Regional tau deposition and digital assessment of cognition in preclinical AD and MCI

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PROJECT SUMMARY The applicant seeks this K99/R00 award to achieve research independence focused on integrating imaging and digital biomarkers to examine early cognitive and psychiatric symptoms of Alzheimer’s disease and related dementias. To achieve this goal, the applicant will receive training in three areas critical to her independence: (1) longitudinal study design and analysis in Alzheimer’s disease, (2) amyloid and tau PET imaging, and (3) spoken language features of cognition. She will also receive guidance from her expert mentorship team who has an established record of mentoring junior scholars to full independence, and obtain comprehensive training through a detailed training plan. Her research will examine the relation between regional tau deposition and domain-specific cognitive decline given that pathological and clinical evidence of Alzheimer’s disease converges to suggest that both episodic and semantic memory are vulnerable years before the onset of dementia. During the K99 phase, she will examine how regional tau deposition relates to episodic and semantic memory decline in two large cohorts consisting of Aβ- clinically normal (CN), Aβ+ CN, and Aβ+ mild cognitive impairment (MCI) individuals. Episodic and semantic memory will be measured by traditional neuropsychological test scores as well as innovative spoken language features of cognition extracted from recordings of in-person neuropsychological assessments. This research aim, in combination with the training and mentorship she will receive, will prepare her for independence by the R00 phase. During the R00 phase, she will examine the relation between regional tau deposition and domain-specific cognitive decline assessed frequently through smartphones, an increasingly ubiquitous platform. Specifically, she will administer verbally based mobile cognitive tests and assessments of mood every 3 months for 1 year to Aβ- CN, Aβ+ CN, and Aβ+ MCI individuals with tau PET data. Episodic and semantic memory will be measured by neuropsychology scores and spoken language features extracted from structured responses captured in the real world. Thus, the K99 and R00 phases of this proposal test the overarching hypothesis that where tau deposition occurs in the brain relates to domain-specific cognitive decline. This knowledge will improve the accuracy of Alzheimer’s disease diagnosis as well as enhance the screening and monitoring of those at risk for dementia. Completion of the R00 phase will generate data to support a future R01 application integrating multimodal imaging and spoken language features extracted from passively collected unstructured voice recordings that maximize ecological validity and minimize participant burden. This approach can also be applied to Alzheimer’s disease and related dementias more broadly. The K99/R00 award will thus provide the applicant with a platform to launch an independent career using multimodal imaging and real-world assessments to understand cognitive and psychiatric symptoms of Alzheimer’s disease and related dementias.