Alzheimer’s dependent on more factors than just amyloid?

Danish researchers critically question amyloid hypothesis

Alzheimer’s dementia and amyloid have usually been mentioned in the same breath since the 1980s. Even though numerous studies on antibodies for amyloid removal failed in the past decades and a scandal about falsified studies last 2022 repeatedly led to considerable doubts about the so-called “amyloid hypothesis,” it seems to be more solidified again due to the two amyloid antibodies lecanemab and donanemab.

Since at least a statistical benefit was found with lecanemab and clinical effects were also shown with donanemab, at least in the early stages of the disease, there has been talk in recent months of a “milestone in Alzheimer’s research.” But much criticism has also been voiced, especially because of the side effects, some of which have been severe and in three cases so far even fatal.

Danish researchers critically question hypothesis and bring other factors into play

In light of a possible upcoming approval of both drugs in Europe as well, a team led by Prof. Kasper P. Kepp of the Department of Chemistry at the Technical University of Denmark has looked into the antibody therapies. In a critical review, the scientists:inside note that despite its high complexity, Alzheimer’s research is mainly based on the idea that Alzheimer’s is a kind of “systemic failure” that leads to an overload of beta-amyloid in the brain.

The amyloid hypothesis faces resistance because many drugs remove amyloid but show little or unclear effects on the disease – including lecanemab. Researchers also fault the inconclusive rationales for these failures. In addition, there is skepticism because the clinical impact of anti-amyloid drugs is small and no correlation between cognition and amyloid deposition is apparent. In addition, genetic and lifestyle risk factors such as obesity, diabetes, hypertension, and depression have long been neglected.

Amyloid also present in healthy brains and function not yet known

According to Kepp, genetic risk factors linking amyloid to Alzheimer’s (FAD, presenilin and APP mutations) account for less than five percent of all cases. Thus, in over 95 percent of patients, amyloid plaques occur in the absence of genetic risk factors. Many mutations even produce less amyloid than the wild form of the protein. Moreover, amyloid is also present in many healthy brains and probably has a function like other proteins produced, which are not yet known.

Another criticism of the scientists:in is that the amyloid hypothesis (ACH) is based mainly on animal studies, particularly with rodents. They note that support for the ACH comes mainly from transgenic rodent models expressing FAD mutants. However, differences in human aging processes and neurological development limit the value of pathogenic processes observed in mice.

Skepticism about the amyloid hypothesis raises the question of whether the amyloid antibodies lecanemab and donanemab can actually revolutionize Alzheimer’s therapy after the failure of their predecessors. Previous antibodies such as solanezumab and bapineuzumab have not worked convincingly, and post-mortem studies show that despite removal of the plaques, severe dementia had nevertheless progressed in many patients.

Kepp therefore sees the focus exclusively on amyloid therapies as inappropriate: “The latest anti-amyloid antibodies (donanemab, lecanemab) show small but uncertain effects and have side effects, especially as they are expensive. However, they could be part of a broader treatment approach.” For Alzheimer’s research and treatment, early diagnosis and causal research remain critical, with “prevention and promotion of different drug approaches such as proteostasis, brain metabolism, tau protein, and other disease-related pathways”also essential.

Scientists:inside urge caution against exaggerated expectations

The authors therefore urge caution against exaggerated hopes regarding anti-amyloid therapies as a cure for Alzheimer’s disease. Although amyloid may be a part of Alzheimer’s pathology, it may play only a minor role in treatment. However, if amyloid is not the primary cause of dementia symptoms in Alzheimer’s, questions arise about alternatives. Infections, vascular disease, and metabolic disorders could be potential causes that require further research. In these scenarios, amyloid might serve more as a marker of increased APP turnover, which is more a response to impairment than a disease factor.

Viruses may play a role not only in multiple sclerosis but also in Alzheimer’s disease

Since the 1980s, the hypothesis that viruses or bacteria might contribute to the development of Alzheimer’s has been floated repeatedly. Although the idea was derided at the time, it is now regaining credibility. Last year, a major U.S. study clearly demonstrated that the Epstein-Barr virus, or EBV for short, which is highly prevalent worldwide, is almost certainly the main cause of multiple sclerosis. Studies on Alzheimer’s disease have also shown that people with herpes simplex infections have an increased risk of Alzheimer’s disease. In an interview with The Guardian in the U.K., Davangere Devanand, a neurologist at Columbia University Medical Center, highlights a 2018 formative study from Taiwan that found treating herpes patients with a standard antiviral reduced dementia risk by ninefold.

In turn, in a recent preprint, researchers at Stanford University in the U.S. found that herpes zoster vaccination could potentially protect against dementia. For their study, the scientists led by Dr. Pascal Geldsetzer took advantage of the fact that in Wales, approval for herpes zoster vaccination is linked to a fixed date of birth. They were able to show that the vaccination reduced the probability of a new dementia diagnosis by 3.5 percentage points over an observation period of seven years. This could equate to a nearly 20 percent reduction in the incidence of dementia, and the effect was greater for women than men. The study also showed that vaccination had no effect on other common causes of morbidity or mortality, which avoids typical biases of correlation analyses, according to study author Dr. Pascal Geldsetzer.

Alzheimer’s disease is too complex to be explained by amyloid alone

These discouraging findings related to the amyloid theory and the renewed interest in the role of viral infections in the development of dementia mark two notable developments in Alzheimer’s research. They reemphasize that Alzheimer’s is more complex than could be explained by amyloid alone.

Geldsetzer and his team call for randomized trials to further investigate the impact of herpes zoster vaccination and to identify a potential timing for its use in dementia treatment. Prof. Kepp of Denmark also recommends not focusing solely on amyloid approaches. He emphasizes that while the hypothesis has been important for research and model development, it has little impact on patients, especially given the complexity of the disease.