Is Alzheimer disease a disease?

Abstract

Dementia, a prevalent condition among older individuals, has profound societal implications. Extensive research has resulted in no cure for what is perceived as the most common dementing illness: Alzheimer disease (AD). AD is defined by specific brain abnormalities - amyloid-β plaques and tau protein neurofibrillary tangles - that are proposed to actively influence the neurodegenerative process. However, conclusive evidence of amyloid-β toxicity is lacking, the mechanisms leading to the accumulation of plaques and tangles are unknown, and removing amyloid-β has not halted neurodegeneration. So, the question remains, are we making progress towards a solution? The complexity of AD is underscored by numerous genetic and environmental risk factors, and diverse clinical presentations, suggesting that AD is more akin to a syndrome than to a traditional disease, with its pathological manifestation representing a convergence of pathogenic pathways. Therefore, a solution requires a multifaceted approach over a single 'silver bullet'. Improved recognition and classification of conditions that converge in plaques and tangle accumulation and their treatment requires the use of multiple strategies simultaneously.

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.