Antiquity, past, present, and future of in vivo diagnosis of Alzheimer’s disease

Abstract

2026 will mark the 120th anniversary of the publication of the first case of Alzheimer’s disease (AD). However, the first case was very atypical for today’s standards: a lady with early-onset behavioral problems. This led to the classification of AD as pre-senile dementia, a very rare disease, and consequently, almost non-existent AD research in the first 3 quarters of the 20th century. This era can be named as the antiquity of AD. It ended with the realization that senile dementia is indeed AD. The last quarter of the previous century first witnessed the birth of behavioral neurology, which subsumed the entire cognitive disorders, including dementia, under its wings. This was followed by the publication of the first formal clinical diagnostic criteria set for AD (NINCDS-ADRDA). This was a major step in establishing a common language and more or less homogenous patient groups for AD research. However, it equated AD with its terminal dementia stage and allowed the use of laboratory methods only for exclusionary purposes. Ignoring the very long period of pre-dementia stages became a major flaw of that era, which we can call the past of AD. The very significant advances in all areas of AD research, including neuropsychology, neuroimaging, neuropathology, and genetics, during the last two decades of the past finally succeeded in getting rid of these flaws. This step was taken by International Work Group (IWG 2007) and marked the beginning of the present of AD. It was followed by the 3 sets of criteria of National Institute of Aging-Alzheimer’s Association (NIA-AA 2011). In the present era, AD can now be diagnosed at any point during its progression with the aid of biomarkers, even during its preclinical stage. The IWG and NIA-AA criteria sets kept on being revised up to the present day. The NIA-AA 2024 was a biological-clinical integrated staging system (ISS), allowing for to follow the clinical and biological progression of AD along its ever-increasing stages. Not only this, but ISS also allowed the physician to differentiate the comorbidities. This may be considered as a door opened to the future of AD, signaling the end of its present. It can be claimed that the major flaw of the present was to conceive every neurodegenerative disease, including AD, as an effect caused by the singular protein deposits, and consequently targeting them for treatment purposes, despite repeated failures of this treatment strategy. It became increasingly clear that co-proteinopathies are not an exception but are the norm. Overcoming the flaw of the present will necessitate looking to the neurodegeneration through the co-proteinopathy lens in the already heralded future.

Cite this article as: Gürvit H. Antiquity, past, present, and future of in vivo diagnosis of Alzheimer’s disease. Turk J Neurol 2025;31(4):391-409. doi: 10.55697/tnd.2025.533.