About Authors:
Ajay Kumar*1, Dr. Bharat Prashar2, Robin Sharma1
1M. Pharm (Pharmacology)
2Head of Pharmacy Department
Manav Bharti University, Solan.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, primarily manifesting as a loss of memory in old aged people. In this disease the destruction of neurons in the cortex and limbic structures of the CNS occurs, particularly in basal forebrain, amygdala, hippocampus, cerebral cortex.  These areas are associated with functions of higher learning, memory, reasoning, behaviour, identification, an emotional control in brain. Alzheimer's disease is a devastating disease whose recent increase in incidence rates has broad implications for rising health care costs. Clinically, patients initially present with short-term memory loss, subsequently followed by executive dysfunction, confusion, agitation, and behavioural disturbances. This review comprises aspects of the introduction, history, types, etiology, pathophysiologic mechanisms of neurological pathways of Alzheimer’s disease and the drug treatments and their target site.

Reference Id: PHARMATUTOR-ART-1448

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-β42 peptide (Aβ42). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated Tau protein.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for the majority (50 to 75%) of dementia cases in clinical and population samples [1, 2] .The clinical manifestations of AD include the progressive deterioration of episodic memory and other intellectual abilities, leading to global cognitive decline, behavioral and psychiatric symptoms and personality changes. Most AD cases begin after 65 years old (i.e. late-onset AD). However, some cases manifest in younger subjects (i.e. early-onset AD). The dementia syndrome in these patients usually begins in the 5th or 6th decade of life.

Age and low-educational status are the most important risk factors for late-onset AD[3] . Other important risk factors include the presence of the allele ?4 of the apolipoprotein E (APOE) gene, history of head trauma with loss of consciousness, life-long uncontrolled cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia), sedentary life style, life-long low cognitive demand [4]. On the other hand, early-onset AD is usually associated to genetic mutations, the most commonly described being the Amyloid Precursor Protein (APP) gene on chromosome 21, and the Presenilin 1 and 2 genes on chromosomes 14 [5].
Regardless of age of dementia onset, the neuropathological findings in AD patients are very similar. The hallmarks of AD are the presence of senile (neuritic) plaques (NP) and neurofibrillary tangles (NFT), together with neuronal loss, dystrophic neurites, and gliosis [6]. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-β42 peptide (Aβ42). Neurofibrillary tangles are intracellular lesions and are mostly composed of hyperphosphorylated TAU protein. Despite controversial findings, the progression of the clinical AD dementia syndrome correlates with the pattern of progression of these lesions in the brain [7].

AD is identified by German physician, Dr. Alois Alzheimer in the year 1906, specifically identified a collections of abnormalities in the brain cells .One of Dr. Alzheimer’s patients died after years of severe memory problems, confusion and difficulty understanding questions. Upon the death death of that patient, while performing a brain autopsy, he noted dense deposits surrounding the nerve cells (neuritic plaques) and inside the nerve cells he observed twisted bands of fibers (neurofibrillary tangles). Today, this degenerative brain disorders bears his name, and when found during an autopsy, these plaques and tangles mean a definite diagnosis of AD.

The scientists discovered another link between cognitive decline and the number of plaques and tangles in the brain in the year 1960. The medical community then formally recognized Alzheimer’s as a disease and not a normal part of aging. This attention get increased when the important discoveries and a better understanding of complex nerve cells in the brains of AD patients is led down in 1990. More research was done on AD susceptibility genes, and several drugs were approved to treat the cognitive symptoms of the disease [8].

Types of AD
Presenile or early onset Alzheimer’s disease

Researchers have directed their energies towards understanding very early stage AD, reasoning that any defects appearing early are likely to be more relevant to the true underlying cause. These efforts have borne fruit in at least two related directions.

• Researchers have noted a strong correlation between insulin resistance in the brain and early AD, suggesting that AD might be considered a neuroendocrine disorder of the brain or so-called “type 3 diabetes”[9, 10] .

• The association of AD with mitochondrial dysfunction [11].A genetic defect in mitochondrial Complex I genes is associated with a small minority (2%) of AD cases. It is noteworthy that mitochondrial defects, particularly in Complex I, have been found to be present in all major neurodegenerative diseases, not just AD, but also Parkinson's disease [12]and amyotrophic lateral sclerosis (ALS) [13,14].Mitochondrial dysfunction leads to two damaging conditions: insufficient ATP to fuel the cell's energy needs and oxidative damage due to excessive reactive oxygen species (ROS).

Senile or late onset Alzheimer’s disease
Neuronal apoptosis as more and more damage is incurred by the cell membranes, without sufficient replenishment of the supplies of fats and cholesterol to repair them, an increase in ion leakage across all membranes leads to further depletion of ATP and further exposure to pathogens and oxidative damage. Over time, the accumulated depletion of ATP leads to lysosomal dysfunction, likely because of an inability to maintain a sufficiently acidic pH for the digestive enzymes to work properly. In parallel, the further glycation and oxidation of Aβ convert it into an oligomeric complex with both decreased function and reduced susceptibility to degradation by the lysosomes. Once a sufficient percentage of the cell membrane has been compromised due to oxidative damage, it incurs rapid calcium influx and subsequent apoptosis. The protein plaques and tangles of AD are unrecyclable debris that remains in place after cell death.

Etiology of AD
Synthesis of acetylcholine is reduced in  brain[15]
Amyloid beta (Aβ) deposited in brain
Access production of Apoliopoprotien E (Apo E) in brain by glial cells
TAU Protein
Inflammatory mediators
Degeneration of cholinergic neurotransmission


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