An illness, later to be named Alzheimer’s disease (AD), was first reported by the German psychiatrist Alois Alzheimer about 100 years ago (Fig. 1.1). On November 25, 1901, a 51-year-old woman named Auguste Deter (Fig. 1.2) was admitted to a municipal mental institution in Frankfurt am Main, where Alzheimer served as the department head. The letter of referral said, “The patient has suffered loss of memory, paranoia, insomnia, and a feeling of anxiety for a considerably long time. The patient is believed to be unable to deal with any kind of physical or mental labor.” It all began after Mrs. Deter strongly suspected her husband of having an extramarital affair. Her memory rapidly deteriorated thereafter. When she had to carry things, she could not remember where to carry them; therefore, she wandered back and forth in her apartment. In the end, she could not remember where to put things away, so she hid them in other places. She also had the delusion that someone was trying to kill her, so she would scream for hours. Alzheimer, who was exploring the anatomical basis of mental illnesses, felt that a “specific disease” was concealed behind the woman’s amnesia and pathological jealousy. He therefore examined her almost every day. However, she continued to become increasingly refractory to treatment; therefore, further treatment and examination became impossible. Alzheimer’s writings in the medical record ended in June 1902 with “When I try to examine Auguste Deter, she refuses, as before. She cries, shouts, and even hits me. She abruptly begins crying and often continues for several hours. So I sometimes must forcibly hold her down on the bed. She can no longer eat the meals provided to her. She has developed furuncles on her back.” Several months later, Alzheimer left the mental institution in Frankfurt. In April 1906, he received a phone call from the Munich Royal Psychiatric Hospital and learned that Auguste had died. He asked that her medical records and brain be sent to him. After suffering the disease for 4.5 years, she became bedridden and incontinent during the final days of her life. Auguste Deter died at the age of 55. Upon dissecting her brain, Alzheimer confirmed that it had atrophy, and numerous nerve cells in the cerebral cortex had disappeared. He discovered extensive neurofibrillary changes (Fig. 1.3) and senile plaques (Fig. 1.4). He concluded that these two changes comprised brain changes specific to AD. On November 3, 1906, at a meeting of the South-West German Psychiatrists held in Tübingen in southern Germany, Alzheimer presented Auguste’s case. This was the world’s first report on AD (Okamoto 2014).

In Europe at the end of the nineteenth century, dementia referred to either senile dementia or progressive paralysis. If a patient was aged, the disease was believed to be senile dementia; at middle age, the disease was considered progressive paralysis. In other words, a disease occurring in patients aged over 50 years was classified as senile dementia, a form of intellectual impairment that occurs with age. Auguste, the first known case of AD, was first examined at the age of 51. However, she was believed to have developed symptoms of disease in her 40s; thus, she would have ordinarily been diagnosed with progressive paralysis or a mental illness. Alzheimer, who was well versed in both progressive paralysis and mental illnesses, examined her symptoms, including memory disturbances, speech disruption, and a variety of other symptoms. He studied her brain after death and detected brain atrophy, senile plaques, and neurofibrillary changes. He concluded that she had a disease different from progressive paralysis or mental illness (Okamoto 2013). Emil Kraepelin named this illness “Alzheimer’s disease” and described it as a presenile dementia. He stated, “The pathological findings of the brain suggest it to be a type of severe senile dementia. In view of the fact that the patient had developed the disease in her 40s’, however, her disease cannot be said to be the same as senile dementia.” Kraepelin believed that because senile dementia occurred because of aging, there was no boundary between dementia and normal aging of the brain. The fact that the onset was early in life led him to conclude this was a special type of dementia.

It was later revealed that the brain of patients with senile dementia had senile plaques, but the degree of neurofibrillary changes and cerebral atrophy tended to be lesser. The disease progressed slowly, as did the symptoms; therefore, AD was believed to be distinct from senile dementia. However, some declared that based on clinical and pathological data, AD and senile dementia were the same clinical entity with age of onset being the only difference. Others stressed that since dementia occurs with aging, it should be categorized as a “condition,” not a disease. During the 1970s, after lengthy debates, scientists concluded that AD and senile dementia should not be considered separately but be diagnosed together as AD (Okamoto 2014).

