Abstract This administrative supplement proposal is submitted in response to NOSI NOT-AG-20-034 to add Alzheimer’s-relevant studies to the PIs’ parent proposal “Causes of Immune Cell Senescence in Aging Humans.” The parent grant was designed to test the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated dysregulation of immune cell function. Preliminary data included in the original proposal revealed a dramatic and significant increase in the percentages of senescent CD8+ T cells with advanced age, ranging from about 24% in people’s 20s to levels of about 65% by the time they reach their 60s, but with a range of senescent cells across different donors. The active grant does not include any research questions relating to Alzheimer’s Disease (AD). As such, without changing the aims of the parent grant, we seek supplemental funding for additional methods and participant recruitment to address the possibility that, among the healthy older participants recruited, some may have higher genetic risk for AD, and possibly be in the earliest stages of preclinical AD, despite presenting with no readily-apparent cognitive deficits. This is a significant concern because there is a growing appreciation that AD involves disruption to the immune system. To address this possibility, we have entered into new collaborations with two teams of well-respected and well-funded AD-researchers. With Mark Gluck at Rutgers University-Newark’s Aging & Brain Health Alliance, we propose to recruit 32 additional African-American participants, ages 60 and above, from their Pathways to Health Aging in African Americans cohort. The large size of Gluck’s existing cohort allows us to pre-select those individuals with the highest and lowest APOE risk; half of these participants will be pre-selected for high genetic risk for AD (APOE genotypes ε4ε4, ε3ε4), with the other half having low genetic risk for AD (APOE genotypes ε2ε2, ε2ε3). We will also recruit an additional 16 African- American individuals in their 20’s and 30’s as younger controls. A second new set of collaborators, Drs. Blennow and Zetterberg, from the University of Gothenburg, are experts in blood-based biomarkers for early AD; plasma will be sent to these Swedish collaborators where they will assess blood-based AD biomarkers, including P-Tau181. We will carry out measurements of peripheral immune cell senescence in these cohorts as described in the parent grant using flow cytometric, microscopic and genomic analyses. We hypothesize that older participants (ages 60 and above) who are at high APOE-genetic risk for AD will show enhanced levels of senescence in CD8+ T cells and will have enhanced histochemical evidence of telomere dysfunction in their CD8+ T cells as compared to participants who have low APOE-genetic risk for AD, and will have higher levels of P-Tau181.

Narrative In the parent R21 grant, we have developed a sensitive flow-cytometric marker for senescent white blood cells that accumulate in the blood with aging. In this supplement application, we will determine whether there is an increase of these senescent cells in individuals with evidence of Alzheimer’s Disease (AD) susceptibility, which could ultimately lead to targeting for AD therapy or prevention.