Fig. 1 ∣. Current thinking of Alzheimer disease pathology versus our proposed argument.

According to current thinking, plaques and tangles are at the beginning of the pathological cascade (part a, top), so regardless of the cause or the other pathological cascades that are activated, eliminating plaques (and perhaps tangles) will resolve the problem (part a, bottom). This concept mirrors the notion of treating plaques and tangles as if they represent a single disease, or similarly, it equates to the belief that alleviating fever alone will address the root cause of an illness. Our suggestion (part b) is that plaques and tangles represent the culmination of pathological cascades, not necessarily the same for plaques and tangles, with each aetiology also triggering other pathological sequences (some of which are similar and others distinct across them) that may or may not be connected to the final-stage plaques and tangles. Therefore, plaques and tangles are merely common features across various diseases, and treatment and biomarkers ought to be specific to the disease, grounded in its aetiology. An analogy is pneumonia — treating the inflammatory response is not enough if injury persists.