Clinical characteristics and biomarker profile in early- and late-onset Alzheimer's disease: the Shanghai Memory Study

Abstract

Early-onset Alzheimer's disease constitutes ∼5-10% of Alzheimer's disease. Its clinical characteristics and biomarker profiles are not well documented. To compare the characteristics covering clinical, neuropsychological and biomarker profiles between patients with early- and late-onset Alzheimer's disease, we enrolled 203 patients (late-onset Alzheimer's disease = 99; early-onset Alzheimer's disease = 104) from a Chinese hospital-based cohort, the Shanghai Memory Study. A full panel of plasma biomarkers under the amyloid/tau/neurodegeneration framework including plasma amyloid beta 40, amyloid beta 42, total-tau, neurofilament light chain and phosphorylated tau 181 were assayed using ultra-sensitive Simoa technology. Seventy-five patients underwent an amyloid molecular positron emission tomography scan whereas 43 received comprehensive amyloid, Tau deposition and hypometabolism analysis. Clinical features, plasma and imaging biomarkers were compared cross-sectionally. Compared to those with late-onset Alzheimer's disease, patients with early-onset Alzheimer's disease presented more severe impairment in language function, lower frequency of APOE ɛ4 and lower levels of plasma neurofilament light chain (all P < 0.05). The plasma phosphorylated tau 181 concentration and phosphorylated tau 181/amyloid beta 42 ratios were higher in early-onset Alzheimer's disease than in late-onset Alzheimer's disease (all P < 0.05). More severe Tau deposition as indicated by ¹⁸F-florzolotau binding in the precuneus, posterior cingulate cortex and angular gyrus was observed in the early-onset Alzheimer's disease group. Plasma phosphorylated tau 181 was associated with earlier age at onset and domain-specific cognitive impairment, especially in patients with early-onset Alzheimer's disease. We concluded that patients with early-onset Alzheimer's disease differed from late-onset Alzheimer's disease in cognitive performance and biomarker profile. A higher burden of pathological tau was observed in early-onset Alzheimer's disease and was associated with earlier age at onset and more profound cognitive impairment.

Keywords: APOE; Alzheimer’s disease; PET; plasma NfL; plasma p-tau181.

Graphical Abstract

Figure 1

Concentrations of plasma biomarkers among patients with different AAO. (A–F) Comparison of plasma biomarkers in the total sample and CDR-based subgroups between EOAD and LOAD groups under the ATN framework. AAO, age at onset; CDR-GS, Clinical Dementia Rating-global score; Aβ, amyloid-beta protein; NfL, neurofilament light chain; P-tau181, tau phosphorylated at threonine 181. P-values were calculated based on log-transformed data. ANCOVA analysis was conducted for the group comparison. Sex, education, APOE genotype and CDR-GS were adjusted in the first analysis; sex, education and APOE genotype were adjusted in the subgroup analysis. Statistic values: F = 2.772, P = 0.099; F_(CDR≤1) = 1.745, P = 0.182; F_{(CDR = 2)} = 0.083, P = 0.774; F_{(CDR = 3)} = 1.155, P = 0.294, respectively, for A. F = 5.856, P = 0.017; F_(CDR≤1) = 7.432, P = 0.026; F_{(CDR = 2)} = 1.700, P = 0.253; F_{(CDR = 3)} = 0.050, P = 0.258 for B. F = 0.843, P = 0.271; F_(CDR≤1) = 1.867, P = 0.165; F_{(CDR = 2)} = 0.054, P = 0.938; F_{(CDR = 3)} = 0.032, P = 0.815, respectively, for C. F = 16.302, P < 0.001; F_(CDR≤1) = 10.093, P = 0.001; F_{(CDR = 2)} = 10.285, P = 0.002; F_{(CDR = 3)} = 0.004, P = 0.830, respectively, for D. F = 20.709, P < 0.001; F_(CDR≤1) = 11.217, P = 0.006; F_{(CDR = 2)} = 12.989, P = 0.003; F_{(CDR = 3)} = 0.935, P = 0.102, respectively, for E. F = 0.887, P = 0.454; F_(CDR≤1) = 0.570, P = 0.605; F_{(CDR = 2)} = 0.741, P = 0.265; F_{(CDR = 3)} = 0.364, P = 0.408, respectively, for F.

Figure 2

Mean images and group comparison of PET imaging biomarker. (A) Mean interpolated surface projections of average SUVR maps of EOAD and LOAD groups for amyloid (¹⁸F-florbetapir, upper), tau (¹⁸F-florzolotau, middle) and hypometabolism (¹⁸F-FDG, lower) PET. (B) Voxel-wise comparisons were performed using a two-sample t-test, adjusting for sex. Significant maps were identified at a threshold of P < 0.0001 with a minimum cluster size of 10 voxels, uncorrected for multiple comparisons. EOAD, early-onset Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; SUVR, standardized uptake value ratio; PET, positron emission tomography.

Figure 3

Correlations between plasma biomarker concentrations and cognitive domains. (A) The correlations between plasma biomarker concentrations and cognitive domains in the EOAD group; (B) the correlations between plasma biomarker concentrations and cognitive domains in the LOAD group. The correlation coefficients (r) and P-values were obtained from partial correlation analysis, adjusting for sex, CDR-GS, education duration and APOE genotype. Plasma biomarker concentrations were log-transformed before analysis. Aβ, amyloid-beta protein; NfL, neurofilament protein light chain; p-tau181, tau phosphorylated at threonine 181.