The History of Alzheimer’s Disease, Its Symptoms and Dangers

Abstract

Alzheimer’s disease is a progressive, multifactorial, neurodegenerative disorder manifested by memory and cognitive dysfunction, behavioral disturbance, progressive impairment of activities of daily living. Alzheimer’s disease is associated with the spreading of misfolded protein aggregates in the brain. However reduction in brain volume in Alzheimer is caused by “deposition of a special substance in the cortex” as firstly described by Alois Alzheimer. The resulting plaque found in extracellular space in AD brain and present in hippocampus region is also known as senile plaques. From a rare disease it has reached the top 8 of major health problems in the world. Alzheimer's disease affects 46. million people worldwide in 2015 and it has been estimated that it get double in every year. Between 2000 and 2017, reported death resulting from AD was increased by 145% which is more than the number of death caused from stroke, prostate cancer, heart disease. This review highlights the APP proteolytic cleavage by secreatase enzyme that leads to the formation of Aβ peptide. In addition, various types of carrier system and strategies to deliver drug into the brain is also included.

History of AD

In 1873, Augste Deter married to Karl Deter when she was 23 years old. Then she moved to Frankfurt with her husband. In March 1901, Auguste started showing uncontrollable behavior like accusing Karl, couldn’t write properly, loss of memory, confusion in speech, improper conversation, insomnia and agitation. Karl hospitalized his wife and a doctor declared that she could not work anymore because of several such symptoms. As recommended by doctor Auguste was admitted into Frankfurt mental hospital on November 25th 1901. However, the medical expenses were too much for karl. Alzheimer and karl made a mutual agreement of handing over all the medical reports and brain of Auguste after her death in exchange Auguste was continuously treated in Frankfurt mental hospital. Alzheimer handled Auguste case and explained her symptoms such as local neurological symptom, progressive cognitive disorder, hallucination, psychological social disability and delusion. Later, Franz Nissl who was a Geman psychiatrist and medical researcher joined Alzheimer’s research group. He was excellent in staining neurons.

They started working in collaboration. In the summer of 1902, Kraepelin invited Alzheimer to work with him in his research. Alzheimer agreed with his proposal and moved to Heidelberg immediately. The patient died 4 years after Alzheimer left Heidelberg. Auguste’s brain tissue was sent from Frankfurt to Munich on April 8th 1906. As per agreement, Alzheimer obtained her brain and medical records. Alzheimer carefully investigated Auguste’s case and found abnormal changes in her brain like deposition of Senile plaques in neurons, tangles were found in nerve fibers and the brain part controlling memory, judjement, thinking was severely impaired. On November 3rd 1906, Alzheimer publicly explained that the strange abnormal symptoms of Auguste’s cerebral cortex. Alzheimer declared the biopsy result of her brain in the 37th psychiatry conference of southwestern Germany held in Tubingen. One year later he published a research paper that included all those result explaining Auguste brain’s condition. After three years of his hard work he died on December 19th 1915 at the age of 51 due to heart failure by endocarditis and kidney failure. He is now remembered for his remarkable contribution to the field of modern neuropathology. Emil Kraepelin is acknowledged as the father of scientific psychiatry.

Introduction

Alzheimer’s disease (AD) is a slowly progressing neurodegenerative disorder associated with a progressive loss of cognitive function that leads to dementia. According to the ‘‘cholinergic hypothesis’’, impairment of cholinergic function in the brain especially in areas dealing with learning, memory, behaviour and emotional responses that include the neocortex and the hippocampus majorly contribute to AD symptoms. Brain atrophy is the most obvious clinical finding in AD in which the levels of a neurotransmitter, acetylcholine (ACh) which is responsible for the conduction of electrical impulses from one nerve cell to another nerve cell, are decreased due to its rapid hydrolysis by acetyl cholinesterase (AChE) enzyme. According to ‘‘amyloid hypothesis’’ AChE produces secondary non-cholinergic functions that include promotion in beta-amyloid (Ab) deposition in the form senile plaques/neurofibrillary tangles in the brain of afflicted individuals. 46. million people were suffering from dementia worldwide in 2015; this number is expected to almost double every 20 years. Approximately 5–8% of individuals over age 65, 15–20% over age 75, and 25–50% over age 85 are affected by dementia. Women are more susceptible than men to suffer from AD, because of their higher life expectancy, and because the decrease in estrogen levels due to menopause could increase the risk of developing AD. The atrophy results from the degeneration of synapses and the death of neurons, in particular in hippocampus.

