Figure 1*F* | Aβ toxicity assay, cortical culture, nTg vs 14-3-3θ | nTg = 6; 14-3-3θ = 7 | Two-way ANOVA | Genotype: *F*_{(1,33)} = 20.28; *p* < 0.0001 Ab dose: *F*_{(2,33)} = 38.67; *p* < 0.0001 Interaction: *F*_{(2,33)} = 15.40, *p* < 0.0001 Sidak’s: nTg vs 14-3-3θ at 0 μm *p* = 0.2173, at 1 μm *p* = 0.0012, at 5 μm *p* < 0.0001 |

Figure 1*G* | Aβ toxicity assay, hippocampal culture, nTg vs 14-3-3θ | nTg = 6–7; 14-3-3θ = 7 | Two-way ANOVA | Genotype: *F*_{(1,35)} = 5.801, *p* = 0.0214 Ab dose: *F*_{(2,35)} = 27.00, *p* < 0.0001 Interaction: *F*_{(2,35)} = 1.626, *p* = 0.2112 Sidak’s: nTg vs 14-3-3θ at 0 μm *p* = 0.0506, at 1 μm *p* > 0.9999, at 5 μm *p* = 0.3181 |

Figure 1*H* | Aβ toxicity assay, cortical culture, nTg vs difopein | *n* = 4 | Two-way ANOVA | Genotype: *F*_{(1,18)} = 25.85, *p* < 0.0001 Ab dose: *F*_{(2,18)} = 42.68; *p* < 0.0001 Interaction: *F*_{(2,18)} = 9.481, *p* =0.0015 Sidak’s: nTg vs 14-3-3θ at 0 μm *p* = 0.9551, at 1 μm *p* = 0.0044, at 5 μm *p* < 0.0001 |

Figure 1*I* | Aβ toxicity assay, hippocampal culture, nTg vs difopein | *n* = 4 | Two-way ANOVA | Genotype: *F*_{(1,18)} = 3.952, *p* = 0.0622 Ab dose: *F*_{(2,18)} = 16.47, *p* < 0.0001 Interaction: *F*_{(2,18)} = 0.6126, *p* = 0.5529 Sidak’s: nTg vs 14-3-3θ at 0 μm *p* = 0.9639, at 1 μm *p* = 0.1763, at 5 μm *p* = 0.6845 |

Figure 2*E* | J20, 2 MPI, open field distance traveled | nTg/GF*p* = 10; nTg/14-3-3θ = 10; J20/GF*p* = 9; J20/14-3-3θ = 8 | Two-way ANOVA | Interaction: *F*_{(1,33)} = 3.746, *p* = 0.0615 APP genotype factor: *F*_{(1,33)} = 45.57, *p* < 0.001 AAV injection type factor: *F*_{(1,33)} = 5.910, *p* = 0.0207 Tukey’s: nTg/GFP vs J20/GFP, *p* = 0.0081; nTg/14-3-3θ vs J20/14-3-3θ, *p* < 0.0001; J20/GFP vs J20/14-3-3θ, *p* = 0.0279; nTg/GFP vs J20/GFP, *p* = 0.0081; nTg/14-3-3θ vs J20/GFP, *p* = 0.0184 |

Figure 2*F* | J20, 2 MPI, EPM percent time in open arm | nTg/GF*p* = 10; nTg/14-3-3θ = 10; J20/GF*p* = 9; J20/14-3-3θ = 8 | Two-way ANOVA | Interaction: *F*_{(1,33)} = 0.8565, *p* = 0.3614 APP genotype factor: *F*_{(1,33)} = 2.451, *p* = 0.1270 AAV injection type factor: *F*_{(1,33)} = 0.8338, *p* = 0.3678 |

Figure 2*G* | J20, 2 MPI, MWM latency to platform | nTg/GF*p* = 10; nTg/14-3-3θ = 10; J20/GF*p* = 9; J20/14-3-3θ = 7 | Three-way ANOVA | Time: *F*_{(4,85)} = 16.33, *p* < 0.0001 Genotype: *F*_{(1,85)} = 105.0, *p* < 0.0001 Virus: *F*_{(1,79)} = 2.544, *p* = 0.1147 Time × genotype: *F*_{(4,85)} = 3.840, *p* = 0.0064 Time × virus: *F*_{(4,79)} = 0.7289, *p* = 0.5749 Genotype × virus: *F*_{(1,79)} = 2.266, *p* = 0.1362 Time × genotype × virus: *F*_{(4,79)} = 2.713, *p* = 0.0357 Tukey’s: day 5 comparisons: nTg/GFP vs nTg/14-3-3θ, *p* > 0.9999; nTg/GFP vs J20/GFP, *p* = 0.1287; J20/GFP vs J20/14-3-3θ, *p* = 0.5494; nTg/GFP vs J20/14-3-3θ, *p* < 0.0001; nTg/14-3-3θ vs J20/GFP, *p* = 0.0794; ntg/14-3-3θ vs J20/14-3-3θ *p* < 0.0001 |

Figure 2*H* | J20, 2 MPI, MWM probe trial, time in target quadrant | nTg/GF*p* = 10; nTg/14-3-3θ = 10; J20/GF*p* = 9; J20/14-3-3θ = 7 | Two-way ANOVA | Interaction: *F*_{(1,32)} = 4.622, *p* = 0.0392 APP genotype factor: *F*_{(1,32)} = 3.675, *p* = 0.0642 AAV injection type factor: *F*_{(1,32)} = 3.170, *p* = 0.5773 Tukey’s: nTg/14-3-3θ vs J20/14-3-3θ, *p* = 0.0426 |

