Abstract Background Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). Aim To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. Methods LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain_ECF) and intracellular (brain_ICF) fluids and cerebrospinal fluid of the subarachnoid space (CSF_SAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC₅₀ values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. Results The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain_ECF, brain_ICF and CSF_SAS PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC₅₀ values were not reached. Semagacestat brain PK plateau levels were below the IC₅₀ of gamma-secretase for half of the interdose interval, unlike CSF_SAS PK profiles that were consistently above IC_50. Conclusion This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSF_SAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer’s, this study shows that the impact of aging and Alzheimer’s pathology on CNS distribution of the five drugs is insignificant.