Alzheimer's disease (AD) represents a major medical and health system challenge, and the need for early diagnosis of AD is widely recognized. We have identified a novel biomarker that distinguishes human subjects with mild cognitive impairment (MCI) or AD from similarly aged individuals with normal cognition, and appears to identify patients at risk for cognitive deterioration. The biomarker is a protein termed NPTX2 that is normally present in cerebrospinal fluid (CSF). In its normal function, NPTX2 is essential for "wiring" of the developing brain and for adaptions in the adult brain necessary for memory. In MCI/AD, NPTX2 appears essential to adapt to amyloid Aß accumulation, which is known to precede dementia. Accordingly, down-regulation of NPTX2 in AD represents a loss of brain resilience that can cause disruption of memory. CSF NPTX2 is particularly important as a potential diagnostic since it monitors brain heath that is independent of current best biomarkers including Aß42 and tau. Proposed studies will determine how to best utilize this new tool for the diagnosis of AD, and to assess its utility in other age-related dementing illnesses.