Tau PET Burden Is Associated With Hippocampal Microstructure and Episodic Memory in Amyloid Positive Older Adults
Daniel D Callow1, Nisha Rani1, Kylie H Alm1
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Growing evidence suggests that hippocampal gray matter microstructure, assessed through diffusion-weighted imaging (DWI), is a sensitive marker of neurodegeneration in Alzheimer's disease (AD). While hippocampal atrophy is a characteristic feature of AD, microstructural changes likely precede macrostructural changes such as volumetric loss, offering important insights into the early phases of the disease. This study assessed the relationships between hippocampal microstructure (assessed with mean diffusivity [MD] from DWI) and Braak-staged tau burden (measured by positron emission tomography [PET]) with performance on an episodic memory composite score, among individuals with and without amyloid burden, assessed by PET imaging. The study included 192 participants without dementia (14 with mild cognitive impairment [MCI]) from the BIOCARD cohort (mean age = 68), of which 52 (27%) were amyloid positive. In multiple linear regression analyses, increased hippocampal MD was associated with worse memory and greater tau PET burden in Braak stages II-IV, but only in individuals who were amyloid positive (e.g., significant amyloid × hippocampal MD interactions). Building on prior findings linking early Braak-staged tau to memory, we further assessed whether tau PET burden statistically mediated the relationship between elevated hippocampal MD and poorer memory performance. Tau PET burden in Braak stages II-IV was found to statistically mediate the relationship between elevated hippocampal MD and poorer memory performance, independent of hippocampal volume, but only in amyloid-positive participants. These associations were only significant when MCI participants were included in the analysis. These findings suggest hippocampal microstructure may be sensitive to AD-related pathological burden and associated neurodegeneration, particularly in the early symptomatic phase, and is associated with tau PET and cognitive decline, even after accounting for hippocampal volume.
Insights
Hippocampal microstructure changes, measured by mean diffusivity (MD), are linked to memory decline and tau pathology in amyloid-positive individuals. These microstructural changes may indicate early Alzheimer's disease (AD) neurodegeneration.
Area of Science:
- Neuroimaging
- Alzheimer's Disease Research
- Cognitive Neurology
Background:
- Hippocampal gray matter microstructure, assessed via diffusion-weighted imaging (DWI), shows promise as an early indicator of neurodegeneration in Alzheimer's disease (AD).
- Microstructural changes in the hippocampus may precede macrostructural alterations like volumetric loss, offering insights into early AD pathogenesis.
- Amyloid and tau pathologies are key hallmarks of AD, influencing cognitive function and neurodegeneration.
Purpose of the Study:
- To investigate the relationship between hippocampal microstructure (mean diffusivity [MD]), tau burden (Braak stage PET), and episodic memory performance.
- To determine if amyloid burden modulates the association between hippocampal MD, tau PET, and memory.
- To examine the mediating role of tau PET burden in the link between hippocampal MD and memory decline.
Main Methods:
- The study included 192 non-demented participants (14 with mild cognitive impairment [MCI]) from the BIOCARD cohort.
- Diffusion-weighted imaging (DWI) assessed hippocampal mean diffusivity (MD), while positron emission tomography (PET) measured amyloid and tau burden (Braak stages II-IV).
- Multiple linear regression analyses explored interactions between amyloid status, hippocampal MD, tau PET, and memory composite scores, including mediation analyses.
Main Results:
- Increased hippocampal MD was associated with poorer memory and higher tau PET burden in amyloid-positive individuals.
- Significant interactions between amyloid status and hippocampal MD indicated these associations were specific to the amyloid-positive group.
- Tau PET burden in Braak stages II-IV statistically mediated the relationship between elevated hippocampal MD and poorer memory, independent of hippocampal volume, particularly when MCI participants were included.
Conclusions:
- Hippocampal microstructure, assessed by MD, is sensitive to AD-related pathological burden and neurodegeneration in the early symptomatic phase.
- The findings highlight the interplay between amyloid positivity, hippocampal microstructural integrity, tau accumulation, and cognitive decline in early AD.
- Hippocampal microstructural changes may serve as a crucial biomarker for early AD detection and progression, even before significant hippocampal volume loss.
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