Age and sex are associated with Alzheimer's disease neuropathology in Down syndrome

Abstract

Introduction: This study investigates the association of age and biological sex with Alzheimer's disease (AD) neuropathology in Down syndrome (DS).

Methods: We examined the frontal/occipital cortex in people with DS (n = 14/13, 1-39 years), DS with AD (DSAD) neuropathology (n = 18/19, 42-61 years), late-onset AD (n = 15/16, 72-96 years), and age-matched controls (n = 50/47)(n = 156). The area occupied by AT8 and 6E10 immunolabeling, representing tangle and plaque loads, respectively, was used for segmented linear regression analyses.

Results: There was elevated neuropathology after age 35 in DSAD, with inflection points at ∼31 years (amyloid-β [Aβ]) and ∼28 (phosphorylated tau [p-tau]) in the frontal cortex and ∼36 years (both Aβ and p-tau) in the occipital cortex. Occipital p-tau was higher in women relative to men with DS. Aβ and p-tau pathology were correlated in women with DS but not in men with DS in the occipital cortex.

Discussion: Women with DS may show a more advanced stage of tau pathology relative to men with DS.

Highlights: Amyloid-β (Aβ) and phosphorylated tau (p-tau) Alzheimer's disease (AD) pathology emerge after 30 years of age in the frontal cortex, followed 7 years later by pathology in the occipital cortex in Down syndrome (DS). Women with DS show a more rapid progression of AD neuropathology seen by trends in higher p-tau relative to men, despite similar levels of Aβ. Women with DS show a stronger association between Aβ and tau in the occipital but not frontal cortex relative to men with DS, independent of age.

Keywords: Alzheimer disease progression; beta‐amyloid; neuropathology; tau; trisomy 21.

FIGURE 1

Aβ and p‐tau are significantly elevated in DSAD compared to late‐onset AD and age‐matched controls. (A) Representative images show immunohistochemical labeling of Aβ (6E10) and p‐tau (AT8) in fixed human post mortem tissue. Right side of the grid shows an overlay of a trained pixel classifier in Qupath (Random Trees). (B,C) Differences in the level of Aβ and p‐tau in the frontal cortex. (D,E) Differences in the level of Aβ and p‐tau in the occipital cortex. The Mann–Whitney U test was used to make specific group comparisons and to compare females and males with DSAD. *indicates p < 0.05, **indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001. Aβ, amyloid‐β; DSAD, Down syndrome with Alzheimer's disease; AD, Alzheimer's disease p‐tau, phosphorylated tau

FIGURE 2

Pathology in DS and DSAD is significantly elevated after the age of 40. (A–D) Aβ and p‐tau are highly correlated with age in the DS population. All markers were significantly positively correlated with age (p < 0.001). (E–H) Segmented linear regression was used to determine inflection points in both frontal and occipital cortices for Aβ and p‐tau. Dotted lines indicate 95% confidence intervals. Aβ, amyloid‐β; DS, Down syndrome; DSAD, Down syndrome with Alzheimer's disease; p‐tau, phosphorylated tau

FIGURE 3

Frontal cortex shows earlier and faster estimated accumulation rates in DS and DSAD. Estimated mean positivity rate for Aβ and p‐tau by age, region, and class. Estimates based on β‐binomial regression with 80% confidence interval. Mean positivity increases in all groups with age at autopsy. Mean rates of Aβ are around 10 times higher than those of age‐matched controls. Mean p‐tau positivity was about twice as high as Aβ positivity. The rate of accumulation in the FCX appeared higher than in the OCC. Estimated coefficients in beta‐binomial regression of positivity rate on post mortem age, region, and diagnostic class. Aβ, amyloid‐β; DS, Down syndrome; DSAD, Down syndrome with Alzheimer's disease; FCX, frontal cortex; OCC, occipital cortex; p‐tau, phosphorylated tau

FIGURE 4

Aβ and p‐tau are significantly associated in the occipital cortex of women with DS. Partial correlation scatter plots of Aβ and p‐tau (residuals from regression on age), in men and women with DS and DSAD, show no significance in the frontal cortex (p > 0.05). Aβ and p‐tau show no significant association in men in the occipital cortex but demonstrate significance in the occipital cortex of women (p < 0.05). Aβ, amyloid‐β; DS, Down syndrome; DSAD, Down syndrome with Alzheimer's disease; p‐tau, phosphorylated tau.