In a Perspective, Aimee Pierce and Claudia Kawas discuss risk factors and pathologies of dementia in the oldest-old.

The oldest-old represent the fastest growing segment of society, and the risk of developing dementia continues to increase with advancing age into the 9th and 10th decades of life. The most common form of dementia in the oldest-old is Alzheimer disease (AD), although there are often mixed pathologies contributing to dementia in addition to amyloid plaques and neurofibrillary tangles. Diagnosing AD in the oldest-old is challenging due to cognitive and physical changes associated with aging. Treatment remains supportive, with current approved medications able to provide modest symptomatic benefit but unable to slow the progression of disease.

To achieve the national agenda of developing improved therapies for Alzheimer's disease (AD), greater community engagement and public trust are needed. Ensuring satisfaction among those enrolling in studies is one means to facilitate these goals. We performed telephone interviews to assess satisfaction with the disclosure of study results among thirteen individuals who were enrolled as participants or study partners in a Phase 3 clinical trial for mild AD. Most participants were at least somewhat satisfied with the manner of disclosure. Two participants were dissatisfied; these participants learned results through the media. Most participants indicated that their preference would have been to learn results through the site study team. Ten participants indicated that they wished to learn randomization assignment and several indicated a desire to learn more details about study data. Future trials should undertake a systematic approach to disclosing study results and assessing participant satisfaction with the process.

Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.