Biofluid activity and levels of the angiotensin‐converting enzyme may translate into distinct neuropsychiatric symptoms associated with cerebrospinal fluid amyloid‐beta effects and tauopathy in dementia with Lewy bodies and Alzheimer’s dementia

Abstract

AbstractBackgroundAmyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia.MethodsConsecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer’s dementia (AD, National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β42, amyloid‐β38, ACE‐1, tau and phospho‐tau Thr181 were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at p<0.05.ResultsParticipants with DLB (n = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (p<0.0001) and with plasma ACE‐1 activity (p<0.0001), no differences among the participants. Only in DLB, the ACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β38, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β42/amyloid‐β38. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β42 were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β42. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy.ConclusionsBiofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes.