Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain that is progressive, irreversible and typically characterized by development of abnormal memory loss, along with deterioration of other higher cognitive abilities, including language, judgement, and perception. Behavioral and psychiatric manifestations can also occur during the disease's course. AD is the most common form of dementia accounting for approximately 70% of all adult cases in industrialized countries.2 It is estimated that four million people in the U.S. are affected by AD and that by the middle of this century as many as 14 million could also be affected.¹

AD is a progressive and disabling disorder, eventually leading to death - it is the fourth leading cause of death for adults over the age of 65 in the U.S.³ The course is typically described as a period of slow-onset followed by a period of further functional decline, which can range from one to 20 years, with an average survival of eight to 10 years after diagnosis.²

At autopsy the brains of AD patients exhibit atrophy and neuronal loss. In addition, they contain two pathological hallmarks, which together are confirmatory of the disease: senile (neuritic) plaques and neurofibrillary tangles. Senile plaques consist of a core of ß-amyloid protein (formed from Aß42 protein), glial processes, and dystrophic neurites. Neurofibrillary tangles are intraneuronal structures formed from paired helical filaments, which are composed of abnormally phosphorylated tau proteins, wound together in a double helix.³

Risk factors for AD include age, Down syndrome, family history, and ApoE genotype. In demented individuals, the most prevalent known genetic risk factor for AD is Apolipoprotein E (ApoE) genotype. ApoE is a susceptibility gene that contributes to the risk of developing AD after age 65 in demented individuals. Three alleles of ApoE exist: e 2, e 3, and e 4. A demented patient harboring two ApoE e 4 alleles has a 91% chance of developing AD by age 80, whereas a demented patient harboring one e 4 allele presents a 47% chance of developing the disease by age 80.⁴ ApoE genotyping is useful both as an adjunct to help confirm a suspected clinical diagnosis of AD, as well as a tool to help differentiate AD from atypical presentations of dementia.⁵ In addition to the ApoE gene, there are three autosomal dominant genes for AD (presenilin-1, presenilin-2, and amyloid precursor protein gene) that account for many of the early onset (<60 years old) cases of the disease.

Two proteins, Aß42 and tau, in the cerebrospinal fluid (CSF) have been shown, when used together, to be biomarkers of Alzheimer's disease. Aß42 is a free-floating protein in the CSF; in AD patients it accumulates in the central nervous system and forms amyloid plaques in the brain. Abnormally phosphorylated tau protein is the main component of neurofibrillary tangles. Based on a number of studies, elevated levels of tau protein and low levels of Aß42 protein in the CSF are diagnostic of AD. ^5,6,7

AD patients are typically diagnosed three-and-a-half to five-and-a-half years after symptoms develop.⁸ Although the symptoms can be treated, earlier diagnosis of AD may facilitate the management of this, as of yet, incurable disease. These biochemical markers are useful early in the course of the disease, when drug therapy can be most effective, but the clinical diagnosis is difficult.

With the advent of symptomatic treatment for cognitive symptoms of AD, and as drugs are developed to slow the progression of AD, very early diagnosis is important to define the earliest window of opportunity to apply such treatments.⁶

Early and accurate diagnosis "has important implications for prognosis and anticipatory guidance for the caregiver, as well as treatment and management of the patient."⁹

Learn more about Alzheimer's Disease.

1. Statistics/Prevalence. Alzheimer's Association. www.alz.org/facts/rtstats/htm. 1999.
2. Geldmacher, D.S. and Whitehouse, P.J. Evaluation of Dementia. New England Journal of Medicine 1996; 335(5):330-336.
3. Rossor, M. Primary Degenerative Dementia. In Neurology in Clinical Practice, 3rd ed., Vol II, ed. W.G. Bradley et al., 1703-1720. 2000. Boston: Butterworth-Heinemann.
4. Corder, E.H. et al., Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families. Science 1993; 261:921-923.
5. Consensus Report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease." The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiology of Aging 1998; 19(2):109-116.
6. Galasko, D. et al., High Cerebrospinal Fluid Tau and Low Amyloid ß42 Levels in the Clinical Diagnosis of Alzheimer Disease and Relation to Apolipoprotein E Genotype. Archives of Neurology 1998;55:937-945.
7. Andreasen, N. et al., Cerebrospinal Fluid ß-Amyloid(1-42) in Alzheimer Disease. Archives of Neurology 1999; 56:673-680.
8. Ernst, R.L. and Hay, J.W. The US Economic and Social Costs of Alzheimer's Disease Revisited. American Journal of Public Health 1994; 84(8):1261-1264.
9. Chui, H. and Zhang, Q. Evaluation of dementia: A systemic study of the usefulness of the American Academy of Neurology's Practice Parameters. Neurology 1997; 49:925-935.