Impact of APOE on amyloid and tau accumulation in argyrophilic grain disease and Alzheimer’s disease

Raulin, Ana-Caroline; Doss, Sydney V.; Heckman, Michael G.; Craver, Emily C.; Li, Zonghua; Ikezu, Tadafumi C.; Sekiya, Hiroaki; Liu, Chia-Chen; Martens, Yuka A.; Rosenberg, Cassandra L.; Kuchenbecker, Lindsey A.; DeTure, Michael; Reichard, R. Ross; Nguyen, Aivi T.; Constantopoulos, Eleni; Larsen, Rachel A.; Kounaves, Emmaline K.; Murray, Melissa E.; Dickson, Dennis W.; Petersen, Ronald C.; Bu, Guojun; Kanekiyo, Takahisa

doi:10.1186/s40478-024-01731-0

Acta Neuropathologica Communications

Table 4 Associations of neuropathological measures with AD-related molecules (FA)

From: Impact of APOE on amyloid and tau accumulation in argyrophilic grain disease and Alzheimer’s disease

Variable	N	Unadjusted analysis		Adjusting for age and sex		Full multivariable analysis
Variable	N	β (95% CI)	P-value	β (95% CI)	P-value	β (95% CI)	P-value
Association with Aβ40-FA
Age	333	− 2.58 (− 5.02, − 0.14)	0.038	− 2.45 (− 4.95, 0.06)	0.056	0.60 (− 1.64, 2.83)	0.60
Sex	333	1.79 (− 2.06, 5.64)	0.36	0.91 (− 3.03, 4.85)	0.65	− 0.62 (− 4.07, 2.83)	0.72
APOE4	333	14.02 (10.43, 17.60)	< 0.001	13.87 (10.15, 17.59)	< 0.001	8.78 (4.93, 12.62)	< 0.001
VaD	333	− 1.43 (− 5.46, 2.60)	0.49	− 0.98 (− 5.06, 3.11)	0.64	− 0.41 (− 3.98, 3.16)	0.82
CAA	333	22.92 (15.89, 29.96)	< 0.001	22.76 (15.67, 29.84)	< 0.001	20.94 (14.49, 27.40)	< 0.001
Neuritic plaque score	333	6.05 (4.53, 7.57)	< 0.001	5.97 (4.43, 7.52)	< 0.001	2.67 (0.62, 4.71)	0.011
TDP-43	333	0.44 (− 6.88, 7.76)	0.91	0.82 (− 6.51, 8.15)	0.83	− 3.81 (− 10.17, 2.55)	0.24
Synuclein	333	5.54 (1.08, 9.99)	0.015	4.80 (0.27, 9.33)	0.038	0.17 (− 3.85, 4.19)	0.93
AD-tau	327	12.48 (8.77, 16.19)	< 0.001	12.23 (8.46, 16.01)	< 0.001	4.39 (− 0.28, 9.06)	0.065
AGD-tau	333	− 7.71 (− 13.13, − 2.28)	0.006	− 7.02 (− 12.52, − 1.52)	0.012	− 2.40 (− 7.28, 2.49)	0.33
Association with Aβ42-FA
Age	348	− 4.10 (− 8.31, 0.12)	0.057	− 4.15 (− 8.50, 0.20)	0.062	2.71 (− 0.70, 6.11)	0.12
Sex	348	1.25 (− 5.53, 8.03)	0.72	− 0.34 (− 7.30, 6.61)	0.92	1.47 (− 3.80, 6.73)	0.58
APOE4	348	25.05 (18.75, 31.36)	< 0.001	25.30 (18.69, 31.90)	< 0.001	7.60 (1.68, 13.53)	0.012
VaD	348	− 0.66 (− 7.78, 6.45)	0.86	0.46 (− 6.77, 7.68)	0.90	3.48 (− 1.99, 8.95)	0.21
CAA	348	20.19 (6.72, 33.66)	0.003	19.91 (6.34, 33.47)	0.004	14.11 (3.86, 24.35)	0.007
Neuritic plaque score	348	18.06 (15.85, 20.27)	< 0.001	18.31 (16.05, 20.57)	< 0.001	13.03 (9.93, 16.13)	< 0.001
TDP-43	348	11.83 (− 0.77, 24.44)	0.066	12.04 (− 0.60, 24.67)	0.062	0.18 (− 9.42, 9.77)	0.97
Synuclein	348	11.02 (3.15, 18.88)	0.006	9.97 (1.94, 18.00)	0.015	− 1.23 (− 7.39, 4.94)	0.70
AD-tau	342	35.46 (29.68, 41.25)	< 0.001	35.42 (29.50, 41.34)	< 0.001	12.27 (5.23, 19.31)	< 0.001
AGD-tau	348	− 19.91 (− 29.26, − 10.56)	< 0.001	− 19.18 (− 28.66, − 9.70)	< 0.001	− 3.81 (− 11.20, 3.58)	0.31
Association with apoE-FA
Age	346	− 0.53 (− 0.76, − 0.29)	< 0.001	− 0.51 (− 0.75, − 0.27)	< 0.001	− 0.25 (− 0.48, − 0.02)	0.031
Sex	346	0.30 (− 0.08, 0.69)	0.12	0.12 (− 0.26, 0.51)	0.53	0.14 (− 0.20, 0.49)	0.42
APOE4	346	1.39 (1.03, 1.76)	< 0.001	1.25 (0.88, 1.63)	< 0.001	0.79 (0.39, 1.18)	< 0.001
VaD	346	− 0.36 (− 0.76, 0.05)	0.082	− 0.24 (− 0.64, 0.17)	0.25	− 0.09 (− 0.45, 0.28)	0.63
CAA	346	1.26 (0.51, 2.02)	0.001	1.17 (0.43, 1.91)	0.002	0.82 (0.15, 1.49)	0.016
