|Alzheimer > 1. Introduction to Alzheimer's Disease|
Alzheimer's disease (AD) is named after Dr. Alois Alzheimer who discovered the neurodegenerative disorder in 1906 from the brain tissue characterized by abnormal clumps and tangled filaments. In biology, abnormal clumps are referred to as "inclusion bodies" which are the aggregates of insoluble proteins. The inclusion bodies found in AD are known as amyloid plaque comprising primarily the beta amyloid (Aβ). The tangled filaments are called neurofibrillary tangles composed of Tau protein. They are the hallmarks of AD.
AD is the most common form of dementia, namely, loss of cognitive functioning (thinking, remembering, and reasoning). There are two other common forms of dementia with entirely different pathological origins. The vascular dementia results from impaired blood flow to the brain. "Dementia with Lewy Bodies" is characterized by the inclusion bodies called "Lewy bodies" that comprise mainly α-synuclein. Lewy bodies are also the hallmark of Parkinson's disease.
AD usually begins after age 60, and risk goes up with age. About 3 percent of men and women age 65 to 74 have AD, and nearly half of people older than 85 have the disease. If untreated, the patient will die due to severe brain damage. The time from diagnosis to death varies between 3 to 10 years, depending on age and other health conditions.
At present, no drug can significantly slow the progression of this devastating disease. In the past three decades, drug development was based mainly on the Amyloid Cascade Hypothesis (Hardy and Higgins, 1992) which posits that AD is initiated by aggregates of Aβ and thus Aβ should be a good therapeutic target. Unfortunately, to date, all AD clinical trials based on this idea have failed. A growing number of researchers are questioning the validity of this hypothesis (Rapoport et al., 2002; Schönheit et al., 2004; Ricciarelli and Fedele, 2017; Kametani and Hasegawa, 2018).
As mentioned above, age is an important risk factor for AD. In cognitively normal adults, the level of brain-derived neurotrophic factor (BDNF) decreases with age (Li et al., 2009). This book will explain why BDNF deficiency is prone to develop AD and other neurodegenerative disorders. More specifically, BDNF deficiency may increase total and 4-repeat Tau protein, resulting in neuronal hyperexcitability which subsequently stimulates the production of Aβ and consequently the formation of amyloid plaques. This model will be called the "BDNF Cascade Hypothesis".
Author: Frank Lee