Whether mild cognitive impairment (MCI) has a distinct neuropathological profile that reflects an intermediate state between no cognitive impairment and dementia is not clear. Identifying which biological events occur at the earliest stage of progressive disease and which are secondary to the neuropathological process is important for understating pathological pathways and for targeted disease prevention. Many studies have now reported on the neurobiology of this intermediate stage. In this systematic review, we synthesize current evidence on the neuropathological profile of MCI. A total of 162 studies were identified with varied definition of MCI, settings ranging from population to specialist clinics and a wide range of objectives. From these studies, it is clear that MCI is neuropathologically complex and cannot be understood within a single framework. Pathological changes identified include plaque and tangle formation, vascular pathologies, neurochemical deficits, cellular injury, inflammation, oxidative stress, mitochondrial changes, changes in genomic activity, synaptic dysfunction, disturbed protein metabolism and disrupted metabolic homeostasis. Determining which factors primarily drive neurodegeneration and dementia and which are secondary features of disease progression still requires further research. Standardization of the definition of MCI and reporting of pathology would greatly assist in building an integrated picture of the clinical and neuropathological profile of MCI.

Background

The concept of mild cognitive impairment (MCI) defines an intermediate state between no cognitive impairment (NCI) and pathological cognitive ageing with the aim of identifying individuals who are at high risk of dementia. Numerous different definitions of MCI have been proposed with large variations in the type of impairment that needs to be present (for example, amnestic vs non-amnestic) and the level of deficit severity that is required. 1 Despite intense research to characterize the neuropsychological and clinical profile of MCI and its progression to dementia, the actual neuropathological substratum has not yet been elucidated for any definition of MCI. Defined as a transitional state, MCI is a difficult biological phenomenon to investigate, especially in terms of testing claims about whether it represents an at-risk state, or is simply early-stage dementia, which itself has multiple possible substrates. In this review, we describe the published literature on the neuropathological profile of MCI (Supplementary Table 1). The methodology for article selection is outlined in Supplementary Appendix 1. The focus is on findings which might establish MCI as a distinct and identifiable state between control and dementia groups. Key issues addressed include:(1) the extent to which Alzheimer's disease (AD) and non-AD pathology associated with clinical dementia are observed in MCI;(2) the molecular changes that have been found and,(3) changes in key processes such as neurotransmitter signaling and cellular responses (including downregulation and oxidation).