurance coverage?

Treatments for AD

There is still no cure or prevention for AD, and treatment focuses on managing symptoms. Medication can lessen some of the symptoms, such as agitation, anxiety, unpredictable behavior, and depression. Physical exercise and good nutrition are important, as is a calm and highly structured environment. The object is to help the AD patient maintain as much comfort, normalcy, and dignity for as long as possible.

Until 1997 tacrine (marketed as Cognex®) was the nation's only Alzheimer's medication. But in early 1997 the Food and Drug Administration approved a new drug, donepezil, to be marketed under the trade name Aricept. Both drugs are cholinesterase inhibitors, which produce some delay in the deterioration of memory and other cognitive skills. They offer only mild benefits at best, but currently they are the only alternatives available to AD patients.

By 2002 the National Institute on Aging (NIA) reported that National Institutes of Health (NIH) affiliates and pharmaceutical companies were involved in clinical trials of fifty to sixty new drugs to treat AD. All of the drugs being tested are intended to improve the symptoms of AD and slow its progression, but none is expected to "cure" AD. The investigational drugs aim to address three aspects of AD: to improve cognitive function in persons with early AD, slow or postpone the progression of the disease, and control behavioral problems such as wandering, aggression, and agitation of patients with AD.

By 2005 five prescription drugs were available to treat people who suffer from AD. Four of these—Reminyl® (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine)—are cholinesterase inhibitors and are prescribed for the treatment of mild to moderate AD. These drugs produce some delay in the deterioration of memory and other cognitive skills in some patients. They offer mild benefits at best, and may lose their effectiveness over time, but currently they are the only alternatives available to treat mild to moderate AD.

The fifth approved medication, Namenda® (memantine), is prescribed for the treatment of moderate to severe AD. It acts to delay progression of some symptoms of moderate to severe AD and may allow patients to maintain certain daily functions a little longer. It is thought to act by regulating glutamate, a chemical in the brain that, in excessive amounts, may lead to brain cell death.

Other researchers are examining the roles of the hormones estrogen and progesterone on memory and cognitive function. Since AD involves inflammatory processes in the brain, scientists are also studying the use of anti-inflammatory agents such as ibuprofen or prednisone to reduce the risk of developing AD. Researchers are also investigating the relationship between the various gene sites, particularly the mutation on chromosome 21, and environmental influences that may increase susceptibility to AD. Another NIA-funded study is trying to find out whether antioxidants, such as vitamin E, can prevent people with mild memory impairment from progressing to AD.

In 2005 the NIA and Alzheimer's Association launched the AD Genetics Study, recruiting subjects from families in which two siblings developed AD after age sixty. They hope to compare the genes of the afflicted siblings with those from another family member who does not have AD in an effort to find the genes that contribute to AD.