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. 2025 Aug 12;17(3):e70157.
doi: 10.1002/dad2.70157. eCollection 2025 Jul-Sep.

Sex and ethnicity in early-onset Alzheimer's disease biomarkers and global function

Breton M Asken  1   2 , Wei-En Wang  1   3 , Franchesca Arias  1   2 , Shellie-Anne Levy  1   2 , Warren W Barker  1   4 , Monica Rosselli  1   5 , Rosie Curiel Cid  1   6 , Michael Marsiske  1   2 , Melissa J Armstrong  1   7 , David E Vaillancourt  1   3 , David A Loewenstein  1   6 , Glenn E Smith  1   2 , Ranjan Duara  1   4
Affiliations

Sex and ethnicity in early-onset Alzheimer's disease biomarkers and global function

Breton M Asken et al. Alzheimers Dement (Amst). .

Abstract

Introduction: Early-onset Alzheimer's disease (EOAD) may have distinct biomarker and clinical features from late-onset AD (LOAD). EOAD is understudied in ethnically heterogeneous populations.

Methods: We studied EOAD (N = 44, age 64.7 ± 5.5, 55% female, 52% Hispanic/Latino), LOAD (N = 113), early-onset non-AD (EOnonAD, N = 114), and clinically normal (CN, N = 93) individuals from the 1Florida Alzheimer's Disease Research Center. Group differences and demographic interactions were evaluated in plasma (phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain), neuroimaging (amyloid positron emission tomography, brain magnetic resonance imaging), and global function (Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes).

Results: AD-related biomarkers and global function were consistently worse in EOAD than EOnonAD and CN, and similar or worse than LOAD. Among EOAD, younger age related to greater amyloid burden among non-Hispanic/Latino individuals only. AD-related biomarker changes were more severe in females than males among non-Hispanic/Latino EOAD, but more severe among males in Hispanic/Latino EOAD.

Discussion: The biological and clinical features of EOAD may differ by sex and ethnicity.

Highlights: Alzheimer's disease (AD) biomarkers and global functional measures were measured in Hispanic and non-Hispanic individuals with early-onset AD (EOAD).Overall, AD-related biomarkers and global function were consistently worse in EOAD than non-AD cognitive decline and controls, and similar or worse than late-onset AD.Younger age related to greater amyloid burden among non-Hispanic EOAD, but not Hispanic EOAD.Hispanic EOAD males had more severe changes than females, contrasting findings in non-Hispanic EOAD (females more severe than males).

Keywords: Hispanic; early‐onset Alzheimer's disease; ethnicity; plasma biomarkers; sex.

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Conflict of interest statement

Authors report no disclosures relevant to the content of this work. David E. Vaillancourt reports consulting for Neuroimaging Solutions. All other authors report no disclosures. All author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Group differences in cognition (A‐B), plasma biomarkers (C‐E), amyloid burden (F), and brain volume (G‐H). Data are shown as covariate‐adjusted dependent variables. Solid horizontal black lines represent statistically significant group differences (P < 0.05) relative to EOAD. Dashed horizontal black lines had a medium effect size with P < 0.10. AD, Alzheimer's disease; CDR, Clinical Dementia Rating; CN, clinically normal; EOAD, early‐onset Alzheimer's disease; EOnonAD, early‐onset non‐Alzheimer's disease; GFAP, glial fibrillary acidic protein; LOAD, late‐onset Alzheimer's disease; MMSE, Mini‐Mental State Examination; NfL, neurofilament light chain; p‐tau, phosphorylated tau; ROI, region of interest
FIGURE 2
FIGURE 2
Main effects of demographic and genetic (APOE) predictors on AD‐related plasma biomarkers (A‐C), amyloid burden (D), and brain volume (E‐F). Data shown as standardized betas with 95% confidence intervals, separately for each study group. Confidence intervals that do not include a standardized beta of 0 were statistically significant predictors in that group. AD, Alzheimer's disease; APOE, apolipoprotein E; CN, clinically normal; EOAD, early‐onset Alzheimer's disease; EOnonAD, early‐onset non‐Alzheimer's disease; GFAP, glial fibrillary acidic protein; LOAD, late‐onset Alzheimer's disease; NfL, neurofilament light chain; p‐tau, phosphorylated tau; ROI, region of interest
FIGURE 3
FIGURE 3
Age by ethnicity interaction on cortical amyloid burden stratified by EOAD (A) versus LOAD (B). A significant interaction was observed in EOAD, whereby younger age was associated with greater amyloid burden only among non‐Hispanic participants. EOAD and LOAD status was defined by reported age of symptom onset before or after age 65, respectively. AD status was defined by plasma p‐tau217 concentration with a reference threshold of 0.56 pg/mL. Participants with elevated plasma p‐tau217 but a low amyloid PET burden (CLs < 25) are labeled with their raw plasma p‐tau217 concentrations. Amyloid burden is shown covariate adjusted (see Figure S2 in supporting information for unadjusted amyloid burden). CL, Centiloid; EOAD, early‐onset Alzheimer's disease; LOAD, late‐onset Alzheimer's disease; PET, positron emission tomography; pg/mL, picograms per milliliter; p‐tau, phosphorylated tau
FIGURE 4
FIGURE 4
Sex by ethnicity interaction on AD‐related biomarkers (A‐C) and clinical functioning (D) among EOAD. Statistically significant interactions were observed for plasma p‐tau217 (P = 0.009) and the AD cortical ROI volume (P = 0.005), with similar direction of effects for hippocampal volume (P = 0.14) and CDR Sum of Boxes (P = 0.08). Among non‐Hispanic participants, females had worse AD‐related biomarker and clinical measures than males. Among Hispanic participants, males had worse AD‐related biomarker and clinical measures than females. AD, Alzheimer's disease; CDR, Clinical Dementia Rating; EOAD, early‐onset Alzheimer's disease; p‐tau, phosphorylated tau; ROI, region of interest
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