Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer's disease

Abstract

Background: To assess the effects of apolipoprotein E (ApoE) ε4 genotype on amyloid-β (Aβ) and tau burden and their longitudinal changes in Alzheimer's disease (AD) spectrum.

Methods: Among 272 individuals who underwent PET scans (¹⁸F-florbetaben for Aβ and ¹⁸F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for the partial volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.

Results: The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.

Conclusions: Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on the Aβ burden depending on the existing amyloidosis and may enhance vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

Keywords: Alzheimer disease; Amyloid-β; ApoE; Positron emission tomography; Tau.

Fig. 1

Comparison of baseline ¹⁸F-florbetaben and ¹⁸F-flortaucipir SUVR between the ApoE ε4− and ε4+ groups. a VOI-based comparisons between the ApoE ε4− and ε4+ groups. Data are presented as means (dots) and standard deviations (error bars) of the ε4− (blue) and ε4+ (red) groups. P values for the comparison between the ε4− and ε4+ groups are expressed as -Log₁₀P. Red bars represent the regions that survived correcting for region-wise multiple comparisons (false discovery rate-corrected P < 0.05), and blue dotted lines represent uncorrected P = 0.05. b Surface-based comparisons between the ApoE ε4− and ε4+ groups. Regions surrounded by white lines (ε4− < ε4+ in Aβ and tau burden in all individuals) represent the cortical areas that survived correcting for multiple comparisons (false discovery rate-corrected P < 0.05). P values for the comparison between the ε4− and ε4+ groups are expressed as -Log₁₀P. Aβ±, Aβ-positivity; ApoE, apolipoprotein E; SUVR, standardized uptake value ratio; A, ¹⁸F-florbetaben; T, ¹⁸F-flortaucipir

Fig. 2

Comparison of baseline ¹⁸F-florbetaben (a) and ¹⁸F-flortaucipir (b) SUVR values between the ApoE ε4− and ε4+ groups in each group for cognitive status. Blue and light blue bars represent the -Log₁₀P for ApoE ε4− > ε4+, and red and light red bars represent the -Log₁₀P for ApoE ε4− < ε4+. Blue and red bars represent the regions that survived after correcting for multiple comparisons (false discovery rate-corrected P < 0.05), and blue dotted lines represent uncorrected P = 0.05

Fig. 3

Spaghetti plots showing individual changes in regional SUVR values. In 187 Aβ± individuals, the individual data points measured at baseline and follow-up are displayed as color-coded dots (cyan = Aβ−/ApoE ε4−, green = Aβ−/ApoE ε4+, orange = Aβ+/ApoE ε4−, red = Aβ+/ApoE ε4+). Aβ±, Aβ-positivity; ApoE, apolipoprotein E; SUVR, standardized uptake value ratio; A, ¹⁸F-florbetaben; T, ¹⁸F-flortaucipir

Fig. 4

Comparison of annual changes in ¹⁸F-florbetaben and ¹⁸F-flortaucipir SUVR between the ApoE ε4− and ε4+ groups. a VOI-based comparison between the ApoE ε4− and ε4+ groups. Data are presented as means (dots) and standard deviations (error bars) of the ε4− (blue) and ε4+ (red) groups. P values for the comparison between the ε4− and ε4+ groups are expressed as -Log₁₀P. Red bars represent the regions that survived correcting for region-wise multiple comparisons (false discovery rate-corrected P < 0.05), and blue dotted lines represent uncorrected P = 0.05. b Surface-based comparisons between the ApoE ε4− and ε4+ groups. Regions surrounded by white lines (ε4− < ε4+ in Aβ and tau accumulation rates in all individuals, and ε4− < ε4+ in tau accumulation rate in Aβ+ individuals) represent the cortical areas that survived correcting for multiple comparisons (false discovery rate-corrected P < 0.05). P values for the comparison between the ε4− and ε4+ groups are expressed as -Log₁₀P. P values for the comparison between the baseline and follow-up are expressed as -Log₁₀P. Aβ±, Aβ-positivity; ApoE, apolipoprotein E; SUVR, standardized uptake value ratio; A, ¹⁸F-florbetaben; T, ¹⁸F-flortaucipir

Fig. 5

P for trend analysis of baseline ¹⁸F-florbetaben and ¹⁸F-flortaucipir SUVR and their longitudinal accumulation rates across the ApoE ε4-negative, heterozygous, and homozygous groups. Data are presented as means and standard deviations (error bars) of ε4-negative (blue), ε4-heterozygous (green), and ε4-homogygous (red) groups. Regions that showed significant differences in a dose-dependent manner after adjusting for sex, age, duration of education, and MMSE score (uncorrected P for trend < 0.05) and additionally survived correcting for region-wise multiple comparisons (false discovery rate-corrected P < 0.05) are presented as red bars. Blue dotted lines represent uncorrected P for trend = 0.05. Rightward direction of horizontal bars represents an SUVR value increased with higher numbers of ε4 alleles, while the leftward direction represents an SUVR value decreased with higher numbers of ε4 alleles. Aβ±, Aβ-positivity; ApoE, apolipoprotein E; SUVR, standardized uptake value ratio; A, ¹⁸F-florbetaben; T, ¹⁸F-flortaucipir