History in perspective: How Alzheimer's Disease came to be where it is?

•Core pathological features of AD include deposition of Aβ plaques and tau tangles.•Significant crosstalk is observed between the etiological hypotheses of AD.•2018 research framework has updated the definition of AD to a molecular construct.•Shift in research towards early diagnosis of AD through blood-based biomarkers.•Targeting individual pathological pathways has yielded no therapeutic success. Treatment of Alzheimer’s Disease (AD) remains an unsolved issue despite the pronounced global attention it has received from researchers over the last four decades. Determining the primary cause of the disease is challenging due to its long prodromal phase and multifactorial etiology. Regardless, academic disagreements amongst the scientific community have helped in making significant advancements in underpinning the molecular basis of disease pathogenesis. Substantial development in fluid and imaging biomarkers for AD led to a sharp turn in defining the disease as a molecular construct, dispensing its clinical definition. With conceptual progress, revisions in the diagnostic criteria of AD were made, culminating into the research framework proposed by National Institute on Aging and Alzheimer’s Association in 2018 which unified different stages of the disease continuum, giving a common language of AT(N)11AT(N): Amyloid-β biomarkers, Pathologic tau biomarkers, Neurodegenerative/Neuronal injury biomarkers. classification to researchers. With realization that dementia is the final stage of AD spectrum, its early diagnosis by means of cerebrospinal fluid biomarkers, Positron Emission Tomography and Magnetic Resonance Imaging of the brain holds crucial importance in discovering ways of halting the disease progression. This article maps the insights into the pathogenesis as well as the diagnostic criteria and tests for AD as these have evolved over time. A contextualized timeline of how the understanding of AD has matured with advancing knowledge allows future research to be directed and unexplored avenues to be prioritized.