CURRENT UNDERSTANDONG OF ALZHEIMER’S DISEASE
ARTICLE
Alzheimer’s disease is characterized by two hallmark pathologies: β- amyloid plaque deposition and
neurofibrillary tangles of hyperphosphorylated tau.
Diagnosis based upon clinical presentation fulfilling several criteria as well as fluid and imaging
biomarkers.
Treatment is currently targeted toward symptomatic therapy, although trials are underway that aim to
reduce the production and overall burden of pathology within the brain.
Background About Alzheimer’s (AD)
- Alzheimer’s is the most common cause of dementia and accounts up to 80% of all dementia diagnose.
- The definitive diagnosis of AD requires post-mortem evaluation of brain tissue, though cerebrospinal
fluid (CSF) and positron emission tomography (PET) biomarkers combined with several relatively
new clinical criteria can aid diagnosis in living patients.
Evaluation
- The use of supportive biomarker evidence (imaging, serum, and CSF) of AD pathology were included
to aid in the delineation of AD from other forms of dementia as well as in the diagnosis of MCI due to
AD.
- Non-invasive diagnostic imaging: after injection of a radiolabel tracer agent, patients undergo a
specialized PET scan that detects the deposition of amyloid- β (Aβ) peptides into plaques in the living
brain.
- A more invasive but less costly evaluation involves examination of CSF for Aβ42,
hyperphosphorylated tau peptide (p-tau), and total tau protein content.
- Less-invasive serum assays designed to detect the quantity of circulating proteins implicated in AD are
currently in development and show promise.
- Another blood test that shows promise is the serum microRNA profile screen that demonstrated
validity and reproducibility in smaller trials.
Current Treatment of Alzheimer’s
* The cholinesterase inhibitors donepezil, rivastigmine, and galantamine are recommended therapy for
patients with mild, moderate, or severe AD dementia as well as Parkinson’s disease dementia.
* Memantine has activity as both a non-competitive N-methyl-D-aspartate receptor antagonist and a
dopamine agonist, is approved for use in patients with moderate-to-severe AD who show difficulty
with attention and alertness.
* Nutraceutical Huperzine A has shown benefit in both memory function and activities of daily
living. However, while huperzine A is a government-approved medication outside of the US, it is not
regulated by the US Food and Drug Administration and may be subject to fluctuations in potency and
purity.
* Vitamin D vitamin D deficiency was also identified as an independent risk factor for the
development of dementia of any cause, and supplementation is recommended for patients in whom
deficiency is diagnosed.
* Recreational physical activity increases cognitive function later in life, with benefit noted regardless of
age at the initiation of exercise. Less atrophy was observed in the brain of patients with genetic risk
factors for AD who exercised regularly compared with those who did not, suggesting that aerobic
activity prevents neurodegeneration.
, Anti-Amyloid
According to the amyloid cascade hypothesis, toxic plaques are the Currently, multiple drugs are in
earliest manifestation of disease. development which target β-site APP
Phosphorylation of tau protein, which then spreads almost infectiously cleaving enzyme 1 (BACE1), which
via microtubule transport to neighbouring neurons, leading to neuronal is though to be essential for the
death. production of Aβ peptides.
One class of medications developed using this evidence is the monoclonal
antibodies (passive immunotherapy). This type of treatment involves
injection of an antibody that targets abnormal Aβ and facilitates its
removal from the brain. No medication improved cognitive scores.
Anti-Tau
Many different tau vaccines have shown both safety and efficacy in animal models.
One recent small study, an anti-tau drug demonstrated a good safety profile and even stimulated a
positive immune response in human patients.
Neural Circuitry
Although the abnormal protein is implicated at the onset of AD, the progression of clinical symptoms
is due to more global neural network dysfunction.
Gamma oscillation, a high-frequency brainwave rhythm, is associated with inter-neural
communication in virtually all brain networks and may help to distinguish between true and false
memories.
Recently, researchers found that induction of gamma-frequency oscillations led to reduced Aβ
depolarisation and improved cognitive outcomes in an AD mouse model. This method is also currently
in early phase trials in humans, utilizing both visual and auditory stimulation.
ROLE OF NICOTINIC ACETYLCHOLINE RECEPTOR IN ALZHEIMER’S DISEASE
ARTICLE
Anatomical studies in AD patients showed a massive loss of brain white matter and a specific
reduction of cholinergic neurons of the basal forebrain.
Cholinergic System
Cholinergic neurons are organized in dense nuclei with widespread projections that entirely cover the
central nervous system. These neurons have cell bodies in the basal forebrain and send their long
projections to the neocortex and hippocampus.
A model was released in which acetylcholine (Ach) release leads to the modulation in which cortical
circulatory that finally encodes for storage of long-term memory.
Cholinergic system is also involved in attention processes.
The neurotransmitter Ach binds to two families of receptors, nicotinic acetylcholine receptors
(nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both families of receptors regulate the
cognitive processes mentioned above.
Binding studies showed a significant reduction in nicotine and Ach binding sites in cerebral cortex of
patients suffering from AD.
The enzyme choline acetyltransferase, involved in Ach production, also affected in AD. The activity
of this ChAT enzyme, and consequently the synthesis of Ach, is decreased in AD brains.
