Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal control network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (ps < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (ps < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (ps > 0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.
As the number of adults over 65 years of age is steadily rising, it is increasingly important to identify strategies to either maintain or improve cognition to positively impact quality of life and potentially inform treatment strategies for age-related cognitive disorders. There is evidence to suggest that olfactory cues can aid recall (Rihm, Diekelmann, Born, & Rasch, 2014). It is still unknown whether olfactory cues can cause recalled information to enter a labile state, allowing it to be updated with new information. The current study investigated whether administration of a contextual olfactory cue would improve learning and memory dependent on frontal lobes and the hippocampus respectively in both a rat model of cognitive aging (two-vessel occlusion [2-VO]) and in nondemented older adult humans. Specifically, rats and humans were trained on their respective versions of a elemental visual discrimination task while an olfactory stimulus was presented. Following training, rats and humans were reexposed to the contextual olfactory cue and their performance was tested on a reversal learning (frontal-dependent) and the transverse patterning (hippocampus-dependent) tasks that were constructed from visual stimuli presented during the elemental task. In rats, we found 2-VO related decrements in frontal-dependent memory performance and age-related decrements in hippocampus-dependent task performance in humans. For both rats and humans, we found no rescue of memory through olfactory contextual cueing. Overall, our results suggest that mechanisms underlying olfactory contextual cueing may not be sufficient to enhance declining memory performance with age.
Background: Disease-modifying treatments for Alzheimer’s disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF, COMT, and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. Objective: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF, COMT, and KIBRA and functional connectivity within networks related to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Methods: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Results: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (ps < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (ps < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p < 0.05). There were no COMT-related differences in functional connectivity of any of the three networks investigated (ps > 0.05). Conclusion: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers.
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