Increased risk of Alzheimer’s disease among patients with age-related macular degeneration: A nationwide population-based study: A Mechanistic and a Statistical Comment
Reza Rastmanesh* 1, 2, 3
1 Independent Researcher, Private Clinic, Tehran, Iran.
2 The Nutrition Society, London, UK.
3 American Physical Society, Maryland State, Maryland, USA
* Corresponding author. Reza Rastmanesh, #6, Physicians Building, Sarshar Alley, Vali Asr Street, Tajrish, Tehran, Iran, Postal Code: 1961835555, Email address: r.rastmanesh@gmail.com
ORCID: Reza Rastmanesh: https://orcid.org/0000-00...
Conflict of interest: Author has no competing or conflict of interest.













Increased risk of Alzheimer’s disease among patients with age-related macular degeneration: A nationwide population-based study: A Mechanistic and a Statistical Comment
Dear Editor
I read with special interest the article by Wen et al [1]. In their population-based, retrospective cohort study they conclude that patients with age-related macular degeneration (AMD) have a higher risk of Alzheimer disease (AD) than people without AMD and attributed this association solely to oxidative stress mechanism. There are some issues that worth to be discussed.
Firstly, there are many other well-established mechanisms by which these two degenerative diseases have been previously connected with different mediators [2-6].
Given that the eye and brain are neural tissues derived from the same embryonic germ layer, the coincidence of developmental anomalies of these organs is not unexpected or surprising. Indeed, there are parallel findings in AMD and AD and common pathogenic mechanism exist between AMD and AD [4;7].
The crucial characteristics of AD include distinct changes in both brain behavior and histology. In patients with AD, brain is characterized microscopically by the concurrent presence of two classes of abnormal structures, namely intraneuronal neurofibrillary tangles and extracellular amyloid plaques, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are tau for tangles and amyloid-β peptides for plaques. Amyloid-β peptides are regarded as proteolytic fragments of the transmembrane amyloid precursor protein, while tau is considered as a brain-specific, axon-enriched microtubule-associated protein [8].

The potential role of tau, amyloid precursor protein, and beta-amyloid in the pathogenesis of AMD was proposed at early1990's [3]. Anti-amyloid-beta antibody was successfully tested and shown to attenuate pathologies in an AMD mouse model, supporting the hypothesis that Abeta is meanwhile an efficient therapeutic target for AMD [2].
Wang et al [5] were first to suggest elevated amyloid β production in senescent retinal pigment epithelium (RPE) as a possible mechanism of subretinal deposition of amyloid β in AMD.
Damage of reactive oxygen intermediates and mitochondrial dysregulation are prominent in AD and AMD. In this regard, that would be interesting to find out their relationship with the redox state. According to Vladan and Panfoli, interaction of melatonin vs Amyloid-β are entangled to balance of the intra- and extra-mitochondrial energy production. By the ageing process, this balance would be impaired and environmental/genetic factors, ultimately lead to AD and /or AMD [4].
Briefly, congregation of Amyloid-β in subretinal drusen of AMD patients contributes in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, modulating angiogenesis, affecting RNA splicing, and eventually modifying cell structure in AMD [6].
Secondly, even though that it is generally accepted that retinal amyloid-β accumulation and its pathological influences were shown to occur prior to irreversible neurodegeneration [6], it is not clear whether the inverse may also hold. Wen et al [1] conclusion suggesting that patients with AMD have a higher risk of AD than people without AMD is technically misleading because this statement implies causality, whereas their study was retrospective and causality cannot be proven through a correlational study. In such scenarios, performing causal mediation analysis might be better than calculating a hazard ratio.
In order to come to a better understanding of how AMD and AD are causally related, the possible interaction or modification effect of multiple confounding variables should be considered in future studies. This might facilitate the discovery of better preventive measures and therapeutic agents for the management of both diseases. As an example, a future study might look at whether Alzheimer therapy has a positive impact on AMD (and vise versa). For instance in 2020, results of a study suggested a potential signal for Parkinson's disease related to intravitreal ranibizumab [9]. Another study that determined the rate of hippocampal atrophy in patients treated with radiation and temozolomide followed by bevacizumab, found a significant decrease in the absolute hippocampus volume after 6 months of continuous bevacizumab treatment. Importantly, this volume loss of the hippocampus progressed over the next 3 years [10], and was higher than the one previously reported in AD patients [11].
Another study might seek to find out whether Scopolamine and Diazepam induced Alzheimer models develop AMD spontaneously. A prospective trial design would be best able to answer these questions. A Retrospective study of post mortem histopathological examination may provide some information on whether severity of AMD is cause or consequence of AD. It would be also interesting to look at AD prevalence in a number of categories, such as exudative versus non-exudative AMD
Disclosure statement
The author has nothing to disclose. No outside funding/support was received for this study.
Reference List

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