In Japan, one of the fastest-aging countries in the world, an estimated 1 in 4 people over the age of 65 has dementia or mild cognitive impairment. And Alzheimer’s, the most common form of dementia, accounts for about two-thirds of all cases in the nation.

The condition could affect a family member, a neighbor — or even you someday.

But it’s not all doom and gloom.

New Alzheimer’s disease drugs lecanemab and donanemab, which help slow the progression of the disease by clearing the brain of a harmful protein, were approved in Japan in 2023 and 2024, respectively.

Though far from being a cure, they offer more hope that better tools to fight the disease will emerge in the near future.

In fact, many researchers are working hard to better understand, prevent and treat dementia, while community-level initiatives to make life easier for those living with the condition are gaining ground.

Ahead of World Alzheimer’s Day on Sunday, known in Japan as Dementia Day, The Japan Times asked four scientists at the forefront of dementia research what progress they have made, and what kind of future they envision for people with the condition.

The brain’s immune cells

At Kyoto University, Kimitoshi Kimura studies immune cells called microglia, dubbed the “guardians of the brain” for their role in constantly monitoring the brain and eating away dead or dying cells.

In research published in Nature in April, he discovered that removing a protein called TIM-3 would make microglia more active and prevent the clumping of amyloid beta — a hallmark of Alzheimer’s.

Lecanemab and donanemab, which remove plaques of amyloid beta, have attracted much attention. But side effects such as brain swelling and bleeding remain a big concern.

A possible drug based on TIM-3 could be used with lecanemab to reduce the risk of side effects, Kimura says, noting that the removal of TIM-3 can clear out amyloid beta while containing inflammation.

Given that TIM-3 is an immune checkpoint molecule, acting as a “brake” for immune responses, its removal could raise the chance of the immune system losing control and overworking, at least in theory.

But Kimura says studies on mice have shown no signs of immune system overreaction, and that no major side effects have been reported in clinical trials involving cancer patients, in which TIM-3-removing antibodies are being tested.

The success of amyloid beta-targeting therapies hinges on how soon treatment can start, Kimura says. Alzheimer’s disease is believed to develop when the amyloid beta protein clumps together to form plaques. It is followed by abnormal tangles of tau protein in nerve cells.

“Research suggests that, once the condition worsens to a point where tau tangles happen, nothing works,” he says. “So it’s important to take action before the abnormal taus develop.”

In May, U.S. regulators approved the first blood test to help diagnose Alzheimer’s for people age 55 and older who show signs and symptoms of the disease. Reports say Fujirebio Diagnostics, a unit of Japan’s H.U. Group Holdings that obtained the U.S. approval, will file for regulatory approval of the test in Japan by the end of the year. If approved, it would make Alzheimer’s tests less expensive and less invasive here as well.

Currently, patients must get a specialized PET scan or take a cerebrospinal fluid test to detect amyloid beta in the brain.

Kimura foresees a future when people will take such blood tests as part of their routine health checkup, making detection and prevention of the disease possible even before memory problems begin.

He is also eager to find other proteins that control microglia.

“We discovered the work of TIM-3 by chance, but there should be other ideal substances that work as a switch for the disease,” Kimura says. “I feel we have discovered just 50% of the mechanism of microglia and its key players.”

Mood disorders

Doctors have long observed that depression and other mood problems in older adults may be an early warning sign of dementia. A team including Keisuke Takahata of the National Institutes for Quantum Science and Technology recently made the connection clearer by scanning patients with a new PET imaging agent.

The researchers compared the scanned brain images of people over age 40 with depression or bipolar disorder and those of healthy people, finding that the former were 11 times more likely to have abnormal amyloid buildup and 4.8 times more likely to have abnormal tau accumulation than the healthy group.

The results suggest that, when people over 40 develop mood disorders, some of them may be caused by the abnormal buildup of proteins linked to dementia.

PET technologies are also advancing to help diagnose forms of dementia other than Alzheimer’s. Last year, researchers discovered how a protein called alpha-synuclein builds up in the brains of people with Parkinson’s disease and Lewy body dementia.

