Early β‐amyloid accumulation in the brain is associated with peripheral T cell alterations

Abstract

INTRODUCTIONFast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β‐amyloidosis has raised the question of whether immune markers could be used as proxies for β‐amyloid accumulation in the brain.METHODSHere, we apply multidimensional mass‐cytometry combined with unbiased machine‐learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross‐sectional and longitudinal studies.RESULTSWe show that increases in antigen‐experienced adaptive immune cells in the blood, particularly CD45RA‐reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β‐amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects.DISCUSSIONOur results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes.

No increase of CD8+ TEMRA cells in the blood of healthy adults at high genetic risk of Alzheimer's disease

“…We performed a range of sensitivity analyses by using an optimized AD PRS that explained the largest amount of variance of the TEMRA cell counts, adjusting for CMV as additional covariate, contrasting the top versus lower PRS quintile to allow for a non-linear model, and using arcsinh transformation of the TEMRA cell data as applied in the original study. 2 As expected, we observed a strong and statistically significant increase of CD8+ TEMRA cells in CMV-seropositive participants (young adults: p = 1.17E-15, older: p = 2.46E-24) as well as with increasing age (p = 3.78E-13, Table 1, Figure S2). However, the PRS on genome-wide significant AD risk SNPs did not show statistically significant association with CD8+ TEMRA cells, neither in young adults (incremental phenotypic variance explained [ΔR2] = 0.00003, p = 0.954) nor in the older (ΔR2 = 0.0007, p = 0.670, Table 1, Figure S2).…”

“…While an increase of TEMRA cells had been reported previously in clinically affected AD patients compared to controls (e.g., ref. 3 ), the results by Gericke et al 2 extended these findings to the preclinical disease phase. In the current study, we investigated whether the alteration of TEMRA cells may manifest even earlier in the course of the disease, that is, in younger and in older, cognitively healthy adults at high genetic risk of AD based on polygenic risk score (PRS) analyses.…”

Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease

“…36 A recent study convincingly demonstrated that elevations in antigen-experienced adaptive immune cells in the bloodstream are strongly correlated with the status of cerebral Aβ and its dynamic changes over time. 37 In addition, we found significant associations among peripheral immunity markers and cognitive function, anxiety and depression, blood NfL levels, and brain atrophy. These markers are classified under the "N" category in the ATN (amyloid/tau/neurodegeneration) framework, representing neuronal death.…”

“…Moreover, BACE1 has been found to play a role in activating T cells in both the experimental autoimmune encephalomyelitis and AD mouse models 36 . A recent study convincingly demonstrated that elevations in antigen‐experienced adaptive immune cells in the bloodstream are strongly correlated with the status of cerebral Aβ and its dynamic changes over time 37 …”

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

“…49,50 Finally, various brain diseases are associated with intracellular aggregates and an autoimmune aetiology is increasingly recognized. 51,52 That T lymphocytes recognize MHC-displayed peptides from intracellular proteins was discovered in APC studies arising from early work in the Askonas laboratory. 30,38 This led to the postulates that, to avoid autoimmune attack, there might be intracellular mechanisms for distinguishing foreign from self-peptides (e.g.…”