Alzheimer’s disease is the most common age-associated disease affecting the brain. It gradually affects memory, other thinking skills and behavior. It is highly variable among patients, and often mimics other diseases of memory impairment. Alzheimer’s disease is characterized by the formation of protein clumps inside and outside the brain cells, leading to shrinkage and eventually death of those cells. Although, the two main protein deposits are tau and β-amyloid, it is becoming increasingly evident that other co-existing proteins are driving the variability noted among the so-called ‘same’ disease. The most common co-existing protein deposits are alpha-synuclein and TAR DNA-binding protein-43. The current project aims at establishing a novel approach that can detect a mixture of those proteins in life as they leak into spinal fluid. We propose to use “seed amplification assays”: a panel of tests that can detect minute amounts of the protein clumps. Analysing post-mortem human brain tissues, our panel strongly differentiated the different proteins providing a more precise molecular classification of Alzheimer’s disease and related dementia. Our approach will be explored in well-characterized samples of human biofluids from living patients and healthy people to provide information in life. Our findings will deepen our understanding of the many faces of Alzheimer’s, advance diagnostics, and potentially improve clinical trials aiming at delivering targeted treatment.