The effect of short Aβ(1‐38) peptides on cognitive decline and conversion to AD dementia: longitudinal data using the DELCODE cohort

Abstract

AbstractBackgroundThe current research consensus is that long Aβ(1‐42) peptides are neurotoxic pathological hallmarks of AD. Interestingly, short Aβ peptides, such as Aβ(1‐38), appear to be less neurotoxic and may counteract AD neuropathology. However, research on Aβ(1‐38) is scarce and their effect on AD pathophysiology in humans in vivo remains unclear. Here, we investigate whether higher relative concentrations of Aβ(1‐38) levels in the cerebrospinal fluid (CSF), compared to Aβ(1‐42) alone, with phospho Tau (pTau) or with both, protect against cognitive decline and risk of conversion to AD dementia.MethodParticipants with subjective cognitive decline (n = 56), mild cognitive impairment (n = 60) and AD dementia (n = 61) from the DELCODE study with a likely pathological Aβ42/P‐tau ratio of > 9.68 at baseline were included. Cognitive performance was assessed annually for five years with the Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite (i.e., PACC5), which was derived from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Conversion to AD dementia was assessed with the Clinical Dementia Rating (CDR) and NINCDS‐ARDA criteria. CSF was collected at baseline. Data was analysed using statistical model fitting procedures for linear mixed models, i.e., Likelihood Ratio (LR) testing. Additionally, we controlled for baseline diagnostic status and the relative effect of Aβ(1‐42) and pTau.ResultHigher Aβ(1‐38) baseline levels were associated with better follow‐up performance on the PACC5 in all three groups across the AD continuum (p < .001). For the MMSE, only the MCI group showed significantly better follow‐up performance (p = .003), and a trend was found in the other groups (SCD: p = .090, AD p = .099). Furthermore, higher Aβ(1‐38) baseline levels decreased risk of conversion to AD dementia within three years by 88% (p = .003) in the SCD and MCI groups.ConclusionAcross the AD spectrum, higher Aβ(1‐38) levels protect against cognitive decline and reduce the risk of conversion to AD dementia. This could inform individual risk prediction in memory clinic patients.