“By scanning tau, amyloid and alpha-synuclein through PET, it is becoming possible to detect most types of dementia, not just Alzheimer’s, in early stages,” Takahata says, noting that protein accumulation precedes memory problems and other symptoms by more than 10 years.

Like Kimura, Takahata envisions a future in which people will get an early diagnosis and treatment for dementia. He also sees potential for drugs targeting tau. Numerous clinical trials for tau-targeting therapies are underway worldwide, though most are still in early stages of drug development.

“Since it took 20 years for drugs targeting amyloid to be developed, tau-targeting therapies could take time as well,” he says. “But our technologies will play a key role when such drugs become available, as it is important to evaluate the tau buildup in the brain and then the drugs’ effects on lowering it.”

Familial Alzheimer’s

In May, Kyoto University’s Center for iPS Cell Research and Application (CiRA) and generic drug manufacturer Towa Pharmaceutical started a final-stage clinical trial to treat familial Alzheimer’s disease with bromocriptine, a drug currently used for Parkinson’s disease.

It was the first time a drug candidate discovered through special stem cells called induced pluripotent stem (iPS) cells has reached the final stage of a clinical trial.

Haruhisa Inoue, who leads the study at CiRA, explains that the team tested bromocriptine on disease neurons made from iPS cells derived mostly from blood cells of actual patients with the disease. This way, researchers can test the efficacy and safety of the drug on cells that retain the genetic information of individual patients, without having to rely on animal studies.

He says that cognitive decline was seen in 20% of people who took bromocriptine and 67% in those who took a placebo during early stages of a trial involving eight people conducted between 2020 and 2022.

Behavioral and psychological symptoms, such as excitement, depression and anxiety, were not observed in any of the participants taking bromocriptine, while 33% of those who took a placebo experienced such symptoms, according to Inoue.

A common side effect of bromocriptine is nausea, but the drug does not cause the kind of brain inflammation that lecanemab can cause because it uses a different mechanism to attack the same amyloid beta protein, he says.

“What’s most important, we can create cells directly from patients and, from there, carry out the entire process — from elucidating disease mechanisms to drug screening, and verifying efficacy and safety,” Inoue says. “A key advantage is that this approach can be tailored to individual patients.”

The researchers are aiming to recruit 24 participants for the last stage of the trial. It is being conducted at hospitals nationwide, including at Mie University Hospital, and will run until March 2028.

Hisayama study

The town of Hisayama, Fukuoka Prefecture, a suburban community of just 9,000 people, is known as the birthplace of a long-running community-level health study.

The town has helped researchers track health and lifestyle data of its residents over decades so they can determine the prevalence and risk factors for diseases such as dementia, high blood pressure, strokes and heart attacks.

The Hisayama study was launched in 1961, initially to examine the prevalence of deaths caused by brain hemorrhage, as opposed to brain infarction. Back then, doctors in Japan confused the two, diagnosing the former far more frequently than they did the latter, by a ratio of 14 to 1. The Hisayama cohort study demonstrated that the prevalence of the two conditions is in fact about the same. Dementia was added to the study in 1985.

Toshiharu Ninomiya, a Kyushu University professor who heads the study, recalls how, in the early days, studying dementia was challenging because of the enormous stigma it carried. Until 2004, dementia, known as ninchishō in Japanese, was called chihō, a term that carried derogatory or discriminatory nuances.

Such sentiment eased over time. Research shows that genetics explains only 10% of dementia, with the rest influenced by environmental factors. Ninomiya says dementia risks increase with a range of factors, including high blood pressure, smoking, diabetes, the weakening of the muscles, the lack of exercise, an unbalanced diet and a sense of loneliness.

Ninomiya thinks not everybody will get access to antibody drugs due to their exorbitant prices and side effects. Years of research and health interventions in Hisayama have shown, however, that a healthy lifestyle can delay the onset of dementia, as well as other lifestyle diseases.

“We are aiming to slow the damage to the brain and slow the progression of dementia as much as possible,” he says. “Ideally, people would live out their natural lifespan without developing dementia. If we can shift things that way, I think people would have a happier life.”