Latest developments in neurodegeneration research have sparked debates about the etiology, clinical diagnosis, and future treatment approaches for neuropathological diseases such as Alzheimer’s disease (AD). In February this year, Nature Reviews Neurology published a perspective article by Amos Korczyn and Lea Grinberg ^[1], discussing the very definition of Alzheimer’s disease and raising the question, whether AD should be reconsidered as a syndrome caused by a “convergence of pathogenic pathways” rather than a disease. Amos Korczyn is Professor-Emeritus in the department of neurobiology at the Tel-Aviv University Medical School, Israel, and Lea Grinberg is a neuropathologist and principal investigator at the University of California San Francisco (UCSF), CA, USA.

In this article, the authors dissect the current definition of AD, which involves severe cognitive decline as well as the presence of amyloid-β plaques and tau tangles. “This definition […] includes both the clinical syndrome and the associated pathology without addressing the process leading to these changes” ^[1]. Korczyn and Grinberg state that this definition is ambiguous since other diseases can also cause cognitive decline without displaying amyloid-β and tau pathology; conversely, some individuals exhibit amyloid and tau burden without any signs of cognitive decline.

“The fact that different causes might lead to the same pathological (and clinical) phenotype represents phenotypic convergence. In AD too, the clinical phenotype (or phenotypes) represents a syndrome” ^[1].

The authors state that many different endogenous and exogenous risk factors are hypothesized for AD development, and that different entities of AD can also be described. Early-onset familial AD (EOAD) is caused by different genetic factors such as APP duplication (e.g. in Down Syndrome) or PSEN1 mutation and – as the name suggests – starts comparatively early in life. On the other hand, sporadic late-onset AD (LOAD), the majority of all cases, does not only differ from EOAD in terms of disease onset, but also in pathological and clinical presentation. Besides age, the most prominent risk factor for LOAD is the presence of APOE4 (one E4 allele increases the risk for developing AD 3-fold, while the presence of two E4 alleles increase the risk by 15-fold). Korczyn and Grinberg emphasize the risk of confusion by only using the term ‘AD’ for both syndromes and using genetic EOAD animal models for all AD research, which is still common practice.

High time for a multifaceted approach

The authors also question the pharmaceutical focus on anti-amyloid treatments for several reasons. Past studies have found that patients burdened with amyloid-β but not tangles of hyperphosphorylated tau exhibited few to no cognitive symptoms. Further, clinical trials with lecanemab and aducanumab, two drugs that were recently approved by the FDA but blocked for the European market showed a comparatively weak performance in slowing disease progression despite clearance of amyloid-β from the brain. In many cases, treatment with these drugs can also cause notable side effects such as ARIA-E.

Eric Widera, Professor of the UCSF, who is critical of the definition of amyloid-β as a single AD biomarker and its disease-defining role ^[2] openly endorsed the article.

For their conclusion, Korczyn and Grinberg quote the British economist John Maynard Keynes: “The difficulty lies not so much in developing new ideas as in escaping from old ones” ^[1].

The authors further suggest that future AD research should move away from the original amyloid cascade hypothesis and instead embrace a “comprehensive and multifaceted approach” ^[1]. For example, the authors recommend the development of personalized poly-risk scores, including endogenous and exogenous factors.

The concept of finally defining multi-causal neurodegenerative diseases as syndromes rather than single disease entities also expands to other pathologies: In, August 2024, Korczyn published an article in Movement Disorders, expanding the discussed ideas to Parkinson’s disease (PD), where he states that similar to AD, the clinical presentation of PD underlies phenotypic convergence. Korczyn further emphasizes that dogmas hinder progress and, in order to move forward, we finally need to acknowledge that there is “no singular PD”. He strongly closes his argument with a universal concept:  “In a syndrome, attempts to define common genetics, find biomarkers, or discover a cure are futile and should be replaced by defining subentities based on genetic or molecular characteristics. In each subentity, additional influences, genetic, medical, and environmental, may be present, further emphasizing the need to move away from seeking a universal solution and instead tailoring approaches to specific subtypes“ ^[3].

References:

[1] Korczyn AD, Grinberg LT (2024) Is Alzheimer disease a disease? Nat Rev Neurol 20:245–251. DOI: 10.1038/s41582-024-00940-410.1002/mds.29833

[2] Widera E (2024) Who gets to decide on what it means to have Alzheimer’s disease? J Am Geriatr Soc 72:1939–1941. DOI: 10.1111/jgs.18793

[3] Korczyn, AD. (2024). Korczyn AD (2024) Rethinking Parkinson’s disease: a syndromic perspective. Mov Disord 39:1079–1080. DOI: 10.1002/mds.29833