The impact of amyloid beta burden on white matter dysfunction and associated transcriptomic signatures in cognitively normal elderly individuals

Abstract

Introduction: Amyloid beta (Aβ), a hallmark of early Alzheimer's disease (AD), disrupts white matter (WM) microstructure, but its spatial patterns and transcriptomic links in cognitively normal individuals remain underexplored.

Methods: We compared the WM microstructure between Aβ-positive (Aβ+) and Aβ-negative (Aβ-) individuals at the cognitively normal stage. We investigated the relationship between the fibers and the cortical and subcortical regions to which they are connected, as well as the underlying gene expression.

Results: WM damage observed in Aβ+ individuals was characterized across eight fiber tracts, even prior to the evidence of atrophy and during the cognitive normal stage. This damage is primarily associated with cortical Aβ accumulation and may be linked to genes that regulate oligodendrocyte function and myelination.

Discussion: Cortical Aβ-related WM changes precede gray matter atrophy in preclinical AD, highlighting their potential as early biomarkers. Oligodendrocyte dysfunction and myelination pathways may underlie Aβ-driven WM vulnerability, offering targets for intervention.

Highlights: WM microstructural changes precede gray matter atrophy in preclinical AD.Aβ-driven WM damage persists even after adjusting for age.WM microstructural damage is primarily linked to cortical Aβ burden in cognitively normal individuals.Oligodendrocytes and myelin underlie the vulnerability of WM-related to Aβ.

Keywords: Alzheimer's disease; amyloid beta; transcriptomics; white matter microstructure.

FIGURE 1

Regional differences in Aβ burden between CN Aβ+ and CN Aβ− group. (A) Average SUVR values in cortical and subcortical regions for the CN Aβ+ group, represented by color. (B) Average SUVR values in cortical and subcortical regions for CN Aβ− group, represented by color. (C) Difference in regional Aβ burden between CN Aβ+ and CN Aβ− group quantified with t value represented by color. Aβ burden is primarily in cortical regions. Only the left hemisphere is shown. Aβ, amyloid beta; CN, cognitively normal; SUVR, standardized uptake value ratio.

FIGURE 2

Comparative analysis of WM integrity between groups. (A) The WM fiber tracts analyzed are color‐coded: ATR in blue, FPT in green, STR in light blue, T‐PREM in pink, T‐PAR in purple, ST‐PREM in orange, CC‐III in yellow, and CC‐IV in dark blue. (B) Combined box and violin plots depict MD values in Aβ− (orange) and Aβ+ (purple) groups across each tract. MD were significantly higher in Aβ+ group compared to Aβ− group. Only MD and significant results are shown. *p _FDR < 0.05, **p _FDR < 0.01, ***p _FDR < 0.001. Values are residuals, adjusted for age, sex, APOE ɛ4 status, and education. Aβ, amyloid beta; APOE, apolipoprotein E; ATR, anterior thalamic radiation; CC‐III, corpus callosum rostral body; CC‐IV, corpus callosum anterior midbody; FDR, false discovery rate; FPT, fronto‐pontine tract; STR, superior thalamic radiation; T‐PREM, thalamo‐premotor tract; T‐PAR, thalamo‐parietal tract; ST‐PREM, striato‐premotor tract; WM, white matter.

FIGURE 3

Association of MD with age and global SUVR in impaired fiber tracts. (A) Increasing global SUVR is associated with increased MD in impaired fiber tracts, including age, sex, education, and APOE ɛ4 status as covariates. (B) Increasing age is associated with increased MD in impaired fiber tracts, including sex, education, and APOE ɛ4 status as covariates. Partial correlation coefficient (r) and p value adjusted by FDR (p _FDR) are provided for each tract, with Aβ− represented by orange dots and Aβ+ by purple dots. Solid lines reflect fitted regressions. Shading reflects 95% confidence interval. Only impaired fiber tracts are shown. Values are residuals, adjusted for age (only for [A]), sex, APOE ɛ4 status, and education. Aβ, amyloid beta; APOE, apolipoprotein E; FDR, false discovery rate; MD, mean diffusivity; SUVR, standardized uptake value ratio.

FIGURE 4

Association of MD of damaged fiber tracts and Aβ SUVR in connected cortical and subcortical regions. Increased SUVR in connected cortical regions is associated with increased MD in impaired fiber tracts, including age, sex, education, and APOE ɛ4 status as covariates. No significant association is found between MD in damaged fiber tracts and Aβ SUVR in connected subcortical regions, except for CC‐III and CC‐IV fiber tracts. Partial correlation coefficient (r) are provided for each tract. Solid lines reflect fitted regressions. Shading reflects 95% confidence interval. Only impaired fiber tracts are shown. Values are residuals, adjusted for age, sex, APOE ɛ4 status, and education. *p _FDR < 0.05, **pP _FDR < 0.01, ***p _FDR < 0.001. All partial correlation coefficients (r) and p‐value adjusted by the FDR (p _FDR) for each tract can be found in Table S6. Aβ, amyloid beta; APOE, apolipoprotein E; CC‐IV, corpus callosum anterior midbody; MD, mean diffusivity; SUVR, standardized uptake value ratio.

FIGURE 5

Transcriptomic signatures and cognitive traits of WM integrity. (A) The distribution of PLS1 genes in the brain is depicted as a word cloud, highlighting 509 genes with significant expression (p _FDR < 0.0001). (B) Functional enrichment analysis of PLS1 genes (two‐tailed hypergeometric test; p _FDR  <  0.0001). Only significant results are shown. (C) Cell type specificity of WM integrity (two‐tailed permutation test; ***p _FDR  <  0.0001). (D) Neurosynth‐based decoding of WM integrity. FDR, false discovery rate; WM, white matter.