A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin–angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin–angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.

Advancements in biomedical research have contributed to increasing the life expectancy of humans, but we now observe an increase in age-related diseases such as Alzheimer's disease. Genome-Wide Association Studies (GWAS) and linkage studies have identified human genes associated with Alzheimer's disease (referred to as AD genes). A previous study by Vahdati in 2017 has revealed the human AD genes and counterparts in model species [1]. Thus, we further investigate the co-morbidity genes and alleles. Using ontology analysis combined with cluster analysis, the study identified functional pathways enriched among the human AD genes, including 179 genes out of 695 human AD genes (26%) that were associated with one or more of the four neurological diseases including Amyotrophic lateral sclerosis, Multiple sclerosis, Parkinson's disease, and Schizophrenia [1]. More importantly, the results indicate co-morbidities with Late-Onset Alzheimer's Disease (LOAD) and other neurological conditions, implying the complexity of the phenotypes in the human AD. The co-morbidity genes may account for mixed symptoms for human AD as well as age-related risks of infections. Of them, the three genes are well conserved (Angiotensin I Converting Enzyme gene, ACE; Methylenetetrahydrofolate Reductase gene, MTHFR; and tumor necrosis factor gene, TNF). In this study, we confirmed the comorbidity of the three genes associated with AD. We further identified the comorbidity of two alleles in the MTHFR gene, C677T and A222V, significantly associated with Alzheimer's disease. This study provides an example of evidencebased analysis that is cost-effective and may be an effective approach to develop cure-alls for multiple diseases.