Domain-specific cognitive impairment is differentially affected by Alzheimer disease tau pathologic burden and spread

Abstract

Tau pathology in Alzheimer disease (AD) is often evaluated in regions associated with episodic memory impairment. However, heterogeneous spreading patterns of tau are observed and correspond to impairment in different cognitive domains. We have previously developed a metric to quantify tau spread extent that is robustly sensitive to atypical spreading patterns. Here, we evaluate tau spread relative to domain-specific and general cognitive impairments during early stages of AD. In total, 529 participants with baseline tau positron emission tomography (PET) and neuropsychological testing were separated into disease-stage groups based on amyloid PET positivity and clinical status via Clinical Dementia Rating^® (CDR^®). General cognition was assessed using the Knight Preclinical Alzheimer Cognitive Composite (Knight PACC). Domain-specific composites were calculated for episodic memory, semantic memory, working memory, and attention/processing speed. Baseline tau burden, the average tau intensity across previously defined AD signature regions, and baseline tau spread extent, the proportion of the brain with elevated tau pathology, were quantified for each participant as Tau Index and Tau Spatial Spread, respectively. Tau burden and tau spread were evaluated relative to baseline and longitudinal cognitive performance, as well as longitudinal clinical progression. Tau burden and tau spread extent both significantly correlate with cognitive impairment in symptomatic AD. Tau burden is most strongly correlated with episodic (r = -0.37, p = 0.02) and semantic (r = -0.36, p = 0.02) memory. In contrast, tau spread extent is most strongly correlated with the Knight PACC (r = -0.37, p = 0.01) and attention/processing speed (r = -0.44, p < 0.01), especially in preclinical AD (r = -0.27, p < 0.01). Tau burden captures more variance than tau spread extent in longitudinal change in the Knight PACC, episodic memory, semantic memory, attention/processing speed, and clinical progression. Tau burden strongly relates to baseline episodic and semantic memory, which may reflect that it is heavily weighted by entorhinal tau, a region previously linked to memory processing. In contrast, stronger associations between tau spread extent and baseline attention/processing speed could reflect the inclusion of additional brain regions, particularly the frontal lobe, which support a wider range of cognitive processing. Additionally, tau spread extent is generally more sensitive to baseline preclinical deficits; however, tau burden better estimates future decline across all cognitive domains and clinical symptom onset. Together, these findings suggest complementary utility of evaluating both tau burden and tau spread extent in early AD progression.

Keywords: Alzheimer disease; Positron Emission Tomography (PET); Tau spread; cognitive domains; cognitive impairment.

Fig. 1.

Schematic for the quantification of Tau Index and Tau Spatial Spread. Participant tau PET scans are first preprocessed to calculate voxel-wise SUVR images. These images are then processed in two independent pipelines to calculate Tau Index (TI) and Tau Spatial Spread (TSS). First, participant structural MRIs are segmented in FreeSurfer and applied to the participant SUVR image to calculate partial volume-corrected SUVRs for four regions of interest: the inferior temporal cortex, lateral occipital cortex, entorhinal cortex, and amygdala. TI is then calculated as the mean of the resulting regional SUVRs. Second, participant structural MRIs and SUVR images are compared with younger control scans in order to identify voxels with abnormal tau pathology in a process previously published (Doering et al., 2024). TSS is then calculated as the proportion of abnormal voxels within biologically relevant brain regions.

Fig. 2.

Baseline cognitive performance per disease-stage groups. Comparison of baseline cognitive domain composite scores across disease-stage groups. Pairwise comparisons conducted using Wilcoxon–Mann–Whitney U tests with multiple comparison correction using Benjamini–Hochberg procedure.

Fig. 3.

Tau Index and Tau Spatial Spread per disease-stage groups. Comparison of Tau Index and Tau Spatial Spread across disease-stage groups. Pairwise comparisons conducted using Wilcoxon–Mann–Whitney U tests with multiple comparison correction using Benjamini–Hochberg procedure.

Fig. 4.

Baseline cognitive performance relative to Tau Index or Tau Spatial Spread per disease-stage group. Comparison of baseline cognitive domain composite score and TI (top) or TSS (bottom) per disease-stage group (green: OC; yellow: Preclinical AD; red: Symptomatic AD). Spearman correlations reported with multiple comparison correction using Benjamini–Hochberg procedure per disease-stage group. Shaded area refers to 95% confidence interval of the regression slope.

Fig. 5.

Longitudinal cognitive performance estimated from baseline Tau Index and Tau Spatial Spread. Estimated longitudinal cognitive domain composite score performance dependent on baseline TI (top) or TSS (bottom). Estimated Marginal Means calculated from linear mixed effect regressions (TI Model and TSS Model) accounting for covariates age, sex, and education. Representative “low” and “high” values identified for TI and TSS from the participant sample.

Fig. 6.

Longitudinal clinical progression evaluated by baseline Tau Index and Tau Spatial Spread. Clinical progression evaluated for cognitively normal individuals (CDR = 0) at baseline with Kaplan–Meier survival curves where an event is classified as the first occurrence where participants demonstrate AD symptoms (CDR > 0). Survival is compared for participants with low/high TI (left) or TSS (right), categorized by median split of the participant sample.