Alzheimer’s—The Most Dreaded Age-Related Disease

It can be argued that among the various illnesses associated with aging, including osteoarthritis, osteoporosis, cancer, diabetes, cardiovascular disease and Parkinson's disease, none is more dreaded than Alzheimer's disease. The affected patient suffers a progressive loss of cognitive awareness and his or her independence, and eventually dies, usually within three to nine years after diagnosis.¹ 

Alzheimer's disease causes the mind to slowly vanish, leaving an empty shell of a person behind. More troubling, even after years of research, there remain more questions than answers about Alzheimer's disease. This is not surprising, since the brain is the most complex structure in the universe and there is still much to be learned about its function. While research continues, it is troubling to know that Alzheimer's disease may be inevitable for many people. This article is intended to enhance understanding of the disease by briefly describing its history, incidence, symptoms, diagnosis, etiology and current and possible future treatment.

History

The disease that bears his name was first discussed by Alois Alzheimer, MD, (1864-1915) at a 1906 psychiatry meeting in Tubingen, Germany. He described a peculiar brain abnormality in one of his patients who died of an unusual mental illness that included progressive cognitive impairment, focal symptoms, hallucinations and delusions. The autopsy revealed a thinner cerebral cortex than commonly seen in the elderly, together with tangled bundles of fibers (now called neurofibrillary tangles) and abnormal clumps (now called amyloid plaques). He described the latter as extracellular deposits of a neurotoxic substance. During his presentation, Alzheimer made the assertion that the patient's dementia was likely due to these lesions. His speech was followed by publication of his findings the following year under the title "A characteristic serious disease of the cerebral cortex."² The importance of this patient's case marked the beginning of Alzheimer's disease research. The term "Alzheimer's disease" was coined by Emil Kraepelin in 1910 and first appeared in print in his book, the Handbook of Psychiatry.³ An excellent description of the clinical and histopathological findings of Alzheimer's patients was published in The Lancet in 1997.⁴

Incidence

As mentioned above, the principal risk factor for Alzheimer's disease is age. It is a specific disease that affects about 6% of the population over 65 years of age. The incidence doubles every five years after that age, with an annual diagnosis of 1,275 new cases per 100,000 people older than 65.⁵ The odds of being diagnosed with Alzheimer's disease after 85 years of age exceed one in three. As the elderly population increases, prevalence in the US will approach 13.2 million to 16 million cases by mid-century.⁶

Description and Symptoms

Alzheimer's disease is a chronic, progressive, neurodegenerative disorder characterized by three primary groups of symptoms. The first group (cognitive dysfunction) includes memory loss, language difficulties and loss of higher level planning and intellectual coordination skills. The second group comprises psychiatric symptoms and behavioral disturbances. The third includes difficulties in performing activities of daily living, e.g., driving, shopping, eating, unaided. The symptoms progress from mild memory loss to very severe dementia. Increasingly, the coexistence of vascular disease and Alzheimer's is being recognized clinically, pathologically and epidemiologically.⁷ Alzheimer's disease is irreversible. It slowly destroys memory and cognitive skills, and even the ability to carry out the simplest tasks.⁸

Diagnosis

A diagnosis of Alzheimer's disease is most commonly made by an individual's primary care physician. The physician obtains a medical and family history, including psychiatric history and history of cognitive and behavioral changes. Ideally, a family member or other individual close to the patient is available to provide input. The physician also conducts cognitive tests and physical and neurologic examinations. In addition, the patient may undergo magnetic resonance imaging (MRI) scans to identify brain changes that have occurred so the physician can rule out other possible causes of cognitive decline. ⁹

Etiology

Although scientists do not know how the Alzheimer's disease process begins, it appears likely that damage to the brain starts a decade or more before problems become evident. During the preclinical stage of the disease, people are symptom-free, but toxic changes are taking place in the brain. Abnormal deposits of proteins form amyloid plaques and neurofibrillary tangles (tauopathies) throughout the brain and once-healthy neurons begin to work less efficiently. (The major component of the tangles is an abnormally hyperphosphorylated and aggregated form of tau.¹⁰) Over time, neurons lose their ability to function and communicate with each other and eventually die. The damage begins in the entorhinal cortex (a sliver of tissue behind the ears, toward the middle of the brain). It spreads to a nearby structure in the brain, the hippocampus, which is essential in transforming daily experiences into lasting memories. As more neurons die, affected brain regions begin to shrink significantly.⁸ Many molecular lesions have been detected in patients with Alzheimer's disease, but the overarching theme to emerge from the data is that an accumulation of misfolded proteins in the aging brain results in oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction.¹ The molecular mechanisms of the disease are extremely complicated and many of the factors leading to amyloid deposition and tauopathy in humans are unknown.¹ It has, however, become clear that Alzheimer's disease develops because of a complex series of events that take place over a long period of time. It is also likely that the causes include some mix of genetic, environmental and lifestyle factors.

