[Reporter’s View] The dementia drug efficacy dilemma

A patient visits a hospital, feeling that their memory is not what it used to be. Tests show that the patient does not have dementia but has mild cognitive impairment. The patient then asks, “What medication should I start taking now?”

This question is ridden with anxiety and fear, yet tinged with anticipation.

The fear that the condition may progress to dementia is coupled with hope that doing something now might at least slow that progression. Even when patients cannot be certain how much a prescribed drug actually helps, they may still believe that “taking anything would be better than nothing.”

The problem is that, when it comes to improving cognitive function, it is not easy to clearly distinguish that belief from the drug’s actual effect.

On some days, patients may feel their mind clears up after taking a drug, while on others they may feel fine even without it. Memory and concentration can also vary depending on sleep, stress, and a person’s condition that day. It is difficult for patients and caregivers to discern whether the small changes they experience are the actual effects of the medication or just natural fluctuations."

This issue is not unrelated to the fact that several drugs long used in Korea as cognitive enhancers have failed efficacy verifications.

Acetyl-L-carnitine failed to demonstrate efficacy in a clinical reassessment, leading to the removal of its relevant indications, while oxiracetam also failed its clinical reassessment and exited the market. Choline alfoscerate, meanwhile, has been at the center of years of controversy and litigation over its reimbursement eligibility.

However, a series of drugs continued to fill the void. Ginkgo biloba extract and porcine brain peptide preparations emerged as alternative treatments, while nicergoline, which had previously had a relatively limited presence, began attracting renewed attention in the prescription market.

However, even these are facing scrutiny once again, with ginkgo biloba extracts and porcine brain peptide preparations also facing reassessments.

The shift in prescriptions from acetyl-L-carnitine to oxiracetam and choline alfoscerate, and then again to drugs such as ginkgo biloba and nicergoline, is noteworthy. When one drug disappears, another takes its place, and once use of that drug increases, it too comes under scrutiny.

It would be difficult to view this simply as a problem with the reassessment system. The National Health Insurance cannot be expected to continue covering drugs with unproven efficacy simply because they have been used for a long time. Nor can clinical utility be established solely based on patients’ perceptions that a drug is working. This is precisely why clinical reassessments and reassessments of reimbursement eligibility are necessary.

Yet one question remains in dementia and cognitive impairment: What evidence should determine whether a treatment is effective? The difficulty of answering that question does not stem from drugs alone. Mechanisms underlying the onset and progression of dementia have yet to be fully elucidated.

In Alzheimer’s disease, amyloid-beta accumulation and tau pathology are well-established key features. But the onset and progression of the disease cannot yet be explained through a single pathway. As neuroinflammation, vascular abnormalities, and metabolic changes have also been found to play a role, the understanding of Alzheimer’s disease has become increasingly complex.

The representative amyloid hypothesis has also been the subject of long-standing controversy.

Numerous drug candidates were developed in the hope that removing amyloid could treat Alzheimer’s disease, only to face repeated failures. Aduhelm (aducanumab) demonstrated a clear biological effect in reducing amyloid, yet remained mired in controversy over its clinical utility.

The more recent Leqembi (lecanemab) has gone a step further. In addition to removing amyloid beta, it significantly slowed the decline in cognitive function and activities of daily living in patients with early Alzheimer’s disease, demonstrating its potential as a disease-modifying therapy.

However, questions remain.

Leqembi did not restore lost memory. It delayed progression of a disease that had already begun. Patients receiving treatment still experienced cognitive decline over time, but at a slower rate than those receiving placebo.

The fact that removing amyloid does not completely halt disease progression illustrates the complexity of the onset and progression of Alzheimer’s disease.

Safety is also a concern. Amyloid-targeting antibodies such as Leqembi can cause amyloid-related imaging abnormalities (ARIA), including brain edema and microhemorrhages, which require careful patient selection and repeated MRI monitoring.

Ultimately, even with the latest dementia treatments, we once again confront the question of what constitutes an “effect.”

In dementia treatment, efficacy may encompass not only directly improving cognitive function but also slowing deterioration and extending the period during which patients can maintain independent daily living. Yet determining how meaningful differences in clinical scores are in patients’ lives remains an issue requiring careful judgment.

Ultimately, the dilemma surrounding cognitive enhancers converges on this very point. Changes in mild cognitive impairment and early dementia occur slowly and vary considerably among patients. Cognitive test results can also be affected by numerous factors, including sleep, psychological state, education level, and a patient’s condition on the day of testing.

It is necessary to weed out drugs that do not work. But for a disease like dementia, where multiple pathological processes are involved in onset and progression and treatment goals range from “recovery” to “slowing progression,” it is worth asking whether a single yardstick is sufficient to determine whether a treatment works.

The criteria for assessing treatment effects need to become more sophisticated, encompassing not only cognitive scores but also how long patients maintain independent daily living, how long progression to the next stage of disease is delayed, and how much the burden on patients and caregivers is reduced.

With much still unknown about how dementia develops and progresses, the question is where to draw the line on what constitutes a meaningful treatment effect—and what evidence-based answers can be given to patients seeking reassurance and hope. Finding those answers is a task for both drug developers and regulators.