Alzheimer' s disease (AD) is commonly, not always, associated with insulin-resistant, hyperinsulinemic, and obesity/type-2-diabetic (O/T2D) states. Partial deficiencies of brain insulin receptor (IR) indeed occur in both O/T2D-AD and human AD, but these deficiencies can be bypassed by hyperinsulinemia, which activates atypical protein kinase C (aPKC) and β-secretase, increases Aβ-peptide and phospho-thr-231-tau levels, and induces memory impairments; importantly, these aberrations are reversed by reduction of liver/aPKC-dependent hyperinsulinemia or direct blockade of brain aPKC. New evidence shows that aPKC acts via nuclear factor kappa-B to increase β-secretase mRNA/protein levels in brain, where β-secretase acts on both β-amyloid precursor protein to increase AD risk and IR to limit beneficial (aPKC independent) insulin effects, particularly in normo/hypoinsulinemic AD, and liver, where β-secretase acts on IR to initiate or abet development of insulin resistance and compensatory hyperinsulinemia