Associations Between Insulin-Like Growth Factor-1 and Resting-State Functional Connectivity in Cognitively Unimpaired Midlife Adults.

BACKGROUND: Insulin-like growth factor (IGF)-1 plays an important role in Alzheimer's disease (AD) pathogenesis and increases disease risk. However, prior research examining IGF-1 levels and brain neural network activity is mixed. OBJECTIVE: The present study investigated the relationship between IGF-1 levels and 21 neural networks, as measured by functional magnetic resonance imaging (fMRI) in 13,235 UK Biobank participants. METHODS: Linear mixed models were used to regress IGF-1 against the intrinsic functional connectivity (i.e., degree of network activity) for each neural network. Interactions between IGF-1 and AD risk factors such as Apolipoprotein E4 (APOE4) genotype, sex, AD family history, and age were also tested. RESULTS: Higher IGF-1 was associated with more network activity in the right Executive Function neural network. IGF-1 interactions with APOE4 or sex implicated motor, primary/extrastriate visual, and executive function related neural networks. Neural network activity trends with increasing IGF-1 were different in different age groups. Higher IGF-1 levels relate to much more network activity in the Sensorimotor Network and Cerebellum Network in early-life participants (40-52 years old), compared with mid-life (52-59 years old) and late-life (59-70 years old) participants. CONCLUSION: These findings suggest that sex and APOE4 genotype may modify the relationship between IGF-1 and brain network activities related to visual, motor, and cognitive processing. Additionally, IGF-1 may have an age-dependent effect on neural network connectivity.

Inflammation, negative affect, and amyloid burden in Alzheimer's disease: Insights from the kynurenine pathway.

BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aß) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aß (i.e., Aß-), whereas such associations were fully mediated by Complement 3 in Aß+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aß and the complement system may be critical contributing factors in this process.

Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.

BACKGROUND: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ɛ4). OBJECTIVE: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. METHODS: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). RESULTS: Daily cheese intake strongly predicted better FIT scores over time (FH-: ß= 0.207, p < 0.001; ɛ4-: ß= 0.073, p = 0.008; ɛ4+: ß= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4+: ß= 0.101, p = 0.022) and red wine was sometimes additionally protective (FH+: ß= 0.100, p = 0.014; ɛ4-: ß= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: ß= 0.066, p = 0.008; ɛ4+: ß= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance (FH+: ß= -0.114, p = 0.004; ɛ4+: ß= -0.121, p = 0.009). CONCLUSION: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.