In the last five years, we have entered a quiet revolution in the treatment of dementia from Alzheimer’s disease. Prior to 2022, the few therapies that were available for Alzheimer’s dementia only treated symptoms: Despite decades of work and an estimated $42.5 billion in clinical R&D from the private sector alone,1 no therapy had ever been unambiguously shown to slow down the terrible downward slide into ever-deepening dementia and disability. That changed with the Phase III trials for donanemab (Kinsula®)2 and lecanemab (Leqembi®),2 two monoclonal antibodies that clear specific forms of beta-amyloid out of the brain. (Beta-amyloid is a damaged protein that accumulates in the brain with age, and although likely involved with several neurodegenerative diseases,3 it is the hallmark lesion in Alzheimer’s dementia and—according to the dominant model4—is the root driver of the disease). For the first time, we have therapies that actually slow down the terrible, progressive cognitive decline that makes Alzheimer’s so fearsome.
Despite this remarkable achievement, the effect was understandably underwhelming to many: Donanemab and lecanemab slow down the collapse into progressively-worsening dementia, but the effect is relatively modest, and certainly, they are not a cure.
But the modesty of their effect is likely in substantial part the result of the advanced state of neurodegeneration that patients were in by the time the trials began. To enroll in the trials for these therapies, subjects had to already either have so-called “mild” cognitive impairment (MCI—a misnomer, since MCI is a substantial level of cognitive dysfunction) or be in the early stages of Alzheimer’s dementia per se. And by the time people have early Alzheimer’s dementia or even MCI, their brains are in a state analogous to Dresden after the Allied firebombing in World War II: They not only have high levels of beta-amyloid, but have suffered substantial loss and disconnection of neurons in key areas of the brain; have extensive deposits of aggregated (stuck-together) forms of the protein tau; the support cells in their brains (astrocytes and microglia) have been driven berserk by the desperate work of responding to the wreckage surrounding them; and other damage and dysfunction has accumulated.5 Clearing beta-amyloid cannot undo this pre-existing neuropathological burden.
Instead, a growing body of evidence suggests that, to have a profound impact on Alzheimer’s dementia, we need to act earlier—both earlier in time (before so much irreversible damage has accumulated) and earlier in the neuropathological process (since evidence—including randomized clinical trial data—suggests that much of this damage is downstream of beta-amyloid).
Most aging people have deposits of aggregated tau, but it is typically confined to a region of the brain called the medial temporal lobe (MTL). By contrast, in people with Alzheimer’s dementia and some other neurodegenerative diseases, tau aggregates spread inexorably forward toward the cortex. According to the long-standing “amyloid cascade” model, it’s beta-amyloid that drives aberrant tau to spread from the MTL into the neocortex in Alzheimer’s dementia, as well as causing maladaptive activation of astrocytes and microglia—and it’s these downstream processes that are proximately responsible for major cognitive decline in the disease.4 Amyloid is the gun, in other words, but aberrant tau and dysfunctional support cells are the bullets.
As we shall see, this model now has substantial support from secondary analyses of the Phase III trials of lecanemab and donanemab, and preliminary support from another amyloid-clearing antibody that is in earlier stages of development. Based on this support, the companies that developed these therapies are now betting that the amyloid cascade model is correct, and have launched trials based on its implications: That if we were to clear beta-amyloid out of people’s brains early enough—before the downstream spread of tau and derangement of brain support cells had set in—then we could delay or even prevent many cases of Alzheimer’s dementia, and might even be able to postpone the disease indefinitely.
