NEUROPSYCHIATRIC BURDEN IS RELATED TO INCREASED AMYLOID BUT NOT TAU DEPOSITION IN LATE MIDDLE-AGED COGNITIVELY NORMAL INDIVIDUALS WITH A FAMILY HISTORY OF ALZHEIMER’S DISEASE

Abstract

Neuropsychiatric factors (NPF) are highly prevalent throughout the course of Alzheimer's disease (AD) (Masters et al, 2015). Recent evidence also linked neuroticism, a personality trait associated with negative emotional response, with progression to AD (Terracciano et al, 2017). We investigated whether NPF and/or personality traits were related to AD pathology, brain function and cognition in cognitively normal individuals with a family history of AD dementia. Eighty-two participants (PREVENT-AD study, age=67±5) underwent PET scanning. SUVRs values for Aβ ([18F]NAV4694) and tau ([18F]AV1451) were extracted from all FreeSurfer Desikan neocortical regions (grey cerebellum reference region). Resting-state functional connectivity was examined in 13 networks (Power et al, 2011). Cognitive performance was assessed using the RBANS that provides five composite scores: immediate and delayed memory, attention, language, and visuospatial functioning. All participants answered questionnaires assessing personality, perseverative thinking, depression, anxiety, stress and apathy. We used partial least squares correlation with permutation tests to assess which combinations of factors (derived as latent variables), if any, were related to Aβ and tau deposition. We also investigated whether this combination of NPF and personality traits was related to 1) functional connectivity and 2) cognitive performance in individuals with and without AD pathology. One latent variable related NPF and personality traits with Aβ accumulation (p=0.003). Fig.1A displays the weight of each NPF and personality trait to this relationship and Fig.1B, the brain regions presenting higher Aβ burden as a function of this latent variable. Higher scores on this variable were additionally associated with higher brain connectivity within the dorsal attention and salience networks in Aβ+ subjects, and lower connectivity in Aβ- subjects (both interactions p <0.05, Fig.2A). Furthermore, higher scores on this neuropsychiatric component were associated with worse immediate memory (p=0.05, Fig.2B), regardless of Aβ status. No latent variable related NPF/personality traits with tau accumulation. Partial least squares analysis showing the neuropsychiatrie latent variable related to Aβ burden 1A. Loading of each neuropsychiatri factor (NPF) and personality trait to the neuropsychiatri latent variable related with Aβ accumulation. Confidence intervals are derived from bootstrap resampling. 1B. Cortical regions showing higher Aβ SUVR as NPF/personality burden increases. The importance of each region in the model was identified from bootstrap ratios and projected on a brain template. Regression analysis showing the relationship between the neuropsychiatric latent variable with brain function and cognition 2A. Functional network showing an interaction of Aβ status by functional connectivity on neuropsychiatric burden (Salience network interaction F1,69=5.7, p =0.02; dorsal attentional network interaction F 1, 69=5.2, p =0.03). 2B. Association between neuropsychiatric burden and immediate memory performance (Main effect F1,70=4.1, p=0.05). Our multivariate approach revealed that NPF/personality traits, such as perseverative thinking, neuroticism and low agreeableness, were associated with Aβ accumulation, altered brain connectivity and lower cognition. Neuropsychiatric burden might be a consequence of AD pathology, or, because personality traits are relatively stable across lifespan, a risk factor.