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Can the pattern of lexical difficulties in healthy older adults predict amnestic mild cognitive impairment?

Award Number: R01AG097411
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Can the pattern of lexical difficulties in healthy older adults predict amnestic mild cognitive impairment? - Can the pattern of lexical difficulties in healthy older adults predict amnestic mild cognitive impairment? PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) affects over 6 million Americans, with costs exceeding $350 billion annually. Yet the disease is often detected too late for optimal intervention. This project examines whether the pattern of lexical difficulties in healthy older adults can predict who will develop amnestic mild cognitive impairment (aMCI), an early, prodromal stage of AD, opening the door to earlier diagnosis and treatment. Although emerging evidence suggests that lexical changes can predict cognitive decline years in advance, we are aware of no such work examining the prospective prediction of aMCI. Moreover, the nature and neural bases of lexical deficits in aMCI remain unclear: How is word production affected? Does comprehension also decline? Which brain structures drive these deficits? Understanding these impairments is essential to test whether their early presence in healthy adults foreshadows aMCI. This project—the first systematic examination of word production and comprehension in aMCI—rigorously characterizes lexical deficits and their neural bases, and leverages this knowledge to identify at-risk individuals. Our predictions are based on our innovative account of lexical deficits in aMCI, which integrates two lines of evidence: (1) word production and comprehension rely on specific medial temporal lobe (MTL) structures (hippocampus and rhinal cortex, respectively), and (2) these structures show particular atrophy in aMCI. We predict that hippocampal atrophy drives production deficits while rhinal atrophy impacts comprehension, in both cases mainly for later-acquired words (e.g., 'sudoku') because these structures preferentially support recently-learned knowledge. Mild forms of these deficits should be found prior to aMCI, enabling prospective prediction. AIM 1: Characterize lexical deficits in aMCI by comprehensively testing word production and comprehension in 100 aMCI patients and 200 healthy controls (HCs). We predict deficits in both modalities, disproportionately affecting later-acquired words. AIM 2: Identify the neural substrates using multimodal structural MRI and multilevel mediation analyses. We predict that hippocampal atrophy best explains production deficits, while rhinal atrophy best explains comprehension deficits, even compared to multiple other brain structures. AIM 3: Determine whether lexical patterns foreshadow aMCI by following the 200 HCs across three timepoints over three years, examining if baseline measures or their trajectories predict progression to aMCI (assessed via both a sensitive continuous metric and clinical diagnosis) as well as or better than established AD markers (Aβ/tau, MTL atrophy, APOE genotype, neuropsychological tests), or particularly when combined with these markers. Expected outcomes include accurate language screening tools that are affordable and widely accessible, as well as mechanistic insights into MTL contributions to language decline that inform therapeutic targets. Our multidisciplinary team combines expertise in psycholinguistics, neuroimaging, and aging research, with established access to well-characterized patient populations and robust preliminary data supporting all predictions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $757,100 )
2026	2026	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	1	9/9/2026	NEW	$757,100
														Subtotal = $757,100

Grand Total All Awards = $757,100

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Can the pattern of lexical difficulties in healthy older adults predict amnestic mild cognitive impairment?

Award Number: R01AG097411

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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