Women with the Alzheimer’s risk marker ApoE4 lose Aβ-specific CD4+ T cells 10–20 years before men

Abstract

Adaptive immunity to self-antigens causes autoimmune disorders, such as multiple sclerosis, psoriasis and type 1 diabetes; paradoxically, T- and B-cell responses to amyloid-β (Aβ) reduce Alzheimer's disease (AD)-associated pathology and cognitive impairment in mouse models of the disease. The manipulation of adaptive immunity has been a promising therapeutic approach for the treatment of AD, although vaccine and anti-Aβ antibody approaches have proven difficult in patients, thus far. CD4+ T cells have a central role in regulating adaptive immune responses to antigens, and Aβ-specific CD4+ T cells have been shown to reduce AD pathology in mouse models. As these cells may facilitate endogenous mechanisms that counter AD, an evaluation of their abundance before and during AD could provide important insights. Aβ-CD4see is a new assay developed to quantify Aβ-specific CD4+ T cells in human blood, using dendritic cells derived from human pluripotent stem cells. In tests of >50 human subjects Aβ-CD4see showed an age-dependent decline of Aβ-specific CD4+ T cells, which occurs earlier in women than men. In aggregate, men showed a 50% decline in these cells by the age of 70 years, but women reached the same level before the age of 60 years. Notably, women who carried the AD risk marker apolipoproteinE-ɛ4 (ApoE4) showed the earliest decline, with a precipitous drop between 45 and 52 years, when menopause typically begins. Aβ-CD4see requires a standard blood draw and provides a minimally invasive approach for assessing changes in Aβ biology that may reveal AD-related changes in physiology by a decade. Furthermore, CD4see probes can be modified to target any peptide, providing a powerful new tool to isolate antigen-specific CD4+ T cells from human subjects.

APOE‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

“…) and there is an age‐ and APOE ‐dependent decrease in Aβ‐specific CD4 + T‐cell activity in humans (Begum et al . ). Indeed, Aβ‐specific CD4 + T‐cell activity follows the order: APOE4 ‐negative males > APOE4‐ positive males > APOE4 ‐negative females > APOE4‐ positive females (Begum et al .…”

“…Indeed, Aβ‐specific CD4 + T‐cell activity follows the order: APOE4 ‐negative males > APOE4‐ positive males > APOE4 ‐negative females > APOE4‐ positive females (Begum et al . ). However, the significance of this T‐cell response for AD pathogenesis remains unclear.…”

“…Independent of disease status, APOE4 carriers have lower levels of CXCL9 (a T-cell attractant), and higher levels of IL-13 (anti-parasitic) in the plasma compared to APOE3 carriers (Soares et al 2012). The data for CXCL9 may be significant, as apoE can suppress T-cell levels (Kelly et al 1994;Mistry et al 1995) and there is an age-and APOE-dependent decrease in Abspecific CD4 + T-cell activity in humans (Begum et al 2014). Indeed, Ab-specific CD4 + T-cell activity follows the order: APOE4-negative males > APOE4-positive males > APOE4negative females > APOE4-positive females (Begum et al 2014).…”

“…The data for CXCL9 may be significant, as apoE can suppress T-cell levels (Kelly et al 1994;Mistry et al 1995) and there is an age-and APOE-dependent decrease in Abspecific CD4 + T-cell activity in humans (Begum et al 2014). Indeed, Ab-specific CD4 + T-cell activity follows the order: APOE4-negative males > APOE4-positive males > APOE4negative females > APOE4-positive females (Begum et al 2014). However, the significance of this T-cell response for AD pathogenesis remains unclear.…”

Future Trends and the Economic Burden of Dementia in Manitoba: Comparison with the Rest of Canada and the World

“…Several studies reported a positive correlation between the presence of one or more APOE-e4 alleles and neuritic plaques in AD [58,59]. Furthermore, research has shown that females carrying a copy of the APOE-e4 gene possess a 7-10% greater risk of developing Alzheimer's as compared with men [60,61]. Unlike AD, LBD, VaD, and PDD are more likely to affect men than women [62][63][64].…”