Alzheimer

Alzheimer’s Disease (AD) is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. It has been identified as a proteopathy, a protein misfolding disease, caused by the neurofibrillary tangle and the senile plaque.1,2 The neurofibrillary tangle consists of abnormal accumulation of abnormally phosphorylated tau protein within the perikaryal of certain neurons. By other side, the senile plaques or amyloid plaques are extracellular deposits of the amyloid beta protein.2

According to the Alzheimer’s Disease International (ADI), AD is the most common cause of dementia, a brain disorder that affects memory, thinking, behaviour and emotion. It accounts for 50%-60% of all cases of dementia. The cause for most of the cases is still unknown, but there are several competing hypotheses which try to explain the cause of the disease. Some of those hypotheses are:

  • Genetic. Only 1-2% of the cases are inherited. They are known as early onset familiar Alzheimer’s disease and can be attributed to mutations in one of these three genes: Genes encoding amyloid-beta precursor protein, Presenilins PSEN1 and PSEN2.3,4
  • Osaka Mutation. This mutation was found in Japanese pedigree of familial AD and is characterized the deletion of codon 693 of APP gene, resulting in mutant amyloid beta lacking the 22nd glutamate.5
  • Cholinergic hypothesis. The oldest hypothesis. It proposes that the cause for the AD is the reduced synthesis of the neurotransmitter acetylcholine.6
  • Amyloid hypothesis. Here, the main character are the extracellular amyloid beta deposits. Thet people with trisomy 21 almost universally exhibit earliest symptons of AD, and this seems to be related with the gene for the amyloid precursor protein on chromosome 21.7
  • Tau hypothesis. In this hypothesis, the main proposal is that tau protein abnormalities initiate the disease cascade, leading to the formation of neurofibrillary tangles inside the nerve cell bodies.8
  • Inflammatory hypothesis. There are some studies which connect the misfolded amyloid beta and tau proteins, as bringing about oxidative stress that leads to chronic inflammation.9

REFERENCES

1Wenk, G. L. (2003). Neuropathologic changes in Alzheimer’s disease. The Journal of Clinical Psychiatry, 64 Suppl 9, 7–10.

2Purves, D., Augustine, G. J., Fitzpatrick, D., Hall, W. C., Lamantia, A.-S., McNamara, J. O., & White, L. E. (Eds.). (2011). Neuroscience (5a ed.). Sunderland, MA, Estados Unidos de América: Sinauer Associates.

3Tanzi, R. E. (2012). The genetics of Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 2(10), a006296–a006296.

4Kim, J. H. (2018). Genetics of Alzheimer’s disease. Dementia and Neurocognitive Disorders, 17(4), 131–136.

5Tomiyama T. (2010). Involvement of beta-amyloid in the etiology of Alzheimer’s disease. Shinkei kenkyu no shinpo [Brain and nerve], 62(7), 691–699.

6Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery, and Psychiatry, 66(2), 137–147.

7Hardy, J. A., & Higgins, G. A. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science (New York, N.Y.), 256(5054), 184–185.

8Goedert, M., Spillantini, M. G., & Crowther, R. A. (1991). Tau proteins and neurofibrillary degeneration. Brain Pathology (Zurich, Switzerland), 1(4), 279–286.

9Sinyor, B., Mineo, J., & Ochner, C. (2020). Alzheimer’s disease, inflammation, and the role of antioxidants. Journal of Alzheimer’s Disease Reports, 4(1), 175–183.

Crunkhorn, S. (2021). Predicting Alzheimer disease dementia. Nature Reviews. Drug Discovery. doi:10.1038/d41573-021-00105-8

Palmqvist, S., Tideman, P., Cullen, N., Zetterberg, H., Blennow, K., Alzheimer’s Disease Neuroimaging Initiative, … Hansson, O. (2021). Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nature Medicine, 27(6), 1034–1042.

Neitzel, J., Franzmeier, N., Rubinski, A., Dichgans, M., Brendel, M., Weiner, M., … Alzheimer’s Disease Neuroimaging Initiative (ADNI). (2021). KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease. Nature Communications, 12(1). doi:10.1038/s41467-021-23755-z

Alzheimer disease. (2021). Nature Reviews. Disease Primers, 7(1), 34.

Cullen, N. C., Leuzy, A., Janelidze, S., Palmqvist, S., Svenningsson, A. L., Stomrud, E., … Hansson, O. (2021). Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations. Nature Communications, 12(1), 3555.

