Table of Contents

I. Introduction
• Background of Alzheimer’s disease (AD)
• Prevalence of AD
II. Pathophysiology of AD
• Definition of dementia
• Early symptoms of AD
• Brain changes associated with AD
• Beta-amyloid plaques
• Tau tangles
• Microglia activation
III. Treatment strategies for AD
• Current treatments: AChEIs and NMDA receptor antagonists
• Limitations of current treatments
• Disease-modifying therapies
IV. Conclusion

Alois Alzheimer first described Alzheimer’s disease in 1906 at a conference in Tubingen, Germany. Since its first documentation, many aspects of AD pathophysiology have been discovered and understood, however, gaps of knowledge continue to exist. Alzheimer’s disease (AD) is a degenerative brain disease and the most common cause of dementia 1.

Dementia affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment. Research suggests that AD-associated brain changes start long before symptoms appear. Initially, brain compensates for the changes, enabling individuals to continue to function normally. With significant neuronal damage, the brain becomes unable to compensate for the changes and individuals show subtle cognitive decline followed by memory loss or confusion as to time or place. Later still, basic bodily functions such as swallowing are impaired. Approximately 200,000 people younger than 65 years with AD comprise the younger-onset AD population; 5 million are age 65 years or older. It is expected that by 2050, one new case of AD is expected to develop every 33 s, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million 2. Several hypotheses have been put forward to explain this multifactorial disorder 3.However, to understand the disease it’s important to understand the brain changes which are associated with AD. A healthy adult brain has about 100 billion neurons, and their connection point with other neurons are called synapses which are 100 trillion in number. Information flows in tiny bursts of chemicals that are released by one neuron and detected by a receiving neuron. Synapses allow signals to travel rapidly through the brain’s neuronal circuits. They create the cellular basis of memories, thoughts, sensations, emotions, movements and, skills. The two changes in the brain which have been recorded in AD are (called beta-amyloid plaques) and protein tau (called tau tangles). Beta-amyloid, which is a protein fragment gets accumulated outside neurons and an abnormal form of tau protein accumulates inside the neurons. The neuron-to-neuron communication at synapses is interfered because of beta-amyloid plaques leading to cell death. While tau tangles block the transport of nutrients and other essential molecules inside neurons 4. Due to the presence of toxic beta-amyloid and tau proteins, immune system cells in the brain called microglia gets activated. Microglia try to clear the toxic proteins and when it can’t keep up with the cleaning process it leads to chronic inflammation. AD being a progressive disease early intervention would offer the best chance of slowing the progression. Earlier beginning of AD was defined by dementia symptoms and confirmation was only possible by estimating levels of beta-amyloid and tau in the autopsy brain. However, due to the development of biomarkers, revised diagnostic guidelines were published by the National Institute on Aging (NIA) and the Alzheimer’s Association in 2011. Beta-amyloid PET imaging accurately reflects levels of amyloid deposits (called neuritic plaques) in the brain. While elevated levels of beta-amyloid detected via PET cannot be used in clinical practice to conclusively diagnose the disease, they give clinicians reason to conduct additional Alzheimer’s testing. To aid in the diagnosis of AD three amyloid PET radiotracers florbetapir, flutemetamol and florbetaben are currently approved by U.S. FDA. Elevated cortical tau shown with PET imaging is a biomarker for neurofibrillary tangles. FDG-PET imaging showing reduced glucose metabolism and structural MRI showing atrophy are biomarkers for neurodegeneration. Few promising neuroimaging biomarkers along with CSF/Blood biomarker are under investigation. In 2016 Jack et al 5 proposed a descriptive classification for patients based on the presence or absence of three key factors: Aβ (A), NFTs (T), and neurodegeneration (N), to be complemented by cognitive evaluation. The A/T/N classification system is not an individual diagnostic tool, but rather a biomarker classification scheme that allows the description and characterization of a wide range of patients, based on specific biomarkers.

The currently available treatment strategies include AChEIs (acetylcholinesterase inhibitor) and NMDA (N-methyl D-aspartate) receptor antagonists 6. Though many drugs are under trial only four drugs donepezil, galantamine, rivastigmine and memantine are currently approved for the treatment of AD. First three drugs act on central nervous system (CNS) cholinergic pathways and have anticholinesterase activity. Galantamine, a natural-product alkaloid is also active as an allosteric modulator at nicotinic acetylcholine receptors. Memantine is the recently approved drug and targets the N-methyl-D-aspartate (NMDA) receptor and glutaminergic pathways 7,8 that target symptoms at its best. Early clinical trials for approved AD drugs are insufficient to provide useful guidelines for clinical practice. Safety and efficacy of the drugs in the long-term (for example, greater than six months) are not clear and they contribute least in modifying the primary pathological processes involved in AD. However, the drugs provide symptomatic relief and are generally administered as palliative therapy with the aim of slowing the decline in quality of life. In order to modify the disease process novel strategies have been developed. The major target is Ab and tau-based therapeutics, which is a major key to unlock this disease in the near future. Disease-modifying therapies demand complete knowledge about the various metabolic pathways which includes the production of Ab from APP, in vivo clearance and pathophysiological events that lead to fibril formation and deposition into plaque 9.

Despite the immense knowledge regarding this complex and multifactorial disease, there is a dearth of disease management options. Currently available drugs for the treatment, unfortunately, target symptoms only. New discoveries contributing to the elucidation of the molecular pathogenesis of AD and its relations are crucial. Also, the development of new therapeutic strategies which act at the root level of the disease is the need of the hour, where current drug therapy lacks the ability to prevent occurrence and progression of AD. References

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