SUMMARY/ABSTRACT: Overall ProjectThe strategic vision of the Precision Aging Network (PAN) is to develop the essential scientific knowledge tounderstand the discrepancy that currently exists between cognitive healthspan and human lifespan. We mustreveal the neural mechanisms that 1) account for optimal brain performance in old age resulting in healthycognitive function and 2) those that underlie decline in brain function leading to age-related cognitiveimpairment (ARCI) Alzheimers disease (AD) or Alzheimers disease-related dementias (ADRD). The ultimategoal of the PAN is to develop not only a strong scientific foundation for the essential knowledge needed tomatch cognitive healthspan with human lifespan but also to leverage big data approaches that apply precisionmedicine concepts to prolong optimal brain function. To achieve this goal of sustaining optimal cognitivefunction in old age and to extend quality of life for people across levels of risk for ARCI AD or ADRDwe maintain that methodologies such as those developed and implemented in the PAN will be required.Although chronological age is consistently associated with increasing incidence of disability including chronicbrain disorders such as AD and ADRD the exact mechanistic relationships between biological age anddecline in brain function is not known. The number of people now living with some form of dementia isestimated to be 50 million worldwide which is expected to double every 20 years. Because of the enormousheterogeneity in brain and cognitive function among individuals in their 70s 80s and 90s the urgent challengefor science medicine and healthcare providers is to discover interventions that are individually effective indelaying or preventing ARCI AD or ADRD.Untangling the complex relationship between age and cognitive performance requires a strategy that includesthe study of very large diverse well-characterized and longitudinally sampled populations. This will requirebig data but also the means to translate the massive amounts of information gathered into smart data orknowledge. This demands radically different conceptual models. Currently no single approach adequatelyidentifies the means to modify personal aging trajectories for improved brain health in individuals. Theapproach proposed in PAN is designed to overcome obstacles of earlier methods. The focus is on how todistinguish the various combinations of age sex genetics race-ethnicity health lifestyle choices andenvironmental factors that influence brain drivers that increase susceptibility to dysfunction as well asthose factors that increase brain protection and resistance against dysfunction.The fundamental principle of the precision medicine approach is to individualize. This will enable strongand specific predictions for each person to close the gap between cognitive healthspan and humanlifespan. The root of this concept is in the teachings of Hippocrates who said It is more important to knowwhat sort of person has a disease than to know what sort of disease a person has.