Alzheimer’s Disease

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One of the key functions of the nervous system is storing information in the form of memory. This information is stored in the form of memory tracks that are formed inside the brain. Neurons and their cellular processes are involved in the process of forming memories and retrieving them.

Neurodegenerative diseases are a group of disorders in which the neurons that are functionally related to one another are progressively lost. The loss of neurons impairs one of the key functions of the brain.

Alzheimer’s disease is a neurodegenerative disease that impairs the memory retrieval system of the brain. It is the most common cause of dementia (memory loss) in adults. The symptoms of dementia progress with age. Other symptoms are also seen in the patient as the disease progresses.

In this article, we will discuss the pathophysiology of Alzheimer’s disease, the morphological changes found in the brain, and factors that can cause it. We will also discuss biological markers that can help us diagnose Alzheimer’s as well as the clinical features of the disease.


Neurodegenerative diseases are characterized by the accumulation of protein aggregates in different parts of the nervous system. These protein aggregates may arise from a mutation in the protein synthesis or due to defective processing and clearance of proteins. The same is seen in Alzheimer’s disease.

Alzheimer’s disease is marked by the accumulation of two proteins in different areas of the brain. These are Amyloid beta (Aβ) protein and tau protein. The aggregates of these proteins are formed either due to abnormal and excessive synthesis or defective removal.

In this section, we will talk about the method by which these protein aggregates are formed and how they contribute to the clinical features of Alzheimer’s disease.

Role of Amyloid-beta (Aβ) Protein

Amyloid beta (Aβ) is a small portion of a larger protein called Amyloid precursor protein (APP). It is a cell surface protein that may function as a receptor for prion protein (PrP). Amyloid beta (Aβ) forms the portion of APP that extends from the extracellular region into the transmembrane domain of the protein.

The processing of APP involves cleavage of the extracellular domain as well as an intramembranous cleavage. The Amyloid beta (Aβ) portion of Amyloid precursor protein has three sites for cleavage;

  • Alpha-Secretase (in the middle of Aβ sequence)
  • Beta-Secretase (at the N-terminal of Aβ sequence)
  • Gamma-Secretase (at the C-terminal of Aβ sequence)

Amyloid beta (Aβ) is not generated if the cleavage occurs at the alpha-secretase site. The alpha-secretase enzyme cuts within the (Aβ) sequence of the protein.

However, if the APP is endocytosed, it undergoes intramembranous cleavage at the beta-secretase site. During this cleavage, the Amyloid beta (Aβ) is cut at the N-terminal, generating an intact Aβ segment.

Gamma-secretase enzyme cause cleavage of Aβ at the C-terminal. If it is paired with alpha-secretase cleavage, a soluble fragment is formed that can be removed easily. However, if it is paired with beta-secretase cleavage, an insoluble Aβ peptide fragment is formed.

The length of the Aβ fragment varies because of alteration in the location of the site where the gamma-secretase enzyme acts.

The Aβ peptide fragments thus formed join together to form oligomers. These oligomers than form the Aβ fragments seen in Alzheimer’s disease.

Plaques Formation

Amyloid-beta Plaques and Tau

Plaques are the aggregates of Aβ peptides that are found in the parenchyma of the brain as well as around some brain blood vessels. The Aβ peptide consists of 40-42 amino acids and is regarded as a misfolded protein that aggregates to form plaques having β-pleated configuration. These plaques are considered to be neurotoxic and cause the degeneration of neurons.

The aggregation of Aβ plaques is the major cause of cognitive impairment seen in Alzheimer’s disease.

Disease Progression

The Aβ fibrils thus formed are considered to be toxic proteins that can trigger the degeneration of neurons seen in Alzheimer’s disease. The accumulation of Aβ fibrils within the neurons acts as a signal for activating the apoptosis pathway.

Besides, certain evidence exists about the accumulation of Aβ fibrils within the mitochondria of neurons. Here, these fibrils disrupt the action of certain enzymes and prevent the utilization of glucose by neurons. This factor can also contribute to the auto-degeneration of neurons.

Role of tau Protein

Tau is a protein associated with microtubules; a component of the cytoskeleton. This protein is abundantly found in the axons of neurons as they have abundant cytoskeletal components. In its phosphorylated form, tau protein serves to stabilize the microtubules found in the cytoskeleton. The microtubules are essential to maintain the structure of the cellular processes as well as the transport of nutrients and other biological molecules between the cell body and the axons.

In Alzheimer’s disease, tau protein becomes hyperphosphorylated. The hyperphosphorylated form is unable to bind to the microtubules. Instead, the abnormal tau proteins begin to bind together forming neurofibrillary tangles.

The neurofibrillary tangles of tau protein are seen inside the neurons. They increase the tangle burden on the brain.

