Fig 1: Magnitude of brain NAD+ homeostatic disruption correlates with the severity of human and mouse AD(A) NAD+ homeostasis is disrupted in human AD cerebral cortex, relative to control subjects (n = 14–18 per group, ∗∗∗p < 0.001, unpaired t test). Also see Table S1.(B) Greater disruption in human brain NAD+ homeostasis is associated with more p-Tau pathology. Also see Figure S5A and Tables S1 and S2.(C) Greater disruption in human brain NAD+ homeostasis is associated with more oxidative damage, as evidenced by protein carbonylation levels. Also see Figure S5B and Table S2.(D) Greater disruption in human brain NAD+ homeostasis is associated with more neuroinflammation, as evidenced by GFAP levels. Also see Figure S5C and Table S2.(E) Greater disruption in human brain NAD+ homeostasis is associated with more BBB deterioration, as evidenced by ZO-1 levels. Also see Figure S5D and Table S2.(F) Greater disruption in human brain NAD+ homeostasis is associated with more neuronal cell loss, as evidenced by NeuN levels. Also see Figure S5E and Table S2.(G) Greater disruption in human brain NAD+ homeostasis shows a trend of association with more synaptic loss, as evidenced by PSD-95 levels. Also see Figure S5F and Table S2.(H) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more p-tau pathology.(I) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more oxidative damage, as evidenced by protein carbonylation levels.(J) Greater disruption in 6-month-old 5xFAD brain NAD+ homeostasis is associated with more oxidative damage, as evidenced by protein carbonylation levels.(K) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more neuroinflammation, as evidenced by IL-2 levels.(L) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more neuroinflammation, as evidenced by IL-13 levels.(M) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more BBB deterioration, as evidenced by ZO-1 levels.(N) Greater disruption in 6-month-old 5xFAD brain NAD+ homeostasis is associated with more greatly impaired memory, as evidence by discrimination index in the NOR test.(O) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more greatly impaired memory, as evidence by discrimination index in the NOR test.(P) Greater disruption in 6-month-old 5xFAD brain NAD+ homeostasis is associated with more greatly impaired memory, as evidence by the number of platform crossings in the probe memory test of the Morris water maze.(Q) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with more greatly impaired memory, as evidence by the number of platform crossings in the probe memory test of the Morris water maze.(R) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with decreased ability to stay on the accelerating rotating rod, as evidenced by time until falling.(S) Greater disruption in 12-month-old 5xFAD brain NAD+ homeostasis is associated with decreased ability to stay on the accelerating rotating rod, as evidenced by rotation speed of the rod at falling.(T) Levels of the NAD+-synthesizing enzymes glutamine-dependent NAD+ synthetase (NADSYN1) and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) are reduced in human AD cerebral cortex, relative to control subjects, and present at normal levels in NDAN subjects (n = 73 for control, 80 for AD, and 27 for NDAN; ∗p < 0.05, ∗∗p < 0.01, limma linear regression).(U) Levels of NAD+-consuming enzymes NAD kinase 2 (NADK2), poly (ADP-ribose) polymerase 4 (PARP4), and sirtuin 1 (SIRT1) are increased in human AD cerebral cortex, relative to control subjects, and present at normal levels in NDAN subjects (n = 73 for control, 80 for AD, and 27 for NDAN, ∗∗p < 0.01, ∗∗∗∗p < 0.0001, limma linear regression).See also Figure S5.