Enrichment of S and Z polymorphisms of alpha-1-antitrypsin (AAT) in distinct subsets of patients with cognitive disorder (pre-existing affective disorders and APOE2 allele carriers) suggests that AAT variants are potential endophenotypes for Alzheimer Disease and related disorders of cognition, behavior and affect. Such disorders include ADD/ADHD, learning disabilities, ADEM, and susceptibility to brain injury in toxic/chemical/biological/immunological events. In Alzheimer Disease, S and Z alleles affect age of onset and low AAT levels define faster progression rate. Twenty to thirty percent of all dementia patients display AAT and/or We polymorphisms. Effects of AAT may involve inflammation of liver/lung, macrophage activation and iron and lipid metabolism. AAT, its regulation, and iron metabolism represent therapeutic targets and AAT can serve as a biomarker for vulnerability and disease progression.