Biochemical and Neuroimaging Studies in Subjective Cognitive Decline: Progress and Perspectives

<jats:title>Summary</jats:title><jats:p>Neurodegeneration due to Alzheimer's disease (<jats:styled-content style="fixed-case">AD</jats:styled-content>) can progress over decades before dementia becomes apparent. Indeed, patients with mild cognitive impairment (<jats:styled-content style="fixed-case">MCI</jats:styled-content>) already demonstrate significant lesion loads. In most cases, <jats:styled-content style="fixed-case">MCI</jats:styled-content> is preceded by subjective cognitive decline (<jats:styled-content style="fixed-case">SCD</jats:styled-content>), which is applied to individuals who have self‐reported memory‐related complaints and has been associated with a higher risk of future cognitive decline and conversion to dementia. Based on the schema of a well‐received model of biomarker dynamics in <jats:styled-content style="fixed-case">AD</jats:styled-content> pathogenesis, it has been postulated that <jats:styled-content style="fixed-case">SCD</jats:styled-content> symptoms may result from compensatory changes in response to <jats:italic>β</jats:italic>‐amyloid accumulation and neurodegeneration. Although <jats:styled-content style="fixed-case">SCD</jats:styled-content> is considered a prodromal stage of <jats:styled-content style="fixed-case">MCI</jats:styled-content>, it is also a common manifestation in old age, independent of <jats:styled-content style="fixed-case">AD</jats:styled-content>, and the predictive value of <jats:styled-content style="fixed-case">SCD</jats:styled-content> for <jats:styled-content style="fixed-case">AD</jats:styled-content> pathology remains controversial. Here, we provide a review focused on the contributions of cross‐sectional and longitudinal analogical studies of biomarkers and neuroimaging evidence in disentangling under what conditions <jats:styled-content style="fixed-case">SCD</jats:styled-content> may be attributable to <jats:styled-content style="fixed-case">AD</jats:styled-content> pathology. In conclusion, there is promising evidence indicating that clinicians should be able to differentiate pre‐<jats:styled-content style="fixed-case">AD SCD</jats:styled-content> based on the presence of pathophysiological biomarkers in cerebrospinal fluid (<jats:styled-content style="fixed-case">CSF</jats:styled-content>) and neuroimaging. However, this neuroimaging approach is still at an immature stage without an established rubric of standards. A substantial amount of work remains in terms of replicating recent findings and validating the clinical utility of identifying <jats:styled-content style="fixed-case">SCD</jats:styled-content>.</jats:p>