Hypothesis of alterations in amyloid metabolism in ADC and opportunistic infections compared to AD. The diagram shows proteolytic cleavages of the largest isoform of APP (APP770) and interprets the observed differences in effects of HIV and opportunistic infections from those of Alzheimer's disease on these pathways. In the non-amyloidogenic pathway (a.), cleavage by α-secretase occurs after residue 687, which enables the secretion of the large, soluble ectodomain of APP (sAPPα) into the medium and retention of the 83-residue C-terminal fragment (α-CTF) in the membrane. The α-CTF fragment can undergo cleavage by γ-secretase at residue 711 or 713 to release the p3 peptides (c.). In the amyloidogenic pathway (b.), β-secretase cleaves after residue 671, which causes the secretion of the slightly truncated sAPPβ molecule and the retention of a 99 residue C-terminal fragment (β-CTF). This fragment can undergo further cleavage by γ-secretase to release 40 or 42 aminoacid-long Aβ fragments (c.). Cleavage of both α- and β-CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm. Hypothesized differences in the steps leading to CSF biomarker changes include: 1. an effect of CNS infection or immune activation on an early step in APP metabolism, in contrast to 2. deposition of Aβ1-42 in Alzheimer's disease.