ARTICLE
Alzheimer’s disease is characterized by two hallmark pathologies: β- amyloid plaque deposition and
neurofibrillary tangles of hyperphosphorylated tau.
Diagnosis based upon clinical presentation fulfilling several criteria as well as fluid and imaging
biomarkers.
Treatment is currently targeted toward symptomatic therapy, although trials are underway that aim to
reduce the production and overall burden of pathology within the brain.
Background About Alzheimer’s (AD)
- Alzheimer’s is the most common cause of dementia and accounts up to 80% of all dementia diagnose.
- The definitive diagnosis of AD requires post-mortem evaluation of brain tissue, though cerebrospinal
fluid (CSF) and positron emission tomography (PET) biomarkers combined with several relatively
new clinical criteria can aid diagnosis in living patients.
Evaluation
- The use of supportive biomarker evidence (imaging, serum, and CSF) of AD pathology were included
to aid in the delineation of AD from other forms of dementia as well as in the diagnosis of MCI due to
AD.
- Non-invasive diagnostic imaging: after injection of a radiolabel tracer agent, patients undergo a
specialized PET scan that detects the deposition of amyloid- β (Aβ) peptides into plaques in the living
brain.
- A more invasive but less costly evaluation involves examination of CSF for Aβ42,
hyperphosphorylated tau peptide (p-tau), and total tau protein content.
- Less-invasive serum assays designed to detect the quantity of circulating proteins implicated in AD are
currently in development and show promise.
- Another blood test that shows promise is the serum microRNA profile screen that demonstrated
validity and reproducibility in smaller trials.
Current Treatment of Alzheimer’s
* The cholinesterase inhibitors donepezil, rivastigmine, and galantamine are recommended therapy for
patients with mild, moderate, or severe AD dementia as well as Parkinson’s disease dementia.
* Memantine has activity as both a non-competitive N-methyl-D-aspartate receptor antagonist and a
dopamine agonist, is approved for use in patients with moderate-to-severe AD who show difficulty
with attention and alertness.
* Nutraceutical Huperzine A has shown benefit in both memory function and activities of daily
living. However, while huperzine A is a government-approved medication outside of the US, it is not
regulated by the US Food and Drug Administration and may be subject to fluctuations in potency and
purity.
* Vitamin D vitamin D deficiency was also identified as an independent risk factor for the
development of dementia of any cause, and supplementation is recommended for patients in whom
deficiency is diagnosed.
* Recreational physical activity increases cognitive function later in life, with benefit noted regardless of
age at the initiation of exercise. Less atrophy was observed in the brain of patients with genetic risk
factors for AD who exercised regularly compared with those who did not, suggesting that aerobic
activity prevents neurodegeneration.
, Anti-Amyloid
According to the amyloid cascade hypothesis, toxic plaques are the Currently, multiple drugs are in
earliest manifestation of disease. development which target β-site APP
Phosphorylation of tau protein, which then spreads almost infectiously cleaving enzyme 1 (BACE1), which
via microtubule transport to neighbouring neurons, leading to neuronal is though to be essential for the
death. production of Aβ peptides.
One class of medications developed using this evidence is the monoclonal
antibodies (passive immunotherapy). This type of treatment involves
injection of an antibody that targets abnormal Aβ and facilitates its
removal from the brain. No medication improved cognitive scores.
Anti-Tau
Many different tau vaccines have shown both safety and efficacy in animal models.
One recent small study, an anti-tau drug demonstrated a good safety profile and even stimulated a
positive immune response in human patients.
Neural Circuitry
Although the abnormal protein is implicated at the onset of AD, the progression of clinical symptoms
is due to more global neural network dysfunction.
Gamma oscillation, a high-frequency brainwave rhythm, is associated with inter-neural
communication in virtually all brain networks and may help to distinguish between true and false
memories.
Recently, researchers found that induction of gamma-frequency oscillations led to reduced Aβ
depolarisation and improved cognitive outcomes in an AD mouse model. This method is also currently
in early phase trials in humans, utilizing both visual and auditory stimulation.
ROLE OF NICOTINIC ACETYLCHOLINE RECEPTOR IN ALZHEIMER’S DISEASE
ARTICLE
Anatomical studies in AD patients showed a massive loss of brain white matter and a specific
reduction of cholinergic neurons of the basal forebrain.
Cholinergic System
Cholinergic neurons are organized in dense nuclei with widespread projections that entirely cover the
central nervous system. These neurons have cell bodies in the basal forebrain and send their long
projections to the neocortex and hippocampus.
A model was released in which acetylcholine (Ach) release leads to the modulation in which cortical
circulatory that finally encodes for storage of long-term memory.
Cholinergic system is also involved in attention processes.
The neurotransmitter Ach binds to two families of receptors, nicotinic acetylcholine receptors
(nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both families of receptors regulate the
cognitive processes mentioned above.
Binding studies showed a significant reduction in nicotine and Ach binding sites in cerebral cortex of
patients suffering from AD.
The enzyme choline acetyltransferase, involved in Ach production, also affected in AD. The activity
of this ChAT enzyme, and consequently the synthesis of Ach, is decreased in AD brains.
