Coexistence of Rheumatoid Arthritis, Cerebrovascular Disease, and Alzheimer's Disease: A Case Study With Genetic Insights.

To gain new insights into the molecular underpinnings of coexisting rheumatoid arthritis (RA), cerebrovascular disease (cVD), and Alzheimer's disease (AD), we performed postmortem neuropathological examination and genetic screening of two individuals. The first individual (donor 1, D1) was a 74-year-old man who was diagnosed with both RA and AD and who also underwent hip replacement surgery bilaterally. The second individual (donor 2, D2) was a 90-year-old man with a reported diagnosis of RA, as well as two left hip replacements. A thorough histochemical (hematoxylin and eosin, H&E) and immunohistochemical (β-amyloid and tau protein) examination of D1 and D2 brains revealed the presence of AD-related pathology in both individuals, with AD stages being mild in D1 and intermediate in D2. The cVD-related pathology was also evident in both cases and was characterized by several microbleeds indicative of a compromised blood-brain barrier (BBB) integrity. Blood vessel wall thickening, a characteristic of arteriosclerosis, was significant in D1 but minor in D2. Therefore, the earlier RA diagnoses, along with the results of the neuropathological examination, indicated the coexistence in the donors of three major diseases: RA, cVD, and AD. The whole exome sequencing (WES) of DNA procured from D1 and D2 performed on the next-generation sequencing (NGS) Illumina platform (San Diego, CA) was followed by a very stringent bioinformatics analysis that yielded multiple genes with rare (minor allele frequency {MAF} ≤ 0.01) genetic pathological/deleterious variants associated with RA, cVD, and AD. Seven of those genes,