Medications for the Brain

“Cognitively successful agers” are considered the result of a healthy lifestyle. It is a widespread misconception that we have no influence on whether we become demented or not. To underscore the importance of prevention, I would first like to go through the treatment options currently available. Hopefully, this will make you aware of how important it is to prevent the disease in the first place.

Aricept and Namenda

Until recently, there were essentially two types of treatment: the most common, cholinesterase inhibitors such as the drug donepezil (Aricept), and memantine (Namenda). One of the changes in Alzheimer brains is the destruction of nerve cells that communicate with each other via the neurotransmitter acetylcholine. By inhibiting cholinesterase, the enzyme that breaks down this messenger substance, the decline in acetylcholine levels can be offset. This can relieve some of the symptoms, but it does not stop the actual destruction. The mechanism of memantine is less intuitive. People with Alzheimer’s lose NMDA receptors (N-methyl-D-aspartate), but memantine, an NMDA blocker, also seems to help with symptoms. Unfortunately, neither medication improves symptoms enough to make a major difference.

A meta-analysis of more than 60 randomized clinical trials concluded that symptom relief with both treatments was so small that it should be regarded as “clinically not relevant.” Occasionally there were cases of at least moderate improvement, but no more often than with a placebo. So many studies have been conducted in so many patients that it is now “statistically unequivocal that no pharmacological intervention achieves a clinically significant improvement in dementia symptoms and functioning in Alzheimer’s patients.” But that was before a new agent came onto the market: aducanumab (Aduhelm).

The Aducanumab Farce

Aducanumab is the first drug in almost 20 years to be approved for the treatment of Alzheimer’s. The FDA approval of aducanumab proved to be one of the most controversial in recent history. Not only was the drug regarded as clinically ineffective, one third of patients who received aducanumab developed swelling or bleeding in the brain from it. Not a single member of the FDA’s advisory expert panel voted for approval, and three of the committee members resigned in protest; one spoke of the “probably worst drug approval decision in recent U.S. history.” The reaction of the scientific community is best summed up in a comment by the head of the American Geriatrics Society titled: “My head just exploded …”

You can see the whole fascinating story at see.nf/aducanumab. A congressional investigation concluded that the FDA approval of aducanumab was “rife with irregularities,” raising “serious concerns about the FDA’s procedural violations and [the pharmaceutical company] Biogen’s disregard for drug efficacy.” That did not stop the FDA from granting accelerated approval in 2023 to a similar antibody, lecanemab (Leqembi), with similarly questionable efficacy and safety.

Amyloid Hypothesis Challenged

The development of aducanumab was based on the assumption that Alzheimer’s is caused by the accumulation and clumping of sticky, misfolded protein fragments—beta-amyloid—that forms plaques, which lead to the death of neuronal cells and to neurodegeneration. Rare hereditary forms of Alzheimer’s caused by gene mutations with a large amount of beta-amyloid serve as conclusive proof for this “amyloid cascade hypothesis.” But the vast majority of Alzheimer’s cases—more than 95 percent—are “sporadic,” and nothing indicates that they are caused by a specific gene, so it is not clear whether the same mechanism underlies them.

Skepticism toward the amyloid cascade hypothesis rests on a series of inconsistencies. First, amyloid plaques can build up for decades before symptoms appear. Second, the amount of plaques hardly correlates with the severity of the disease. As mentioned, up to 50 percent of all autopsies classify people without signs of dementia as “probable” Alzheimer’s cases, and by the standard of plaque burden, one third would have had “definite” Alzheimer’s. And third, the brain regions with the greatest neuron loss are elsewhere than the concentrated amyloid deposits. Even Dr. Alzheimer himself wrote five years after his groundbreaking discovery: “We have therefore come to the conclusion that the plaques are not the cause of senile dementia …”

In 2022, the investigation of a landmark publication on amyloid found “shockingly blatant” data falsification, further damaging the theory’s reputation. Perhaps amyloid formation is only an expression of the disease and not its cause, just as skin lesions were a defining feature of smallpox but not the lethal pathology. There is even the view that beta-amyloid has a protective effect and that the brain secretes it as a defense mechanism. That would be consistent with the greater amyloid deposits after a head injury. In any case, the clearest failure of the amyloid cascade hypothesis is that therapies like aducanumab, which reduce amyloid, do not work.

Dozens of different anti-amyloid drugs have not been able to slow cognitive decline. Those who continue to hold to the theory, mocked by skeptics as pious members of the “Church of the Holy Amyloid,” speculate that drugs against amyloid deposits do not work because they are administered only once the disease is already too far advanced. After all, the formation of amyloid deposits can begin as early as the late 30s. This insight has far-reaching implications for dementia prevention.

Theories About Possible Causes

99.6 percent of Alzheimer’s drugs have failed, the worst rate of all therapeutic areas, and the few agents that exist mostly treat only the symptoms. The good news is, as a senior scientist at the Center for Alzheimer’s Disease Research titled a review article: “Alzheimer’s is incurable, but preventable.” Changes in diet and lifestyle could prevent millions of cases each year.

Maintaining the Brain’s Blood Supply

By now, the consensus is growing that “what is good for our heart is also good for our head,” because blockage of the cerebral arteries by atherosclerotic plaques presumably plays a decisive role in the development of Alzheimer’s. In the video see.nf/alzheimers I trace this connection back to Dr. Alzheimer’s first case. The brain has no energy reserves of its own, which is why it reacts very sensitively to nutrient deprivation. If the blood supply is interrupted for just a few minutes—for example, during a stroke—the dementia risk can double and the disease can break out up to ten years earlier.

Autopsy studies repeatedly showed that Alzheimer’s patients typically have significantly more atherosclerotic plaque deposits and narrowing in the cerebral arteries, especially in those that lead directly into the memory centers. Given such findings, some experts even suggested classifying Alzheimer’s as a vascular disease. People with a total cholesterol level above 225 milligrams per deciliter have up to a 25-fold higher likelihood of having amyloid deposits in the brain 10 to 15 years later (compared with 224 mg/dl or less). There is now agreement that an excessively high cholesterol level is an Alzheimer’s risk factor.