Joint spatial associations of amyloid beta and tau pathology in Down syndrome and preclinical Alzheimer's disease: Cross-sectional associations with early cognitive impairments

Abstract

Introduction: Individuals with Down syndrome (DS) have elevated risks for Alzheimer's disease (AD) due to amyloid beta (Aβ) precursor protein overexpression, with nearly all developing AD pathology by age 40 at autopsy. This study examined spatial associations between Aβ and tau burden in DS and neurotypical aging.

Methods: Data included 145 DS (25-67 years) and 191 neurotypical aging individuals (63-89 years). Regional Aβ and tau positron emission tomography outcomes were analyzed using multiset canonical correlation analysis to identify joint Aβ/tau spatial patterns, with regression models assessing associations with age and cognition.

Results: For a given Aβ burden, cognitively stable DS individuals exhibited relatively higher tau burden than neurotypical aging, while DS mild cognitive impairment/AD individuals exhibited more widespread pathology. Joint Aβ/tau patterns were associated with episodic memory impairment in DS and, as the disease progresses, executive dysfunction.

Discussion: DS exhibits overlapping and distinct AD-related neuropathology features, emphasizing the importance of biomarkers for early detection and intervention.

Highlights: There are distinct amyloid beta (Aβ) and tau spatial patterns in Down syndrome (DS): For a given level of Aβ burden, individuals with DS exhibited greater and more widespread tau burden compared to neurotypical aging, even before a clinical diagnosis of dementia. Aβ-associated tau burden was linked to episodic memory impairment in DS prior to dementia, with executive dysfunction emerging as the disease progressed, highlighting the sequential impact of pathology on cognition. The unique pattern of early striatal Aβ accumulation in DS supports its use as a potential biomarker for tracking disease progression and guiding clinical trial inclusion criteria for Alzheimer's disease interventions in DS.

Keywords: Alzheimer's disease; Down syndrome; amyloid; memory; multivariate analysis; preclinical; tau.

FIGURE 1

MCCA‐derived joint spatial patterns of Aβ and tau deposition. A,B, Across DS‐CS individuals, elevated cortical and striatal Aβ burden (highest weights in the striatum and frontal cortex) was associated with elevated tau burden in early‐to‐intermediate tau regions, with highest weights in early‐tau regions (e.g., entorhinal). C,D, Across all individuals with DS, elevated cortical and striatal Aβ burden (highest weights in the striatum and frontal cortex) was associated with elevated tau burden in early‐to‐late tau regions (highest weights in early tau regions). E,F, Across cognitively unimpaired HABS‐CS individuals, elevated cortical Aβ burden (highest weights in the frontal cortex) was associated with elevated tau burden in early‐tau regions, with the Aβ pattern exhibiting lower weights in the striatum compared to DS. * Regional weights were estimated for bilateral regions; however, for visualization purposes, only regional weights for the right hemisphere were displayed. Aβ, amyloid beta; CS, cognitively stable; DS, Down syndrome; HABS, Harvard Aging Brain Study; MCCA, multiset canonical correlation analysis

FIGURE 2

Associations between joint Aβ and tau pattern expressions (subject scores) and clinical outcomes across all DS individuals. Higher expressions of the DS‐related Aβ (A) and tau (B) patterns expressions were correlated significantly with older age and worse episodic memory (Cued Recall Task scores) and executive function (Stroop Dog and Cat scores). Aβ, amyloid beta; AD, Alzheimer's disease; CS, cognitively stable; DS, Down syndrome; MCI, mild cognitive impairment