U n c o r r e c t e d A u t h o r P r o o f Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer's disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive

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... (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing 24 25 26 27 28 29 30 31 1 These authors contributed equally to this work. U n c o r r e c t e d A u t h o r P r o o f 2 M. Pietto et al. / Memory Binding in the Prodromal Stages of AD studied features (shape only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100-250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shapecolor binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD. 32 33 34 35 36 37 38 Keywords: Electroencephalogram (EEG), event related potentials (ERPs), familial Alzheimer's disease, memory binding, mild cognitive impairment, short-term memory 39 40 65 of AD [14]. 66 To this end, we explored whether VSTM binding 67 impairments are associated with electrophysiological 68 changes in two clinical groups at different risk levels 69 for AD: patients who may develop late-onset sporadic 70 AD such as those with MCI (most of them amnestic 71 MCI, single or multi-domain) and patients in the pro-72 dromal stages of familial AD carrying the mutation 73 E280A of the presenilin-1 gene (MCI-FAD). Specif-74 ically, we compared behavioral and event-related 75 potential (ERP) measures between these samples and 76 healthy controls. Building on previous findings, we 77 hypothesized that both patient samples would show 78 behavioral and electrophysiological abnormalities in 79 the VSTM task, particularly in the memory bind-80 ing condition. Moreover, since the risk of conversion 81 to AD is 100% for MCI-FAD and much lesser for 82 MCI, we predicted different behavioral and electro-83 physiological profiles in each group. In particular, we 84 expected that MCI-FAD would show more restricted 85 behavioral and electrophysiological abnormalities in 86 the binding relative to shape only condition of the 87 VSTM task. More generally, this study seeks to test 88 the sensitivity of this memory biomarker as a poten-89 tial contribution to the early identification of AD 90 pathology. 91 MATERIALS AND METHODS 92 Participants 93 Thirteen patients with MCI were recruited from the 94 Institute of Cognitive Neurology (INECO) in Buenos 95 Aires, Argentina. Diagnosis was based on criteria by 96 Pertersen [15] and Winblad et al. [16] (for further 97 details, see Supplementary Data S1). All the patients 98 underwent neurological, neuropsychiatric, and neu-99 ropsychological evaluations. Most of the patients 100 (n = 9) were impaired in memory functions (amnestic 101 MCI single domain or amnestic MCI multi-domain) 102 while three patients were classified as non-amnestic 103 MCI multi-domain. Both amnestic MCI single and 104 multi-domain patients were included since these two 105 clinical phenotypes have been shown high risk for 106 AD conversion [17]. 107 The MCI-FAD sample comprised 10 patients 108 recruited from the Colombian province of Antioquia. 109 U n c o r r e c t e d A u t h o r P r o o f M. Pietto et al. / Memory Binding in the Prodromal Stages of AD 3 All of them carried the mutation E280A of the 110 presenilin-1 gene, which leads to early-onset familial 111 AD in 100% of carriers [5]. These patients also com-112 pleted formal neurological and neuropsychological 113 assessments. 114 Two separate groups of healthy participants were 115 formed as controls for the MCI and MCI-FAD groups. 116