**7. Conclusions: amyloid beta and the retina as a biomarker for Alzheimer's disease**

With increased sophistication of new imaging methods and related technologies, there is a growing interest in developing reliable and cost-effective methods of identifying those at greater risk of developing AD. These advances are welcome as current diagnostic techniques such as magnetic resonance imaging (MRI) do not always provide sufficient image resolution to detect incipient brain pathology, whilst positron emission tomography (PET) is prohibi‐ tively expensive and is not widely available [4]. Consequently, the most conclusive diagnosis of AD is only made following a brain autopsy, which is of little use as a predictor of disease. Various studies have explored the possibility of measuring peripheral Aβ in the blood or cerebrospinal fluid (CSF) as prognostic markers of disease. CSF as a biomarker has consistently been shown to provide an accurate indication of underlying AD pathology but is an invasive and costly procedure [4]. In contrast, plasma Aβ presents a more cost-effective and a less invasive method of diagnosis, but has proved less successful in identifying those at higher risk [101]. Interestingly, a recent study revealed that plasma Aβ levels accurately correlated across progressive stages of AMD [102]. Nonetheless, inconclusive data from other studies, as well as evidence from AD patients, suggest that such approaches require a more rigorous level of standardisation and further fine-tuning before clinical application [101].

In summary, we propose that the eye is not only a useful organ to study Aβ pathology but that a better understanding of retinal dystrophies may reveal insights into AD and dementia. The eye is amiable to manipulation and study in a way that the brain is not, thus providing a powerful diagnostic tool or an anatomical window to detect potential brain pathology. Consequently, non-invasive retinal imaging techniques may be exploited to measure the retinal Aβ burden and thus identify potential individuals at risk of developing AD. Such methods have already been demonstrated by those using retinal photography, scanning laser ophthalmoscopy (SLO), Doppler blood flowmetry and optical coherence tomography (OCT) to assess retinas of AD and dementia patients [23, 103, 104]. For example, funduscopy is widely used to assess the retina, which often detects the first clinical signs of AMD such as macular drusen. Using such an apparatus, a pilot study found a significant correlation between the appearance of peripheral retinal drusen and AD [103]. Furthermore, Doppler blood flowmetry has been used to measure retinal blood vessel diameters in AD patients. These studies show that decreased vessel diameter correlated with disease progression alongside impaired retinal blood-flow and circulation abnormalities [23]. Advances in OCT were also used to demonstrate NFL abnormalities in patients with open-angle glaucoma [104]. However, this may be of limited value as an early-disease indicator since NFL thinning only becomes apparent in advanced AD [23]. SLO, another non-invasive approach, is used to reliably assess optic nervehead damage and optic disc topography in glaucoma patients [105], pathologies that are also evident in some AD patients [24]. Finally, trials have been undertaken in AD rodent models using systemic injections of the naturally occurring food ingredient curcumin, which fluores‐ ces when bound to retinal Aβ [74]. Use of this compound has the added advantage of being able to traverse the BRB and BBB, demonstrating successfully use of a non-invasive retinal imaging in AD-Tg mice which correlated the extent of retinal Aβ with plaque load and disease. Curcumin labelling of retinal Aβ deposits in these mice was detected as early as 2.5 months, whereas Aβ deposition in the brain was only apparent after 5 months [74] supporting the idea that the aged eye may function as an early warning system for incipient brain pathology. As curcumin has also been shown to reliably label Aβ deposits/structures in post-mortem human retinas [74], its use could easily be extended to non-invasively detecting retinal Aβ in AD clinics. Hence, there is considerable interest in the pharmaceuticals industry to identify both natural compounds as well as synthetic agents capable of reliably binding Aβ [106, 107]. Such studies will be highly informative in providing further insights into the role of Aβ in the ageing retina and brain, and help extend current understanding of shared pathologies in these intimately linked tissues.
