Research Article: Mixed pathologies and neural reserve: Implications of complexity for Alzheimer disease drug discovery

Date Published: March 14, 2017

Publisher: Public Library of Science

Author(s): David A. Bennett

Abstract: In a Perspective, David Bennett makes a case for neural reserve to be considered as a therapeutic endpoint in clinical trials for dementia.

Partial Text: The pathologic hallmarks of AD are the extracellular deposits of the amyloid-β peptide and the intracellular accumulation of abnormally phosphorylated tau neurofibrillary tangles (NFT). Much is known about the metabolism of these proteins, and amyloid-β has been and remains the target of many therapeutic trials. The frequency of AD pathology increases markedly with age. Aging, however, is associated with the development of many common chronic diseases, including several brain diseases that affect cognition. Thus, the brains of older persons, many of whom have AD pathology, often exhibit macro- and/or microscopic infarctions, atherosclerosis, arteriolosclerosis, and white matter changes reflecting cerebrovascular disease, as well as tar DNA–binding protein 43 (TDP-43), hippocampal sclerosis, and neocortical Lewy bodies [2–5]. All of these pathologies can contribute to cognitive impairment and the AD dementia phenotype [6–8]. In fact, among older persons, who represent the greatest number of persons with the disease, mixed pathologies are the most common cause of AD dementia. Mixed pathologies are also very common in persons with mild cognitive impairment (MCI), including amnestic MCI, often thought to be relatively specific for MCI due to AD [9]. Some studies suggest that AD pathology accounts for the majority of dementia cases [10,11]. However, other studies suggest that the comorbid pathologies account for an equal amount of dementia and perhaps even more than AD, collectively [12].

The concept of reserve refers to the ability of a physiologic system to maintain function despite damage from injury or disease. All human physiologic systems exhibit reserve. In the context of the AD dementia syndrome, neural (or cognitive) reserve refers to the ability to maintain cognitive function despite the accumulation of the various pathologies that contribute to cognitive impairment. Nearly three decades ago, the first report of a series of persons without dementia who met pathologic criteria for AD was published [14]. It is now known that about a third of older persons without dementia or MCI meet pathologic criteria for AD, suggesting that many people are able to maintain excellent cognition despite the accumulation of brain pathology [15,16]. Amyloid-β cerebrospinal fluid (CSF) and positron emission tomography (PET) studies now suggest that AD pathology begins to accumulate years if not decades prior to the onset of clinical symptoms [17].

The data paint a picture of cognitive decline, MCI, and AD dementia resulting from a complex interaction between the accumulation of one or more brain pathologies in the context of a brain that is more or less resilient to these pathologies. This complexity has important implications for both clinical trial design and drug discovery.



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