Advancements in the Neuropsychology of Alzheimer's Disease

Abstract

Background: In Alzheimer's disease (AD), the buildup of amyloid-β and hyperphosphorylated tau protein in the brain starts years before clinical symptoms appear. This process then progresses in parallel with cognitive decline, from mild cognitive impairment to dementia. Developments in AD biomarkers have improved the detection of underlying pathophysiological processes. Concurrently, methodological advancements in cognitive testing have been made. In this thesis, key challenges in the neuropsychology of AD are addressed to improve clinical practice and inform clinical trials. These challenges include the lack of demographically adjusted cognitive test norms, the need to map the sensitivity of cognitive measurements across AD stages, and the use of remote, unsupervised cognitive testing as a scalable tool to facilitate early detection of AD. Methods and results: In Paper I, demographically adjusted norms for a cognitive test used in Swedish clinical practice were developed. These norms demonstrated better performance compared to the original norms in an independent validation sample. In Paper II, novel non-linear mixed-effects methods were used to construct a timeline of disease progression, from preclinical AD to dementia, for various cognitive measures. The sensitivity of these measures was assessed, revealing variability both across and within clinical AD stages. In Papers III and IV, the feasibility, reliability, and validity of digital cognitive tests, administered remotely and unsupervised, were investigated. Paper III demonstrated that meaningful cognitive data could be collected remotely, and validity in relation to conventional cognitive measures was established. In Paper IV, the relationship between preclinical AD biomarkers and digital test performance was examined in individuals from a population-based study, revealing associations between cerebrospinal fluid amyloid-β levels and test performance. Conclusions: This thesis contributes to the advancement of neuropsychological methods for AD assessment, addressing key challenges. In Paper I, the findings emphasize the need for updated norms in neuropsychological practice. The revised norms in Paper I can be directly implemented by clinicians to improve diagnostic processes. In Paper II, insights into the cognitive trajectory of AD were provided, supporting more informed selection and interpretation of cognitive tests, with applications in both clinical practice and trials. Findings in Papers III and IV highlight the potential of digital tests as cost-effective, non-invasive tools for cognitive screening, particularly in clinical trials evaluating disease-modifying interventions in preclinical AD.