Figure 2*I* | AAV-injected J20 survival curve | nTg/GF*p* = 7; nTg/14-3-3θ = 10; J20/GF*p* = 10; J20/14-3-3θ = 11 | log-rank/Mantel–Cox | *p* = 0.201 |

Figure 2*J* | J20, 6 MPI, open field distance traveled | nTg/GF*p* = 9; nTg/14-3-3θ = 10; J20/GF*p* = 7; J20/14-3-3θ = 5 | Two-way ANOVA | Interaction: *F*_{(1,27) }= 0.7530, *p* = 0.3932 APP genotype factor: *F*_{(1,27)} = 40.84, *p* < 0.0001 AAV injection type factor: *F*_{(1,27)} = 0.1557, *p* = 0.9016 Tukey’s: nTg/GFP vs J20/GFP, *p* < 0.0001; nTg/14-3-3θ vs J20/14-3-3θ, *p* = 0.0044; nTg/GFP vs J20/14-3-3θ, *p* = 0.0015; nTg/14-3-3θ vs J20/GFP, *p* = 0.0002 |

Figure 2*K* | J20, 6 MPI, EPM percent time in open arm | nTg/GF*p* = 9; nTg/14-3-3θ = 10; J20/GF*p* = 7; J20/14-3-3θ = 5 | Two-way ANOVA | Interaction: *F*_{(1,27)} = 0.3644, *p* = 0.5511 APP genotype factor: *F*_{(1,27)} = 4.821, *p* = 0.0369 AAV injection type factor: *F*_{(1,27)} = 0.1706, *p* = 0.6828 |

Figure 2*L* | J20, 6 MPI, MWM latency to platform | nTg/GF*p* = 9; nTg/14-3-3θ = 10; J20/GF*p* = 7; J20/14-3-3θ = 5 | Three-way ANOVA | Time: *F*_{(4,75)} = 12.86, *p* < 0.0001 Genotype: *F*_{(1,75)} = 46.69, *p* < 0.0001 Virus: *F*_{(1,60)} = 6.839, *p* = 0.0113 Time × genotype: *F*_{(4,75)} = 0.5912, *p* = 0.6700 Time × virus: *F*_{(4,60)} = 0.6958, *p* = 0.5978 Genotype × virus: *F*_{(1,60)} = 0.3838, *p* = 0.5379 Time × genotype × virus: *F*_{(4,60)} = 0.2333, *p* = 0.9186 Tukey’s: day 5 comparisons: nTg/GFP vs nTg/14-3-3θ, *p* > 0.9999; nTg/GFP vs J20/GFP, *p* = 0.1562; J20/GFP vs J20/14-3-3θ, *p* > 0.9999; nTg/GFP vs J20/14-3-3θ, *p* = 0.3373; nTg/14-3-3θ vs J20/GFP, *p* = 0.3086; ntg/14-3-3θ vs J20/14-3-3θ *p* = 0.5425 |

Figure 3*C* | APP KI, 8–9 months, open field distance traveled | nTg = 10; APP KI = 16; APP KI/14-3-3θ = 11 | One-way ANOVA | *F*_{(2,34)} = 0.9122, *p* = 0.4112 |

Figure 3*D* | APP KI, 8–9 months, EPM percent time in open arm | nTg = 10; APP KI = 15; APP KI/14-3-3θ = 9 | One-way ANOVA | *F*_{(2,31)} = 11.17, *p* = 0.0002 Tukey’s: APP KI/14-3-3θ vs APP KI, *p* = 0.0001; APP KI/14-3-3θ- vs nTg, 0.0175 |

Figure 3*E* | APP KI, 8–9 months, passive avoidance latency to dark side, D2 | nTg = 10; APP KI = 14; APP KI/14-3-3θ = 8 | One-way ANOVA | *F*_{(2,29)} = 0.1705, *p* = 0.8441 |

Figure 4*A* | J20 hippocampal Aβ plaque load | J20/GF*p* = 6; J20/14-3-3θ = 5 | Unpaired, two-tailed, *t* test | *t* = 0.09254, df = 9; *p* = 0.9238 |

Figure 4*B* | APP KI hippocampal Aβ plaque load | APP KI = 16; APP KI/14-3-3θ = 10 | Unpaired, two-tailed, *t* test | *t* = 1.038, df = 24; *p* = 0.3084 |

Figure 4*C* | APP KI cortical Aβ plaque load | APP KI = 15; APP KI/14-3-3θ = 10 | Unpaired, two-tailed, *t* test | *t* = 1.475, df = 23; *p* = 0.1538 |

Figure 5*A* | J20 hippocampal synapsin immunoreactivity | nTg/GF*p* = 8; nTg/14-3-3θ = 9; J20/GF*p* = 5; J20/14-3-3θ = 5 | Two-way ANOVA | Interaction: *F*_{(1,23)} = 0.3085, *p* = 0.5839 APP genotype factor: *F*_{(1,23)} = 0.1737, *p* = 0.6807 AAV injection type factor: *F*_{(1,23)} = 0.7492, *p* = 0.3957 |

Figure 5*B* | APP KI hippocampal synapsin immunoreactivity | nTg = 9; APP KI = 16; APP KI/14-3-3θ = 9 | One-way ANOVA | *F*_{(2,31)} = 0.4169, *p* = 0.6627 |