Treatment

Because Alzheimer's disease is complex, current treatment and research approaches focus on helping patients maintain mental function, managing behavioral symptoms and attempting to slow or delay eventual memory loss. Four medications have been approved for treatment. Donepezil, rivastigimine and galantamine are used to treat mild to moderate conditions. Donepezil can also be used for severe cases. Memantine is used to treat moderate to severe Alzheimer's. These drugs work by regulating neurotransmitters. They may help maintain thinking, memory and speaking skills, and address certain behavioral problems. The drugs, however, do not change the underlying disease process and may help for only a limited time.⁸ Drugs and other supportive treatment are used to manage other common symptoms including sleeplessness, agitation, wandering, anger and depression.

Fortunately, there are methods, in addition to a physical examination, to detect Alzheimer's before other symptoms are apparent. The gold standard for detecting neurofibrillary tangles and beta amyloid plaques is a radiotracer, 18 F-FDDNP, a molecule that binds both lesions, and positron emission tomography. This technique developed by researchers at the University of California at Los Angeles makes it possible not only to detect but also to measure both types of lesions in the brains of living Alzheimer's patients.¹¹ The technique may be particularly useful in tracking the effectiveness of interventions designed to delay the onset of dementia symptoms and eventually prevent the disease.¹²

Final Thoughts

New research focuses on clearing amyloid fragments from the brain. Scientists have known that a gene (ApoE) acts to degrade such proteins and the search is on to find a drug that can switch on this gene. One such drug, bexarotene, used for skin cancer, has this property. When it was fed to mice with Alzheimer's-like symptoms, it quickly improved their cognitive, social and olfactory functions. It, of course, is a long way from being an approved Alzheimer's drug,¹³ but this has not stopped patients and their families from clamoring for it.¹⁴

References

1. Querfurth HW, LaFerla FM. "Alzheimer's disease." N Eng J Med. 2010;362(4):329-44.
2. Alzheimer A. "Uber eine eigenartige Erkrankung der Hirnrinde." Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtliche Medizin. 1907;64:146-8.
3. Kraepelin E. Psychiatrie: Ein Lehrbuch fur Studierence und Arzte. Leipzig: Barth, 1910;593-632.
4. Mauer K et al. "Auguste D and Alzheimer's disease." Lancet. 1997;1546-49.
5. Hirtz D et al. "How common are the 'common' neurological disorders." Neurology. 2007;68:326-37.
6. Hebert LE et al. "Alzheimer disease in the US population: prevalence estimates using the 2000 census." Arch Neurol. 2003;60:1119-22.
7. Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009 5 February;338:b158. doi: 10.1136/bmj.b158.
8. Alzheimer's Disease Fact Sheet. National Institutes of Health website. http://www.nia.nih.gov/print/alzheimers/publication/alzheimers-disease-fact-sheet. Accessed 4 February 2012.
9. Alzheimer's Association. 2011 Facts and Figures.
10. Liu L et al. "Trans-synaptic spread of tau pathology in vivo." PLoS ONE. 2012;7(2):e31302.
11. Op cit 8.
12. Op cit 1.
13. Ibid.
14. Op cit 8.
15. SNM press release. Society of Nuclear Medicine website. http://interactive.snm.org/index.cfm?PageID=2601&RPID=627. Accessed 15 February 2012.
16. Small GW et al. "Prediction of cognitive decline by positron emission tomography of brain amyloid and tau." Arch Neurology. 2012;69(2):215-222.
17. Naik G. "New attack on Alzheimer's." Wall Street Journal. 10 February 2012.
18. Wang SS. "Alzheimer's families clamoring for drug." Wall Street Journal.. 11 February 2012.

Published on regulatoryfocus.org, February 2012. Copyright © 2012 Regulatory Affairs Professionals Society.