In 2005, 13.8% of Japanese people were under age 14, 66.1% were between ages 15 and 64, and 20.1 percent were over age 65. These percentages are predicted to become 8.6%, 51.8%, and 39.6% in 2050 (from Latest Demographic Statistics). Therefore, in 2050, every person at the productive age of 15–64 years will have to support one elderly person (currently, every three people support one elderly person). Furthermore, data shows that one out of every four elderly people over age 85 has dementia. This means that understanding and treatment of the causes of dementia will be a major issue for the 21st century.
Dementia is detected when there are changes in personality, such as when a gentle person suddenly becomes bad tempered, and by changes in behavior, such as when a person claims that things have been stolen, repeatedly makes the same comments, and repeatedly buys the same items. This disease is caused by a sudden decrease in neurons. Dementia is classified into a type that occurs as a stroke after-effect or after a head injury, and a type that has other causes. The latter type of dementia is called Alzheimer's disease.

Fig. 6-11. Senile Plaque in the Brain of an Alzheimer's Disease Patient

Alzheimer's disease was first reported in 1907 by the German neurologist A. Alzheimer, who detected a characteristic pathological finding in the brain of a woman in her early 50's exhibiting dementia (Fig. 6-11). Silver staining of the brain shows miliary foci outside of neurons, which is characteristic of Alzheimer's disease patients. These deposits are called senile plaques and consist mainly of amyloid β protein (). Silver staining also reveals twisted filaments inside the neurons. These filaments are called neurofibrils and consist mainly of the phosphorylated microtubule protein tau. This early stage of Alzheimer's disease is accompanied by mild cognitive disorder and atrophy of the brain. Five percent of dementia cases are familial, while other cases are individual cases associated with age.
Aβ, the main component of senile plaques, is cleaved from the amyloid precursor protein (APP) (Fig. 6-12). There are mainly two types of this protein: readily soluble Aβ40 consisting of 40 amino acids, and poorly soluble Aβ42 consisting of 42 amino acids. Large amounts of Aβ42 accumulate around Aβ40 and form senile plaques.

Fig. 6-12. Formation of Amyloid β Protein (Aβ)

APP is expressed in almost all organs, but Aβ does not accumulate in the body because the main pathway of APP metabolism does not accumulate amyloid. Since the breakpoint of Aβ is at its center, Aβ does not accumulate. In the brains of Alzheimer's disease patients, however, β-secretase catalyzes APP and produces a 99 amino-acid membrane-bound peptide in the first step. This peptide includes Aβ in its amino-acid sequence. Then another enzyme, γ-secretase (consisting of the four protein complexes presenilin, nicastrin, Pen2, and Aph1), cuts Aβ out from this peptide.
Alzheimer's disease occurs when amyloid accumulates in the brain over a very long period of time, a bias toward these accumulation pathways is thought to increase Aβ production and cause Aβ to be deposited in the brain. Furthermore, it is now clear that the causative genes of familial Alzheimer's disease are APP, presenilin 1, and presenilin 2. These are enzymes and proteins involved in the above pathways.
At the same time, the polymorphism apolipoprotein E gene (ApoE) is now under scrutiny as a cause of dementia associated with age in most cases in the world. This protein is present in blood and transports lipids. ApoE consists of 299 amino acids, and there are polymorphisms in the 112th and 158th amino acids. Apolipoprotein is called E2 when the 112th and 158th amino acids are both cysteine, E3 when the 112th amino acid is cysteine and the 158th amino acid is arginine, and E4 when both amino acids are arginine. Almost everyone has one of these three types of apoliprotein. The human genotype is divided into six types: E2/E2, E2/E3, E3/E3, E2/E4, E3/E4, and E4/E4. Among these types, E4/E4 carries the highest risk of Alzheimer's disease, followed by E3/E4.
The genetic frequency of E4 among the Japanese population is 0.08; therefore, the frequency of E2 + the frequency of E3 = 0.92, and the frequency of homozygous E4 Japanese people is 0.082 = 0.0064. The frequency of Japanese people who are heterozygous and who have E4 is 2 x 0.92 x 0.08 = 0.147, which is about one out of seven people. Furthermore, the frequency of E4 is higher in Caucasians than in Asians.


A Drug that Increases Intelligence?

Drugs are essential for our lives, but can also cause various problems. Glucose and nicotine increase concentration, and glucose makes us feel revitalized after we eat sweets. Nicotine causes a smoker's head to become clear after he or she smokes tobacco. Caffeine in coffee also increases concentration.
Drugs for improving memory are already being used for humans. A well-known example is Ritalin (methylphenidate), which was originally used to treat attention-deficit hyperactive disorder (ADHD). This drug binds strongly to dopamine transporter molecules at nerve terminals and is thought to increase mental concentration by changing the function of dopamine. Ritalin is used for people with depression, and has been known to cause addiction.
Other drugs are approved as effective for improving concentration, such as Aricept (Donepezil) for treatment of Alzheimer's disease and Modafinil for treatment of narcolepsy, a disease that causes people to spontaneously fall asleep even in the middle of the day. These drugs are approved for patients, but are problematic because it is uncertain whether they are effective for healthy people or whether they have adverse effects.
Many people approve of drugs that improve memory, but not drugs that degrade memory. If a drug that degrades memory is abused, precious memory will be lost, and it will be possible to control minds at whim. On the other hand, such drugs can be used to treat post-traumatic stress disorder (PTSD). However, it is uncertain whether unpleasant memories can be selectively erased. It is undesirable to erase memories unrelated to unpleasant memories, or to erase pleasant memories. After all, it is only natural to think there is something strange about the very idea of using a drug to improve intelligence. It is also important to realize that all drugs have the possibility of causing side effects. In the end, drugs used to change intellectual functions are only symptomatic treatments, and their range of application is limited.

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