Disrupted role of the connectivity between the locus coeruleus and the hippocampus in cognition of healthy, middle-aged individuals at risk of dementia: the PREVENT-Dementia study

Abstract

It is well acknowledged that Alzheimer′s Disease (AD) pathological processes start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. To address this gap, we examined whether risk factors for late-life AD are associated with disrupted connectivity between two key structures in AD pathophysiology — the Locus Coeruleus (LC) and hippocampus — and its role in cognition, in a cohort of middle-aged and cognitively healthy individuals. Detailed neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and LC—Hippocampus functional connectivity with apolipoprotein ϵ4 (APOE4) genotype, and dementia family history (FHD) were investigated using linear regression. Correlations between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score and cognitive and functional measures were further investigated. APOE ϵ4 allele was significantly associated with better performance in verbal, spatial and relational memory. Higher CAIDE scores were significantly associated with worse performance in verbal, visuospatial functions and short-term (conjunctive) memory. The CAIDE dementia risk score moderated the relationship between cognition and LC—Hippocampus functional connectivity. In individuals with low (=<3)/high (>=8) CAIDE scores, higher functional connectivity was significantly associated with better/worse cognition. These results shed light on the brain mechanism of incipient AD neuropathology in individuals, who are at high risk for late-life dementia on the cardiovascular risk score, but presently cognitively healthy.

Sex differences in the associations between risk for late-life AD, protective lifestyle factors and cognition in mid-life

“…Known risk factors for sporadic late-onset AD (Apolipoprotein E Ɛ 4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were investigated. Replicating our key previous findings (Deng et al, 2022 and Heneghan et al, 2022), we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score, (b) positively associated with stimulating lifestyle activities, and (c) that females performed significantly better than males in episodic and relational memory. The key novel finding of this study was that inherited dementia risk (i.e., APOE Ɛ 4 genotype) modulated the association between sex, lifestyle and cognition.…”

“…These findings validated the data-reduction method, in that it carved up the cognitive data into three coherent and distinct cognitive spaces – episodic and relational memory, multisensory processing, and short-term memory binding – two of which (episodic and relational memory (Bäckman et al, 2001) and short-term memory binding [Parra et al, 2016; Parra et al, 2017]) are known to be very vulnerable to early AD processes in mild cognitive impairment. The first component being the same as in Deng et al (2022), provides very strong evidence that episodic and relational memory is the top cognitive function undergoing performance variability in mid-life. The differing and stronger results here relative to Deng et al (2022) for the other two components are likely due to the larger sample (N = 461 vs N = 208) yielding higher power to detect the underlying distribution of pattern performance variability in this age group.…”

“…Our objectives in this study were twofold. First, we aimed to replicate findings from two recent studies [Deng et al (2022) and Heneghan et al (2022)] on the contribution of mid-life modifiable activities to cognition in individuals with dementia risk, in a larger cohort of the PREVENT–Dementia research program. Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance.…”

“…Studies of this and other similar cohorts of cognitively healthy middle-aged individuals have revealed these three risk factors – APOE Ɛ 4 genotype, FHD, and CAIDE score – impact cognition and brain health in mid-life. APOE Ɛ 4 carriership has been associated with impaired attention (Zimmermann et al, 2019), better form perception (Ritchie et al, 2017), better verbal, spatial and relational memory (Deng et al, 2022), decreased volume in the hippocampal molecular layer (Dounavi et al, 2022; Dounavi et al, 2020), and reduced cortical thickness in the entorhinal cortex (McKiernan et al, 2020). FHD has been associated with worse visual working memory (Ritchie et al, 2017), worse visuospatial memory and executive function (Debette et al, 2009), cerebral hyperperfusion (McKiernan et al, 2020), hippocampal volume loss (McKeever et al, 2020), and impaired white matter integrity (Bendlin et al, 2010).…”

“…Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance. A cohort of cognitively healthy middle-aged individuals was assessed cross-sectionally (N = 461), with the same detailed neuropsychological assessments and research protocols as those published previously (Deng et al, 2022; Heneghan et al, 2022). While the dichotomies of sex and gender are no longer considered to be sharply discrete, in this study ‘sex’ will be defined as an individual’s natal or biological sex.…”