Alzheimer’s Disease

By Sarika Garg

Alzheimer’s disease (AD) is named after German psychiatrist and pathologist Dr. Alois Alzheimer. In 1907, he published an account of a 51-years old female patient, Auguste D from Frankfurt, who suffered from strong feelings of jealousy towards her husband, increased memory impairment, disorientation, hallucinations, and often loud and aggressive behaviour. After four and a half years of rapidly deteriorating mental illness, Auguste D died in a completely demented state. Postmortem histological analysis of her brain using the Bielschowsky silver technique revealed dense bundles of unusual fibrils within nerve cells (neurofibrillary tangles or NFTs) and numerous focal lesions within the cerebral cortex, subsequently named as ’’senile plaques’’.

Alzheimer’s disease is a devastating neurodegenerative disorder. It is an irreversible, progressive and fatal brain disease. It is neither infectious nor contagious, but it is the single most common form of dementia, a term used to describe a general decline in all areas of mental ability. The symptoms are deterioration in cognitive processes- memory, language, thinking and so on- with important repercussions on behaviour. About 50 per cent of the people with dementia suffer from Alzheimer’s disease, about 20 per cent from vascular dementia (caused by blockages in the supply of blood to the brain), and about 20 per cent from Lewy body dementia (characterized by tiny spherical deposits in the brain). The risk of getting Alzheimer’s disease increases as one gets older (beyond age 65). By age 85, about 35 out of 100 people have some form of dementia. Alzheimer’s disease is the ninth leading cause of death. It is estimated that more than 60 per cent of people with dementia live in developing countries, however, by 2040, it is expected to rise by 71 per cent.

Studies have supported the notion that 70 to 80% of the risk to develop Alzheimer’s disease is determined by genetic factors. Alzheimer’s disease is not a single-gene disorder. Genetically, Alzheimer’s disease (AD) is a complex and heterogeneous disease involving mutations and polymorphisms in multiple genes on several chromosomes. The two basic types of Alzheimer’s disease are: the late sporadic AD (SAD) and the early familial AD (FAD). The SAD represents the vast majority of cases whose aging itself is the unique important risk factor known. The apolipoprotein E (APOE) gene located on chromosome 19q13.2 has been confirmed unequivocally as a risk gene. Its ε4 allele increases the susceptibility to SAD whereas its ε2 allele confers protection against the late onset of AD. Besides cases arising sporadically, epidemiological studies indicate that about 30% of AD patients have a family history of disease and at least one first-degree relative is affected, however, only a few of them have a clear autosomal dominant inheritance. The FAD starts before 60 and accounts for less than 1% of the total number of AD cases. It is associated with gene mutations on chromosomes 1, 14, and 21. Only 5% of the amyloid precursor protein (APP) mutations have been estimated for FAD. Most of the FAD cases are caused by mutations in two genes namely presenelin 1 (PSEN1) and presenelin 2 (PSEN2). In AD, no mutation has been identified in the gene, MAPT which codes for Tau protein. However, more than 40 exonic and intronic mutations in MAPT present on chromosome 17q21.1, have been found in a familial dementia related to AD, and in the frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).   

The actual causes of Alzheimer’s disease are not yet known with certainty. Alzheimer’s disease is not related to problems of the circulatory system. However, pathologically, Alzheimer’s disease is a progressive neurodegenerative disorder characterized by two main types of protein aggregation, intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (SPs). The NFTs consist of paired helical filaments (PHF) resulting from the hyper-phosphorylation of the microtubule-binding protein Tau. Senile plaques are principally composed of extracellular amyloid-ß (Aß) depositions. The amyloid cascade hypothesis posits that Aß triggers Tau pathology, but details of this relationship are poorly understood. However, there has been surprisingly scant attention focused on Tau as a therapeutic target. Advances in generating animal models with Tau pathology are helping to erase this deficit.

Fig.: Pathological hallmarks of Alzheimer’s disease. Extracellular plaques contain deposits of a protein fragment called ß-amyloid and tangles are twisted fibers of protein called Tau. Plaques build up between nerve cells and tangles form inside dying cells. The plaques and tangles tend to form in a predictable pattern, beginning in areas important in learning and memory and then spreading to other regions. The plaques and tangles contribute to the degradation of the neurons in the brain and is a central feature associated with Alzheimer’s disease.

References:

http://www.ahaf.org/alzheimers/about/understanding/plaques-and-tangles.html

Alzheimer, A., Stelzmann, R.A., Schnitzlein, H.N., Murtagh, F.R., 1907. Uber eine eigenartige Erkankung der Hirnrinde. Allg Zschr f Psychiatr Psychisch-Gerichtl Mediz. 64, 146-148.

Beers, M. H., Jones, T. V., 2004. The Merck manual of health & aging. Whitehouse Station, NJ: Merck Research Laboratories.

Bertram, L., Tanzi, R.E., 2005. The genetic epidemiology of neurodegenerative disease. J Clin Invest. 115(6), 1449-1457.

Braak, H., Braak, E., 1997. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging. 18, S85-S88.

Delacourte, A., Sergeant, N., Champain, D., Wattez, A., Maurage, C.A., Lebert, F., Pasquier, F., David, J.P., 2002. Nonoverlapping but synergetic Tau and APP pathologies in sporadic Alzheimer's disease. Neurology. 59(3), 398-407.

Gatz, M., Pedersen, N.L., Berg, S., Johansson, B., Johansson, K., Mortimer, J.A., Posner, S.F., Viitanen, M., Winblad, B., Ahlbom, A., 1997. Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci. 52(2), M117-M125.

Giacobini, E., 2000. Cholinesterase inhibitors stabilize Alzheimer's disease. Ann N Y Acad Sci. 920, 321-327.

Glenner, G.G., Wong, C.W., 1984. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 120(3), 885-890.

Haass, C., Selkoe, D.J., 2007. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 8, 101-112.

Hardy, J., Selkoe, D.J., 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.

Mandelkow, E.M., Mandelkow, E., 1998. Tau in Alzheimer’s disease. Trends Cell Biol. 8, 425-427.

McGowan, E., Eriksen, J., Hutton, M., 2006. A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet. 22(5), 281-289.

Simchowicz, T., 1911. Histologische studien uber der senile demenz. Nissl-Alzheimer Histologische histopathologische. Arbeiten. 4(2), 267-444.

Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al., 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 375(6534), 754-760.

Tanzi, R.E., 1999. A genetic dichotomy model for the inheritance of Alzheimer's disease and common age-related disorders. J Clin Invest. 104(9), 1175-1179.

Waldemar, G., Dubois, B., Emre, M., Georges, J., McKeith, I.G., Rossor, M., Scheltens, P., Tariska, P., Winblad, P., 2007. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol. 14(1), e1-e26.

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