**4. Relation of Mice Models to Human Studies**

A number of shortcomings exist to studies of AA in humans, such as accurate assessment of intake and determination of tissue levels of AA (discussed below). Thus, information from animal models can be critical to understanding changes in the brains of humans under AA deficiency. The gulo and SVCT2 knockout models have already been used to model long-term AA deficiency in disease states such as Alzheimer's disease, diabetes and atherosclerosis [88,105–107] by crossing them with other mouse models of disease (e.g., APP/PSEN1, ApoE). These models can even be crossed together to create *in vivo* models of extreme deficiency [108], although these may be less directly applicable to the human case. One key advantage to such models is the ability to investigate numerous biochemical correlates to disease and nutritional deficiency, including behavioral and cognition changes. Of course there are weaknesses to any animal model, particularly when genetic changes are artificially manufactured, and follow an all-or-none approach rather than the gradations of functional change from mutations seen in the general population. Nevertheless, the availability of models to study all aspects of transport and synthesis together provides a very strong future for pre-clinical AA research. It is important to note, however, that the changes reported in these models, particularly oxidative damage, or changes in neurotransmitter function, are not specific to Alzheimer's disease, and in fact are relevant to many types of neurodegenerative diseases, and to an extent in normal as well as pathological aging. For example, none of these mouse models exhibits robust cognitive deficits from AA deficiency alone. Future research must identify exact roles for AA in disease pathology, and how this can be applied specifically to Alzheimer's disease process as well as other disease states where applicable. This includes studying the impact of chronic deficiency resulting in sub-optimal brain levels, without clinical signs associated with scurvy. Knowledge of how AA transport and accumulation is regulated in specific brain areas, and how this may be affected by specific SNPs or disease states may permit better understanding of when and how best to intervene to correct levels, or how to identify populations that may be more at risk of deficiency.