Michael Kidd discovered paired helical filaments (PHFs) (Fig. 1.5), comprised of two twisted filaments, as the major structural component of neurofibrillary changes or tangles (Kidd 1963). To elucidate neurofibrillary changes, it was necessary to identify the structural components of PHFs. Robert Terry et al. succeeded in doing this using a biochemical strategy (Terry et al. 1964). Khalid Iqbal and Yasuo Ihara then found that this structural component was the tau protein, one of microtubule associated proteins, with abnormal phosphorylation (Grundke-Iqbal et al. 1986; Ihara et al. 1983). Inside the nerve cells, there are proteins in the form of microtubules acting as the cytoskeletal structure. Tau stabilizes microtubules by attaching and detaching itself from them by phosphorylation level. Abnormal phosphorylation causes tau protein to separate from the microtubules. Free tau protein aggregates to form a β-sheet structure that forms PHFs, leading to neurofibrillary changes. Researchers believe that this in turn destroys microtubules and nerve cells, triggering AD.

It is well known that Parkinson’s disease occurs because of a reduction in levels of the neurotransmitter dopamine. Several research groups suspected that the secretion of neurotransmitters might also be involved in causing AD; therefore, they investigated the secretion of acetylcholine, a neurotransmitter involved with memory. They found that acetylcholine secretion decreased drastically in the AD brain and observed the following: (1) reduced choline acetyltransferase activity (Bartus et al. 1982), (2) a deficit of cholinergic nerves in the basal forebrain (Whitehouse et al. 1982), and (3) a reduction in nicotinic acetylcholine receptors (Sihver et al. 1999). This led to the establishment of the “acetylcholine hypothesis,” which claims a reduction in acetylcholine is the cause of AD. If a person develops AD, neurofibrillary tangles occur at the early stages in brain regions originally containing large amounts of acetylcholine. This fact appeared to confirm the hypothesis. Supporters of this hypothesis believed that if a reduction in acetylcholine caused AD, then replenishing acetylcholine might help. They therefore attempted a method of treatment that involved supplementing with substances that are metabolic precursors of acetylcholine. They believed that since providing l-DOPA, which is converted to dopamine inside the brain, to treat Parkinson’s disease was proving successful, the same principle might also apply to AD. Unfortunately, the treatment was ineffective because other neurotransmitters, not just acetylcholine, were found to be decreased in the AD brain (Okamoto 2014). As a result, the acetylcholine hypothesis, which attracted enthusiastic support in the latter half of the 1970s, exited from mainstream research. Nevertheless, activation of acetylcholine is still considered an important strategy in the treatment of AD. A leading example is the use of inhibitors of acetylcholinesterase, such as tacrine, donepezil, galantamine, and rivastigmine.

During the 1980s, AD researchers made significant progress investigating senile plaque. Senile plaques are deposits of amyloid outside nerve cells. They are also deposited in the cerebral blood vessels of patients with AD and Down syndrome. George G. Glenner at the University of California took note of this fact. He isolated amyloid from the cerebral vascular walls of subjects with AD and those with Down syndrome, purified it, and determined its amino acid sequence. In 1984, Glenner and Wong named the peptide they discovered β-amyloid (Glenner and Wong 1984). In 1985, Konrad Beyreuther et al. in Germany also revealed β-amyloid in the nuclei of senile plaques to be the same as that which Glenner had discovered (Masters et al. 1985). β-Amyloid was found to be comprised of over 40 amino acids linked together, and senile plaques were a hardened aggregation of β-amyloid. β-Amyloid was suspected to be a fragment of an even larger protein. In 1987, a group led by Jie Kang et al. in Germany identified amyloid precursor protein (APP). APP was found to be present inside brain cells, and β-amyloid was a fragment of APP cleaved by enzymes. They also found that the APP was a transmembrane protein. Moreover it was discovered that the APP gene was on chromosome 21 (Kang et al. 1987). This identification of APP resulted in the emergence of the amyloid hypothesis, which states that AD begins when there is an abnormal increase in β-amyloid (Okamoto 2014).

