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7 Stages of Alzheimer's Disease and its Symptoms

Alzheimer's disease, the most common cause of dementia, was named after Dr. Aloysius Alzheimer, a German psychiatrist and neuropathologist.1 In 1901, Dr. Alzheimer observed a 51 year female patient named Auguste Deter at the Frankfurt Asylum and described has having a peculiar cerebral cortex disease associated with dementia. Mrs. Deter later became the first person diagnosed with Alzheimer's disease. This was after Dr. Alzheimer studied her brain when she died in 1906 and identified amyloid plaques and neurofibrillary tangles. These brain anomalies became the two pathological hallmarks of Alzheimer's disease:

  • 1. Neuritic plaques containing amyloid beta (also known as Abeta or beta amyloid) protein
  • 2. Neurofibillary tangles containing aggregates of hyperphosphorylated tau protein.

Tau aggregates are also referred to as tau paired helical filaments (PHFs). PHFs are not exclusive to Alzheimer's disease and are also found in other neurodegenerative diseases such as progressive supranuclear palsy, tuberous sclerosis, and lead encephalopathy.

It is well-known that Alzheimer's disease is a progressive neurodegenerative condition associated with deterioration of cognitive skills, behavioral changes, and loss of daily living skills. The cerebral cortex atrophies, and plaques and tangles form in various parts of the brain including the temporal cortex and hippocampus. There is an accompanying loss of neurons, leading to reduced levels of neurotransmitters such as acetylcholine which is essential for learning and forming memories. The progressive loss of cognitive functioning and memory has been divided into seven stages. 3

The basic pathological causes and mechanisms of Alzheimer's disease remain to be fully elucidated. For example, we don't understand the exact mechanisms of either amyloid beta deposition in the brain leading to clumps of plaque-forming amyloid beta peptide or neurofibrillary tangle formation. Furthermore, it remains controversial as to whether plaques or tangles are primary causes of Alzheimer's or if one or the other has more of a peripheral role.

Many hypotheses 1 have been put forth to help elucidate Alzheimer's disease pathogenesis including the:

  • 1. Amyloid cascade hypothesis
  • 2. Mitochondrial cascade hypothesis
  • 3. Tau hypothesis

Accumulation of amyloid beta 42 (abeta42) peptide accumulation and deposition into neuritic plaques is the basic pathology underlying Alzheimer's disease in the amyloid cascade hypothesis. The Abeta42 peptide is formed from the amyloid precursor protein (APP) by the sequential cleavages of Beta-secretase and gamma-secretase. Abeta42 peptides are insoluble and rapidly aggregate to form oligomers, protofribils and fibrils resulting in the neuritic amyloid plaques.

The plaques cause oxidative damage and inflammation, resulting in neuronal cell death. Some familial inherited forms of Alzheimer's disease have pathogen mutations in the APP gene that increase risk for Abeta42 plaque formation. Hyperphosphorylation of tau proteins and the subsequent formation of tau aggregates are thought to be secondary to amyloid deposition in the amyloid cascade hypothesis.

Lending further support to the amyloid cascade hypothesis are persons with Down syndrome who are at risk for the early onset of Alzheimer's disease. The APP gene is located on chromosome 21 and people with Down syndrome have an extra chromosome 21. Most people with Down syndrome have the hallmarks of Alzheimer's disease pathology, amyloid-beta plaques and tau tangles, by their 40's. Many, but not all, persons with Down syndrome will develop Alzheimer's disease. Their higher risk of Alzheimer's disease is thought to be related to the extra copy of chromosome 21 which leads to increased APP production and accumulation of APP in the brain.

The mitochondrial cascade hypothesis is based on the premise that impaired mitochondrial bioenergetic function causes Alzheimer's disease. This hypothesis proposes that a reduced ability of the mitochondria to handle free radicals such as reactive oxygen species (ROS) is the key initiating step in the Alzheimer's disease.

The tau hypothesis grew out of observations that there is a lack of correlation between levels of amyloid deposits and degrees of cognitive decline. Furthermore, the amyloid cascade hypothesis does not adequately explain sporadic cases of Alzheimer's disease. The tau hypothesis proposes that the deposition of tau and formation of neurofibrillary tangles containing tau aggregates is the basic pathology underlying Alzheimer's disease and that amyloid deposition occurs secondarily.

Many other hypotheses to explain Alzheimer's disease pathogenesis have been described. However, the amyloid cascade hypothesis is the major hypothesis supported by neuropathological and genetic evidence.3

The risk of Alzheimer's disease and other forms of dementia increases with age. Aging populations and increased life spans worldwide are generating an unprecedented urgency to better understand the pathology and mechanisms of dementia in the hopes of mitigating the disease. Although age is the biggest risk factor for developing dementia, dementia is not an inevitable part of aging. Other factors include genetics, medical history and lifestyle factors.

The increasing availability of commercially available ready-to-use reagents is critical for fueling dementia research. MyBioSource is a worldwide research reagents company offering the most extensive portfolio for studying Alzheimer's disease and other forms of dementia. Products include ELISA and CLIA assays, antibodies, recombinant proteins, and tissue microarrays and genomic DNA from persons with Alzheimer's disease.

Products for research on Alzheimer's disease:

Reference

  • 1. Khan M, Ahsan F, Ahmad U, et al. Alzheimer disease: A review. 2016. WJPPS doi:10.20959/wjpps20166-7045.
  • 2. Rosenberg RR. Genomics of Alzheimer disease. 2016. JAMA Neurol. doi:10.1001/jamaneurol.2016.0301.
  • 3. Rowe JE. "I've fallen and I can't get up," a basic primer for caregivers to understand falls in persons with dementia, Alzheimer's disease, and cognitive impairment. 2015. Home Health Care Manag Pract. doi: 10.1177/1084822314559833

  • 7 Stages of Alzheimer's Disease and its Symptoms
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