There is something in the age related macular degeneration (AMD) story that does not fit comfortably within the framework of an ageing disease. First, in those with complement polymorphisms, which accounts for 50% of sufferers, abnormal choroidal blood flow occurs decades before disease .initiation [1]. Second, choroidal inflammation is present at similar early stages [2]. Likewise, early disease manifestations occur in complement factor H knock out mice. Here there is a significant decline in retinal adenosine triphosphate (ATP), which occurs long before a retinal phenotype appears [3, 4]. Reduced ATP signals senescence, and with its high metabolic demand, such a decline likely heralds trouble for the retina. These events imply that complement disruption impacts much earlier than expected.

But we should not be surprised. Complement is a player in CNS development [5]. Further, complement factor H (CFH) is expressed in the retinal pigmented epithelium (RPE), which during development is the ventricular margin where neuronal cell division occurs. The RPE guides retinal development by regulating the cell cycle and signalling cycle exit. Along its outer surface it guides choroidal development. Hence, in the eye complement and development are linked via the RPE [6, 7].

To address this, Sivapathasuntharam et al. [8] examined retinal development in Cfh−/− and Cfh+/− mice and showed significant disruptions at the retinal/RPE interface. However, after retinal differentiation there are no obvious deficits. But when mitochondria are examined in the newly differentiated tissue abnormalities are obvious, matching subsequent reductions in ATP and abnormalities in the ERG [8].

As cell cycle exit point is critical in determining cell fate [9], it is likely that abnormalities exist in retinal cell populations and/or their patterns of connectivity as a consequent of complement reduction. Likewise, there are probably differences in chordal architecture/function that harbour vulnerability exploited by age. Interestingly, these mice do not develop a retinal phenotype when kept in a pathogen free environment [10]. Hence, exploitation by age and environment are needed for disease progression.

Those with polymorphism of complement remain largely hidden without genotyping. Given the deficits revealed already [1, 2] it is likely that psychophysical or physiological investigations may show differences that distinguish these people whose problems may originate before birth.