Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease which results in a loss of mental functions due to the deterioration of brain tissue. The most common early symptom is difficulty in remembering recent events (short-term memory loss). As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioural issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years.

The cause of Alzheimer's disease is not clearly understood. About 70% of the risk is believed to be genetic with many genes usually involved. Other risk factors include a history of head injuries, depression, or hypertension. The disease process is associated with plaques and tangles in the brain. A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal aging. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise, and avoiding obesity may decrease the risk of AD. There are no medications or supplements that decrease risk. Approximately 95% of Alzheimer's is late onset (age >60-65 years) and 5% is early onset (age <65 years).

Clinical features

The typical visible symptom is progressive and chronic memory loss. Alzheimer's disease is also manifested in behavorial changes, which may include confusion, disorientation, sudden periods of defiance, abusive behavior, or violence, etc. in people who have no previous history of such behavior (rarely, an affected person experiences euphoria). Thus, Alzheimer's disease presents a considerable problem in patient management, as well. Average duration is approximately 10 years. The disease duration has been been noted to vary as very roughly half of the normal life expectancy of a healthy person of the same age as the patient in whom the Alzheimer's is diagnosed, subject to a maximum of 10 to 12 years for those diagnosed at a young age.


There are several changes found in the brain in AD.

1) The deposition of an abnormal protein outside nerve cells in the form of amyloid. These are called diffuse plaques and amyloid also forms the core of more organized plaques called senile or neuritic plaques.
2) The accumulation of abnormal filaments of protein inside nerve cells in the brain. The protein is called tau and is normally present to stabilise microtubules. In AD, an abnormally phosphorylated form of tau protein accumulates as paired helical filaments. Tau accumulates as masses of filaments inside nerve cell body termed neurofibrillary tangles. inside nerve cell processes in the brain termed neuropil threads. inside nerve cell processes that surround amyloid plaques - termed plaque neurites.

3) Amyloid accumulation in the walls of small blood vessels in the brain. Termed amyloid angiopathy (also called congophilic angiopathy)
4) Diffuse neuropathology, nerve cells and their processes including synapses die and are lost from key brain regions. This results in atrophy of the affected areas and enlargement of the ventricles.
5) Loss of synaptic contacts between neurons. May be related to the regulation of cell adhesion proteins by presenilins. The presenilins have been identified as part of the processing apparatus that produces the amyloid beta protein. Also-- see bottom of page Role of Microglial cells and Complement System.

There is also regional involvement of gross atrophy, and enlarged ventricles in the brain. Massive synaptic and dendritic loss is expected. The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.


Amyloid hypothesis
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age. ] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease. One study found possible evidence of human to human transmission.

Tau Hypothesis

The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.

Role of Microglial Cells and Complement System -- Beth Stevens group shows evidence that complement and microglia are involved much earlier than previously thought in the disease process, when synapses are already vulnerable. Researchers also found that beta-amyloid protein, C1q (complement system) and microglia work together to cause synapse loss in the early stages of Alzheimer's. In the Alzheimer's mouse models, Stevens team showed that synapse loss requires the activation of a C1q, which "tags" synapses for elimination. Immune cells in the brain called microglia then "eat" the synapses -- similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed. A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences -- (founded by Ben Barres). The researchers believe it has potential to be used to protect against synapse loss in a variety of neurodegenerative diseases.


Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein, and tau protein in the brain.[94] Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Aβ is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

Inflammation and Alzheimer's

Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression. Use of ibuprofen pain relievers like Advil and Motrin for more than five years reduced Alzheimer's risk by 44% in a study reported in the May 2008 issue of Neurology.


There are currently 5 drugs approved for Alzheimer's, (Aricept, Razadyne, Namenda, Exelon and Namzaric). The last drug to be approved -Namzaric- was in 2014. The current Alzheimer's drugs only mask the symptoms but do not treat the underlying disease or stop or delay the cell damage that eventually leads to the worsening of symptoms. The treatment of Alzheimer's disease will require addressing the pillars of pathogenesis, namely, the advent and spread of neurotoxic oligomeric aggregates of beta-amyloid, the production of tau tangles, and chronic local inflammatory responses in the brain.

Pipeline Therapies in Alzheimer's

Targeting Beta-Amyloid--Beta-secretase drugs and monoclonal antibodies to target to target beta-amyloid---Beta Secretase inhibitors (BACE) Eli Lilly and Co.'s solanezumab, and CNP520 from Novartis. NPT088 from NueroPhage which allows the compound to universally recognize and disrupt the shape of misfolded proteins and target them for degradation through the body's natural mechanisms.

Targeting Tau Tangle - Vaccines to target tau protein. Among these possible breakthroughs---NPT088, therefore, has potential, because it has demonstrated ability to prevent the formation of and disrupt existing toxic aggregates of amyloid beta, tau and alpha-synuclein, leading to functional benefits in animal models.

Targeting Inflammation -- Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene.

BACE inhibitors from merck -- The drug in this study, MK-8931, is a BACE inhibitor, which means it helps stop the BACE enzyme from producing amyloid beta peptides. Amyloid plaque deposits in the brain may be the underlying cause of Alzheimer's disease. By inhibiting the actions of the BACE enzyme, it may in turn help stop the formation of those amyloid plaque deposits.

Curcumin -- Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. see references below.

Readings and References

Alzheimer Disease Overview

Late-Stage Drug Pipeline Holds Hope for Alzheimer's Treatments

Treatment Horizon -- Research Center

10 Things You Want To Know About Alzheimer's Drug Research

A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

Curry Derivative J147 Beats Aricept for Alzheimer's

Turmeric-Derived Compound Curcumin May Treat Alzheimer's

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

The roles of inflammation and immune mechanisms in Alzheimer's disease

Complement and microglia mediate early synapse loss in Alzheimer mouse models

The Rogue Immune Cells That Wreck the Brain