Neuritic plaque score	346	0.74 (0.59, 0.89)	< 0.001	0.70 (0.55, 0.85)	< 0.001	0.65 (0.44, 0.85)	< 0.001
TDP-43	346	0.43 (− 0.30, 1.17)	0.25	0.51 (− 0.21, 1.23)	0.16	0.04 (− 0.61, 0.69)	0.91
Synuclein	346	0.55 (0.09, 1.00)	0.018	0.38 (− 0.07, 0.83)	0.10	− 0.15 (− 0.56, 0.26)	0.47
AD-tau	340	1.08 (0.70, 1.46)	< 0.001	0.96 (0.58, 1.34)	< 0.001	− 0.30 (− 0.77, 0.16)	0.20
AGD-tau	346	− 0.64 (− 1.19, − 0.10)	0.021	− 0.48 (− 1.03, 0.06)	0.080	0.04 (− 0.45, 0.54)	0.86
Association with tTau-FA
Age	353	0.03 (− 0.03, 0.09)	0.29	0.03 (− 0.03, 0.09)	0.37	0.00 (-0.07, 0.06)	0.92
Sex	353	− 0.04 (− 0.14, 0.06)	0.41	− 0.03 (− 0.13, 0.07)	0.56	− 0.03 (− 0.13, 0.07)	0.52
APOE4	353	− 0.16 (− 0.26, − 0.06)	0.001	− 0.16 (− 0.26, − 0.05)	0.003	− 0.11 (− 0.22, 0.00)	0.059
VaD	353	0.01 (− 0.09, 0.12)	0.79	0.01 (− 0.10, 0.11)	0.88	0.02 (− 0.09, 0.12)	0.74
CAA	353	− 0.06 (− 0.26, 0.13)	0.52	− 0.05 (− 0.25, 0.14)	0.60	− 0.05 (− 0.25, 0.14)	0.61
Neuritic plaque score	353	− 0.04 (− 0.09, − 0.00)	0.041	− 0.04 (− 0.09, 0.00)	0.055	0.01 (− 0.05, 0.06)	0.82
TDP-43	353	− 0.13 (− 0.32, 0.05)	0.15	− 0.14 (− 0.33, 0.04)	0.13	− 0.08 (− 0.27, 0.10)	0.37
Synuclein	353	− 0.11 (− 0.22, 0.01)	0.069	− 0.10 (− 0.21, 0.02)	0.11	− 0.08 (− 0.20, 0.04)	0.21
AD-tau	347	− 0.15 (− 0.25, − 0.05)	0.003	− 0.15 (− 0.25, − 0.05)	0.004	− 0.11 (− 0.25, 0.02)	0.098
AGD-tau	353	0.08 (− 0.06, 0.22)	0.27	0.07 (− 0.08, 0.21)	0.36	0.02 (− 0.12, 0.17)	0.74
Association with pTau181-FA
Age	340	− 0.39 (− 0.52, − 0.25)	< 0.001	− 0.40 (− 0.54, − 0.26)	< 0.001	− 0.22 (− 0.34, − 0.10)	< 0.001
Sex	340	0.06 (− 0.17, 0.29)	0.62	− 0.10 (− 0.32, 0.13)	0.39	− 0.07 (− 0.26, 0.12)	0.45
APOE4	340	0.85 (0.64, 1.07)	< 0.001	0.74 (0.53, 0.96)	< 0.001	0.28 (0.07, 0.49)	0.010
VaD	340	− 0.08 (− 0.32, 0.15)	0.49	0.04 (− 0.19, 0.27)	0.73	0.10 (− 0.10, 0.29)	0.34
CAA	340	0.46 (0.02, 0.90)	0.041	0.44 (0.01, 0.87)	0.044	0.29 (− 0.06, 0.65)	0.10
Neuritic plaque score	340	0.52 (0.44, 0.61)	< 0.001	0.49 (0.41, 0.57)	< 0.001	0.31 (0.20, 0.42)	< 0.001
TDP-43	340	0.39 (− 0.04, 0.83)	0.077	0.41 (− 0.01, 0.83)	0.056	0.03 (− 0.32, 0.38)	0.87
Synuclein	340	0.35 (0.09, 0.62)	0.009	0.22 (− 0.04, 0.49)	0.092	− 0.08 (− 0.30, 0.14)	0.50
AD-tau	334	1.09 (0.89, 1.28)	< 0.001	1.00 (0.81, 1.20)	< 0.001	0.41 (0.16, 0.66)	0.002
AGD-tau	340	− 0.57 (− 0.90, − 0.24)	< 0.001	− 0.48 (− 0.80, − 0.17)	0.003	− 0.08 (− 0.35, 0.19)	0.57

β regression coefficient; CI Confidence interval. β values, 95% CIs, and p-values result from linear regression models. β values are interpreted as the change in mean AD-related molecule on the cube root (Aβ40-FA, Aβ42-FA, apoE-FA, pTau181-FA) or natural logarithm scale (tTau-FA) corresponding to each 10-year increase in age, male sex, presence of APOE4, presence of VaD, presence of CAA, 1 unit increase in neuritic plaque score, presence of TDP-43 pathology, presence of synucleinopathy, presence of AD-tau or presence of AGD-tau. Full multivariable models were adjusted for age, sex, and all variables with an association P-value < 0.05 in the unadjusted analysis for the given AD-related molecule. P-values < 0.005 were considered as statistically significant after applying a Bonferroni correction for multiple testing separately for each AD-related molecule; significant findings are shown in bold

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