Optimizing semantic memory measures of Alzheimer's disease biomarkers

Recent evidence suggests that neuropsychological testing is sensitive to the accumulation of key Alzheimer’s disease (AD) pathologies in older adults without dementia. Semantic memory, meaning factual knowledge about the world, has emerged as a potentially sensitive cognitive domain to early AD pathology. Yet, barriers limit our understanding of semantic memory’s promise for detecting AD-related cognitive decline. Notably, efforts to examine semantic memory’s sensitivity to amyloid and tau have not capitalized on key cognitive mechanisms - identified through advancements in cognitive neuroscience - that may maximize sensitivity to AD pathology. Additionally, there remains uncertainty as to how semantic memory maps to hippocampal/medial temporal lobe (MTL) integrity, despite being relevant to revealing mechanisms and profiling AD pathology. Guided by contemporary cognitive neuroscience theories, the present proposal aims to ascertain, among older adults without dementia, the sensitivity of several new semantic memory tasks to: 1) a promising plasma biomarker of AD-specific amyloid/tau pathology and 2) hippocampal/medial temporal lobe atrophy. Led by PI Dr. Grilli, our team combines expertise in the cognitive neuroscience of semantic memory, hippocampal/medial temporal lobe functioning, and the neuropsychological detection of early AD. Together, we will undertake an innovative project integrating novel cognitive assessment, comprehensive neuropsychological profiling, structural MRI, and plasma assays. We will test, among 225 older adults spanning from cognitively unimpaired to those with mild cognitive impairment, the relationships between AD biomarkers and several mechanisms of semantic memory functioning. In Aim 1, we will investigate whether adding precision to semantic memory enhances this cognitive construct’s sensitivity to AD biomarkers, as measured by plasma and hippocampal/medial temporal lobe atrophy. Aim 2 will explore our hypothesis that experience-nearness, another property of semantic memory, is sensitive to the same AD biomarkers. Finally, Aim 3 will assess our hypothesis that generative processing, as a third semantic memory property, can detect early signs of AD through our target biomarkers. All three aims are not only informed by contemporary theory but also supported by extensive preliminary data from our team. The aims also are aligned with the NIH’s Notice of Special Interest: Novel Approaches to Diagnosing and Studying Clinical Alzheimer's Disease and Related Dementias (NOT-AG-21-036). This project, to our knowledge, will be the first to evaluate the sensitivity of these three semantic memory properties to critical, early AD biomarkers. Ultimately, the results of this project may lead to the development of more sensitive and specific cognitive tools for early tracking of AD-related pathologies, with broad implications for scientists conducting clinical trials, as well as clinicians on the frontline of healthcare treatment. The knowledge gained also may significantly advance our understanding of hippocampal/medial temporal lobe functioning by clarifying the mechanistic role of these neural structures in semantic memory.