Disease Progression

The exact mechanism by which these tangles can cause degeneration of neurons is still unknown. However, there are two hypotheses.

  • The aggregates of tangles increase the stress on neurons. The stress response may cause neuronal degeneration
  • The microtubules are no longer stabilized by the tau protein. These tangles disturb the transport system of the neurons. The neurons may undergo degeneration due to defective transport of the nutrients.

It is also found that the defective tau protein blocks the function of its normal counterpart.

Interplay of Plaques and Neurofibrillary Tangles

Recall that plaques are formed by aggregates of Aβ peptides while neurofibrillary tangles are due to defective tau protein accumulation. Both these signs are considered as the pathological hallmarks of Alzheimer’s disease.

The interplay of these two aggregates is seen in Alzheimer’s disease. There are some neurodegenerative diseases in which tangles are seen but Aβ deposits are not found. This suggests that tau aggregates in the brain are not sufficient stimulus to initiate the Aβ deposits. However, it is seen that mutations that lead to the formation of Aβ deposits also result in the formation of neurofibrillary tangles of tau protein.

Thus, the mutations that cause Aβ deposits are more likely to cause Alzheimer's disease.

Inflammatory Response

Any injury to a cell or a foreign invasion causes an inflammatory response. The purpose of the inflammatory response is to protect the body from further harm. But in some cases, it can cause more trouble. The same is seen in Alzheimer’s disease.

The Aβ aggregates cause an inflammatory response by the glial cells found in the brain. These include microglia and astrocytes. This inflammatory response primarily assists in clearing the protein aggregates but also results in the release of inflammatory cytokines and other mediators of inflammation. These compounds are considered to have a role in neurodegeneration.

The inflammatory cascade may also cause oxidative injury to the neurons. It may also interfere with the phosphorylation of tau protein.

Cause of Cognitive Impairment

Cognitive Impairment

Cognitive impairment is defined as a change in the brain that affects the person’s ability to think, reason, recall, and learn. Permanent cognitive impairment that progresses with the disease is seen in patients with Alzheimer’s disease.

Cognitive decline in Alzheimer’s is due to the accumulation of large amounts of Aβ plaques and neurofibrillary tangles that impair the normal functioning of neurons. The vascular abnormalities caused by these plaques are considered to be the major cause of the cognitive impairment of patients.

Morphological Changes

As we have understood the various pathological factors that contribute to Alzheimer’s disease, let us now continue our discussion and study how the brain looks like in this disease. In this section, we will be discussing the morphological changes that are seen in the brain of patients with Alzheimer’s.

Gross Changes

When viewed with the naked eye, the brain of patients shows a varying degree of cortical atrophy, depending on the stage of the disease they are in. The cortical atrophy is characterized by the widening of the sulci more prominently on the frontal, parietal and temporal lobes.

As the brain volume decreases, the ventricles become enlarged. Hydrocephalus develops with the progressing cortical atrophy. Structures in the medial temporal lobe like the hippocampus and amygdala are involved earlier. Severe atrophy of these structures is seen in the later stages of the disease.

Microscopic Changes

The major microscopic changes seen in Alzheimer’s disease are neuritic plaques and neurofibrillary tangles. We have already discussed a lot about how these abnormal aggregates are formed. Here, we will only focus on their histology.

Neuritic Plaques

These are the spherical collection of dilated neuritic processes around an amyloid core. These plaques are often surrounded by microglia and astrocytes. The size of the neuritic plaques varies from 20 to 200 micrometers. They are mainly found in the hippocampus, amygdala, and neocortex of the brain.

The amyloid cores of these plaques can be seen after staining with Congo red stain. It contains abundant abnormal protein, Aβ being the major component. Other proteins that are found in the plaques include proinflammatory proteins, components of the complement cascade, alpha-1-antitrypsin, etc.

Sometimes, the Aβ peptides deposit within the brain and are not surrounded by the neuritic processes as in the neuritic plaques. These deposits are termed as diffuse plaques. They are mostly seen in the early stages of plaque formation in the superficial areas of the cerebral cortex, basal ganglia, and cerebellar cortex. They have the same characteristic amyloid staining as seen in the neuritic plaques.

Neurofibrillary Tangles

These are the fibrillar structures visible inside the cytoplasm of neurons with an H&E stain. They become more prominent when viewed using a silver staining technique. These tau-containing fibrillar networks often displace the nucleus of neurons or surround it.

These tangles are mainly seen in the cortical neurons as well as neurons of the hippocampus, amygdala, and basal forebrain. They are insoluble and remain in the tissue sections of the brain even after the death of parent neurons.

