Taken together, we have deciphered the temporal appearance of some of the AD-associated pathological alterations using the App knock-in mouse models which includes a striking early compensatory mitochondrial hyperactivity in both mild and more aggressive AD model mice, i.e., AppNL-F and AppNL-G-F mice, followed by a strong neuroinflammation and autophagic decline leading to faulty synapses. The gene discussed is APP; the disease is Alzheimer disease.