APP comprises about 700 amino acids. It was found that the phenomenon which causes APP fragmentation to create β-amyloid occurs very slowly even in the normal human brain (Haass et al. 1992). However, due to genetic abnormalities or other reasons, β-amyloid may end up being produced in large amounts. This led to the emergence of the “amyloid hypothesis” which states that senile plaques result from accumulation of β-amyloid in bulk outside nerve cells; this damages nerve cells and triggers neurofibrillary tangles that in turn cause neuropathy, nerve cell death, and neurologic deficits. Dementia is hypothesized to develop as a result of this series of events (Hardy and Selkoe 2002) (Fig. 1.6). However, the role of APP in human metabolism as well as the normal action of β-amyloid was unknown (Okamoto 2014).

The amyloid hypothesis has predominated AD research due to a major discovery that helped make this hypothesis rock-solid: the discovery by John Hardy in the UK of a mutation in the APP gene. Although most AD cases are not familial, approximately 10 % are of familial onset (Okamoto 2014). Many researchers have therefore attempted to identify the causal gene of familial AD and based on this research have tried to investigate the cause of general AD that develops in old age (i.e., “sporadic AD”). Hardy studied the brains of patients with familial juvenile AD and in 1991 discovered a characteristic APP gene mutation (Goate et al. 1991; Chartier-Harlin et al. 1991). Most types of β-amyloid that deposit on senile plaques have either 40 (Aβ40) or 42 amino acids (Aβ42). The type comprising 42 amino acids is especially prone to agglutination. It was shown that if the APP gene had mutations of the type Hardy discovered, then β-amyloid with 42 amino acid sequences becomes even more prone to being cleaved, making it easier for β-amyloid to deposit and form senile plaques at an early stage. Consequently nerve cells are damaged and develop neurofibrillary tangles under these conditions. The fact that a person subject to this cascade develops dementia while still young provided good evidence to support the amyloid hypothesis (Hardy and Higgins 1992).

However, even among families with familial AD, extremely few individuals had the APP gene mutation (Okamoto 2014). Researchers continued to expand their studies, strongly suspecting the presence of other causal genes. In 1995, a gene named presenilin 1 was discovered by Peter St. George-Hyslop in Canada (Sherrington et al. 1995). This was followed by the discovery of another gene which he named presenilin 2 (Sherrington et al. 1996).

A cleavage enzyme is required at two locations to cut β-amyloid from APP. The enzyme at the first location is called β-secretase and at the second location is γ-secretase (Fig. 1.7). The two presenilins St. George-Hyslop had discovered were found to work as γ-secretases. If presenilin has a genetic mutation, it becomes liable to cleave Aβ 42. The cleavage of Aβ 42 continues to be stepped up: it accumulates, forms senile plaques, and eventually causes dementia. This process is similar to the APP genetic mutation. Therefore, mutations in the APP and two presenilin genes cause steady accumulation of β-amyloid and generate the pathology of familial AD. It was also supposed that even sporadic AD was also caused by β-amyloid accumulation as the patoent ages (Okamoto 2014). As described, the discovery of presenilin led to understanding that dementia originates with β-amyloid, further strengthening the amyloid hypothesis.

On the other hand, α-secretase which cleaves within the fragment of β-amyloid was also identified (Sisodia 1992). The α-secretase pathway is the predominant APP processing pathway. Thus, α-secretase cleavage precludes β-amyloid formation and is considered to be the non-amyloidogenic pathway of APP processing in the physiological condition (Fig. 1.7). α-Secretase is a member of the ADAM (“a disintegrin and metalloprotease domain”) family, which are expressed on the surfaces of cells. α-Secretases cleave APP to release its extracellular domain – a fragment known as APPs – into the extracellular environment (Lammich et al. 1999).