Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels

Abstract

IntroductionEmerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer’s patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels.MethodsThe CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured.ResultsApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity.ConclusionsThese are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.

Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery

“…Pattern separation is a memory assay used in humans to identify cognitive deficits critical to the encoding and retrieval of episodic memories that become reduced with age [5, 6]. Twenty-four month-old male C57Bl/6 mice were treated for 6 months with either J147 chow or normal chow without drug, using 8 month-old mice as controls.…”

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…Patients affected by amnesic mild cognitive impairment (aMCI) and mild AD show reduced performance in hippocampusdependent tasks like pattern separation (Ally et al 2013). Importantly, impairment in performance correlates with CSF levels of Aβ42 and patients carrying the ApoE4 genotype perform worse than others in difficult pattern separation tasks (Wesnes et al 2014). As discussed previously, performance in pattern separation appears to require hippocampal neurogenesis in the dentate gyrus and growing evidence supports alterations in the neurogenic process in AD.…”

Integrating new findings and examining clinical applications of pattern separation

“…In addition, the authors observed hyperactive BOLD signals in the DG/CA3 and hypoactive signals in the EC during discrimination 36 . Additional evidence suggests that lure-discrimination performance may be linked to ApoE4 status as well as cerebrospinal fluid β-amyloid burden 95 . A recent study found that cognitively normal older adults showed increased amyloid and tau as measured by in vivo positron emission tomography imaging and that this was associated with aberrant activity in the medial temporal lobes during an object-discrimination task 96 .…”