Novak, P., Kovacech, B., Katina, S., Schmidt, R., Scheltens, P., Kontsekova, E., … Zilka, N. (2021). ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nature Aging, 1(6), 521–534.

de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I. E., … Ruiz, A. (2021). Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nature Communications, 12(1), 3417.

Montagne, A., Nikolakopoulou, A. M., Huuskonen, M. T., Sagare, A. P., Lawson, E. J., Lazic, D., … Zlokovic, B. V. (2021). APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nature Aging, 1(6), 506–520.

Brinkmalm, G., & Zetterberg, H. (2021). The phosphorylation cascade hypothesis of Alzheimer’s disease. Nature Aging, 1(6), 498–499.

Jaladanki, S. K., Elmas, A., Malave, G. S., & Huang, K.-L. (2021). Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types. Scientific Reports, 11(1), 12107.

Vogel, J. W., Young, A. L., Oxtoby, N. P., Smith, R., Ossenkoppele, R., Strandberg, O. T., … Hansson, O. (2021). Four distinct trajectories of tau deposition identified in Alzheimer’s disease. Nature Medicine, 27(5), 871–881.

Baglietto-Vargas, D., Forner, S., Cai, L., Martini, A. C., Trujillo-Estrada, L., Swarup, V., … LaFerla, F. M. (2021). Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology. Nature Communications, 12(1), 2421.

Martin, I. (2017). Resveratrol for Alzheimer’s disease? Science Translational Medicine, 9(375), eaam6055.

 Zarow, C., Lyness, S. A., Mortimer, J. A., & Chui, H. C. (2003). Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Archives of Neurology, 60(3), 337–341.

Mann, D. M. (1983). The locus coeruleus and its possible role in ageing and degenerative disease of the human central nervous system. Mechanisms of Ageing and Development, 23(1), 73–94.

  • Alzheimer’s Disease International (ADI)
  • Alzheimer’s Association
  • National Institute for Health Research
  • Alzheimer’s Research UK
  • John’s Hopkins School of Medicine Alzheimer’s Disease Research Center
  • National Alzheimer’s Coordinating Center (NACC)
  • National Cell Repository for Alzheimer’s Disease (NCRAD)
  • Alzheimer’s Disease Cooperative Study (ADCS)
  • Mayo Clinical Alzheimer’s Disease Research Center
  • University of Pennsylvania Alzheimer’s Disease Center
  • Yale University Alzheimer’s Disease Research Unit
  • University of California – Irvine, Alzheimer’s Disease Research Center
  • Emory University Alzheimer’s Disease Center

In the case of AD, women are more affected than men. For example, almost two-third of Americans with AD are women.1 The reason is that women live longer than men on average and the greatest factor risk for AD is the older age.2 However, when a group of men and women, with the same age, is compared, some American studies found that there are not significant differences between them in the proportion who develop the disease.3 In contrast to these results, when a similar study is carried in Europe, the results point that women are more affected than men.4 So, the risk of dementia between men and women may therefore depend on age and/or geographic region.5,6

REFERENCES

1Rajan, K. B., Weuve, J., Barnes, L. L., McAninch, E. A., Wilson, R. S., & Evans, D. A. (2021). Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020-2060). Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, (alz.12362). doi:10.1002/alz.12362

2Hebert, L. E., Scherr, P. A., McCann, J. J., Beckett, L. A., & Evans, D. A. (2001). Is the risk of developing Alzheimer’s disease greater for women than for men? American Journal of Epidemiology, 153(2), 132–136.

3Hebert, Liesi E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013). Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology, 80(19), 1778–1783.

4Fratiglioni, L., Viitanen, M., von Strauss, E., Tontodonati, V., Herlitz, A., & Winblad, B. (1997). Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology, 48(1), 132–138.

5Mielke, M. M., Ferretti, M. T., Iulita, M. F., Hayden, K., & Khachaturian, A. S. (2018). Sex and gender in Alzheimer’s disease – Does it matter? Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 14(9), 1101–1103.

6Rocca, W. A. (2017). Time, sex, gender, history, and dementia. Alzheimer Disease and Associated Disorders, 31(1), 76–79.

  • Alzheimer’s Disease is the most common cause of dementia.
  • There is currently no cure for dementia.
  • Alzheimer’s Disease kills more than breast cancer and prostate cancer combined.
  • There are around 50 million people with dementia in the world. 
  • The main risk factors are the age, genetic, gender, smoking, excessive alcohol consumption, physical inactivity, air population, head injury, less education, obesity, hypertension, diabetes, depression and hearing impairment.