Cerebral Amyloid Angiopathy

It is another morphological feature accompanying Alzheimer's disease. It results from the Aβ peptides deposits in the walls of medium and small-sized cerebral vessels. The amyloid deposits weaken the wall and can cause cerebral hemorrhage. Due to the cerebral amyloid angiopathy, several small hemorrhages are often seen in patients with Alzheimer’s disease.

Although cerebral amyloid angiopathy can be seen in non-Alzheimer patients, it is an invariable accompaniment of Alzheimer’s disease.


The cause of Alzheimer’s is still unknown. However, several hypotheses exist about the following factors being a cause of this disease.

Genetic Factors

Studies involving twins and families have found that some genetic basis exists for Alzheimer’s disease. In most of the hereditary cases, it shows an autosomal-dominant inheritance. It is considered that Alzheimer's tends to run in families.

Other Factors

Other environmental factors also exist that can have some correlation with Alzheimer’s. It might arise due to a spontaneous mutation causing formation and aggregation of the Aβ peptides, due to mutations in the tau protein, or due to some inflammatory causes.

It must be kept in mind that the exact cause of Alzheimer’s is not known yet.

Stages of Disease

Alzheimer’s is a progressive disease that becomes worse with the age of the patient. Based on the clinical features, the disease is said to have four stages.

Pre-Dementia Stage

The initial symptoms of the disease are often ignored and mistaken as some other mild conditions. This preclinical stage is also known as mild cognitive impairment. It is often difficult to distinguish this stage from normal aging.

These symptoms include forgetting things at some times, misplacing things, and then forgetting about them, not remembering the exact details of an event, short-term memory loss, etc. Sudden depressive symptoms are also seen.

Early Stage

The impairments seen in the pre-dementia stage progress leading to the eventual diagnosis of the disease. In the early stage, the memory capacities of the person start deteriorating.

Older memories are less affected than the new memories. The person starts forgetting names of family or friends, language problems are seen with less fluency in the speech, movement coordinations are absent when performing fine motor tasks. These changes are noticeable by family members and friends.

Moderate Stage

In the early stage, patients can perform tasks independently with little supervision. However, as the disease progresses, cognitive impairment causes them to depend on others for daily activities.

Patients have trouble remembering their location, they cannot recall recently learned things or recent events, are often confused by trivial events, and also have problems with sleep.

Delusional symptoms also develop. The patients also have anger attacks. They may also develop urinary inconsistency.

Advanced Stage

The disease worsens and the patient cannot live without caregivers. The patients have very poor ability to think, speech problems eventually resulting in complete loss of speech, and inability to perform even simple tasks.

The patients in this stage become more aggressive, abusive, and paranoid. However, apathy and exhaustion are also present.


The diagnosis of the disease is based on the correlation between the signs and symptoms of the disease. It involves identifying the current cognitive stage of the patient and correlating it with the biological hallmarks of the disease.

The biomarkers of the disease are the Aβ deposits in brian that can be demonstrated by some imaging techniques. This can also identify Alzheimer’s in patients who are still asymptomatic or are in the pre-dementia stage.

Besides, the increased presence of phosphorylated tau and the Aβ in the CSF is also considered an important biomarker of Alzheimer’s disease.


Alzheimer’s is a neurodegenerative disease that is the number one cause of dementia associated with age.

It is characterized by deposits of amyloid plaques and neurofibrillary tangles in the brain.

The amyloid plaques consist of the Aβ peptides. These are generated by the cleavage of the Amyloid precursor protein via beta and gamma-secretase enzymes. The Aβ peptides join to form fibrils that ultimately form the amyloid core of plaques.

These plaques signal the auto-degeneration of neurons via apoptosis.

Neurofibrillary tangles consist of hyperphosphorylated tau protein. The protein normally stabilizes the microtubules found in the cellular processes of neurons. The abnormal variant of tau protein fails to bind to the microtubules. Rather, it binds to other tau proteins forming neurofibrillary tangles.

These tangles disrupt the nutrient transport system of neurons and can cause their degeneration.

The gross morphological changes include atrophy of brian characterized by widening of sulci and the ventricles of the brain.

The microscopic changes include;

  • Accumulation of neuritic plaques surrounding the amyloid core
  • Accumulation of tangles inside the neurons containing tau protein aggregates
  • Cerebral amyloid angiopathy due to amyloid aggregates in the vessel walls

The clinical features of the diseases are divided into four stages;

  • Pre-dementia stage with mild symptoms before diagnosis
  • Early-stage with symptoms leading to the diagnosis
  • Moderate disease with worsening symptoms
  • Advanced stage with full-blown symptoms causing dependence on others

The diagnosis involves correlating the symptoms with the laboratory findings. The imaging techniques can help in the early diagnosis of Alzheimer’s disease.


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