There is considerable controversy related to the functional link between the insoluble A?? residing in plaques and cognitive dysfunction kinase inhibitor Calcitriol in AD [66-69] or in normal aged individuals [70]. However, the available post mortem evidence indicates significant associations between amyloid pathology and cognition in AD patients [6,71-73], with total amyloid load or burden being the most reliable and powerful manifestation of clinically diagnosed dementia [74]. While A?? plaque burden does not likely represent the immediate causal factor underlying dementia, our results suggest that it might be a robust surrogate marker indicating the severity of the impairment, at least in the fear conditioning paradigm applied in pre-clinical research using mouse models.

Conclusions The advantage of applying the fear conditioning paradigm to evaluate cognitive dysfunction in human studies is that the test focuses on nondeclarative, unconscious memory, which depends on frontal and temporal regions, including cortical sensory processing areas, the thalamus, and the amygdala [75-77]. Several studies demonstrated that in humans fear conditioned memory also depends on the same neural structures that are affected at the early stage of AD [78-81]. Also, unlike declarative or conscious memory, nondeclarative, implicit memory depends less on subjective recall and recognition of information [82,83], providing a better comparative platform between pre-clinical studies involving animal models, and clinical studies of human dementia with neurodegeneration.

Although few studies have demonstrated that fear conditioned memory is impaired in AD [84] and in frontotemporal lobar degeneration [85] (of note, an unconditional stimulus used in these studies was a one second burst of 100 db white noise presented through headphones), the association between the impairment in implicit memory and amyloid plaque load in AD patients assessed in vivo [86] has yet to be addressed. Abbreviations AD: Alzheimer’s disease; A??: amyloid beta; ANOVA: analysis of variance; APP: amyloid precursor protein; CR: conditioned response; CS: conditioned stimulus; CSF: cerebrospinal fluid; CV: coefficient of variation; c.p.s: clicks per second; FA: formic acid; FC: fear conditioning; NS: non-significant; nTg: non-transgenic mice; SEM: standard error of the mean; SDS: sodium dodecyl GSK-3 sulfate; Tg: transgenic mice; UR: unconditioned response; this US: unconditioned stimulus. Competing interests The authors declare that they have no competing interests. Authors’ contributions CJ conceived and supervised the study, analyzed the data and prepared the manuscript.