It is the most common form of adult-onset dementia and is the fourth leading cause of death in the United States. Commonly observed cognitive changes in AD include not only impairments in memory, but also disturbances in language use, perception, the ability to learn necessary skills, solve problems, think abstractly, and make judgments. The uncommon case of a 51-year-old patient who was suffering from memory loss, disorientation, hallucinations and cognitive impairment. After the death of the patient, post-mortem examination showed an atrophic brain with “striking changes of the neurofibrils” and “minute military foci” caused by the “deposition of a special substance in the cortex”.

Pathological features that accompany AD include amyloid plaques (APs) and neurofibrillary tangles in the brain parenchyma, although the mechanisms of their formation and their specific roles in the progression of this disease are not yet clear (Hardy, 1997). Amyloid β1-42, a major component of amyloid plaques, binds with exceptionally high affinity to the K7 nicotinic acetylcholine receptor and aggregates intracellularly in neurons of Alzheimer's disease brains.

Specifically, cells involved in the CNS immune response includes microglia, astrocytes, and dendritic cells that have been shown to be detected through receptors such as Toll like receptor generating reactive oxygen species (ROS) and pro-inflammatory cytokines. As is produced, it happens increased IFN-IF, IL-1β, IL-6 and TNF-α), which contribute to neuronal death. Therefore, other therapeutic strategies for AD are imperative and may include the administration of anti-inflammatory agents and drugs that decrease the production and increase the clearance of the amyloidogenic A β peptide and prevent the phosphorylation and aggregation of tau protein.

Drug discoveries continue to be made in plentiful numbers but even though these novel therapeutic molecules give good results in the early phase of drug development, they often fail to successfully clear subsequent clinical trials, owing in part to their inability to cross the BBB. CNS market is underperforming and the major reason for this is the inability of drugs to cross the BBB. However, this also provides the opportunity for researchers to develop novel formulations for CNS disorders.

Stages of Alzheimer’s disease

Alzheimer's disease is the commonest cause of dementia and is rarely seen below the age of 50. The disease may be classified based on the age of onset into early-onset AD and late-onset AD. Early onset AD accounts for approximately 1%-6% of all cases and manifests roughly between 30 and 60 years. Late onset from accounting for around 90% of cases has an age at onset later than 60 years. The distinctive histopathological features of abundant neocortical senile plaques and neurofibrillary tangles are found both in young and in old patients, and hence it is no longer usual to make a distinction between presenile dementia in patients below 65 and senile dementia of Alzheimer type in the older patient.

AD disease is classified as different stages according for amyloid deposits and neurofibrillary changes- The first two stages I and II (Transentorhinal stages), are characterized by either mild or severe alteration of the transenthorinal region. In this stage the mild-temporal cortex, as well as other isocortical areas, is free of neurofibrillary changes. Stages III and IV (limbic stage) are characterized by the severe involvement of the enthorinal and transenthorinal region, while the isocortex gradually becomes mildly affected. Stages V and VI (Isocortortical stage) are marked by the severe occurrence of neurofibrillary changes in the isocortex.

Stage A- In this stage, deposition of low density amyloid in the basal portion of the isocortex is started.

Stage B- In this stage, Amyloid deposition in virtually all isocortical association areas, while the hippocampal formation in mildly involved.

Stage C- It is the last stage, all area of the isocortex including sensory and motor core fields by the deposition of amyloid plaque.