Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity suggestive of impaired skeletal muscle mitochondrial function. However, direct measures of muscle mitochondrial function have not been performed in ad. This study (n = 50) compared skeletal muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; n = 11) or MCI taking an ad medication, donepezil (MCI + med; n = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from skeletal muscle biopsies of the vastus lateralis. Untreated MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH (P = 0.043) and MCI + med (P = 0.007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = 0.014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs. MCI) and medication treatment (MCI vs. MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezeil powerfully impacts the transcriptional profile of skeletal muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that skeletal muscle mitochondrial changes occur in the very early stages of ad, but is likely influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted.

Oxygenated lipids, called “oxylipins,” serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) are also associated with Alzheimer’s disease (AD) risk, we set out to characterize the serum oxylipin profile in elderly and AD subjects to understand if there are shared patterns between AD and T2D. We obtained serum from 126 well-characterized, overnight-fasted elderly individuals who underwent a stringent cognitive evaluation and were determined to be cognitively healthy or AD. Because the oxylipin profile may also be influenced by T2D, we assessed nondiabetic and T2D subjects separately. Within nondiabetic individuals, cognitively healthy subjects had higher levels of the nitrolipid 10-nitrooleate (16.8% higher) compared to AD subjects. AD subjects had higher levels of all four dihydroxyeicosatrienoic acid (DiHETrE) species: 14,15-DiHETrE (18% higher), 11,12 DiHETrE (18% higher), 8,9-DiHETrE (23% higher), and 5,6-DiHETrE (15% higher). Within T2D participants, we observed elevations in 14,15-dihydroxyeicosa-5,8,11-trienoic acid (14,15-DiHETE; 66% higher), 17,18-dihydroxyeicosa-5,8,11,14-tetraenoic acid (17,18-DiHETE; 29% higher) and 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid (17-HDoHE; 105% higher) and summed fatty acid diols (85% higher) in subjects with AD compared to cognitively healthy elderly, with no differences in the DiHETrE species between groups. Although these effects were no longer significant following stringent adjustment for multiple comparisons, the consistent effects on groups of molecules with similar physiological roles, as well as clear differences in the AD-related profiles within nondiabetic and T2D individuals, warrant further research into these molecules in the context of AD.

Introduction: Fasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D). Methods:We leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow-up.Results: Individuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex.Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status.Discussion: Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.

Objective: To test the validity of a common measure of health-related quality of life (Short-Form-36 [SF-36]) in cognitively healthy older adults living in rural and urban Costa Rica. Method: Confirmatory factor analysis was applied to SF-36 data collected in 250 older adults from San Jose and Guanacaste, Costa Rica. Results: The best fitting model for the SF-36 was an eight first-order factor structure. A high correlation between the Mental Component Summary and Physical Component Summary scores was found. Region differences indicated that rural dwellers perceive a poorer health-related quality of life compared with the urban group. Discussion: Costa Rican older adults perceived health as a unidimensional construct. Age and urbanity of older adult Costa Ricans should be appreciated when trying to measure self-reported physical and mental health. Cultural context of the individuals should be considered when studying health-related quality of life.

Background: First-degree relatives of individuals with late-onset Alzheimer’s disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. Objective: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. Methods: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. Results: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. Conclusion: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

Background First‐degree relatives of individuals with late‐onset Alzheimer’s Disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. We sought to test how structural or functional abnormalities in the default mode network (DMN) during the brain’s “resting state” characterized individuals at risk for AD. Method We used MRI and fMRI to study cognitively healthy individuals (n=28) with and without AD family history (FH+ and FH‐, respecitvely), those with amnestic mild cognitive impairment (aMCI; n=31) and early‐stage AD (n=25). We tested connectivity within the DMN, as well as measures of volume and thickness within both the medial temporal cortex and in selected seed regions. Our primary hypothesis was that there would be a linear decline within the risk groups on all measures of AD risk (FH‐>FH+>aMCI>AD). Result As expected, we identified significantly decreased medial temporal cortex volumes in the aMCI and AD groups compared to both nondemented groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH‐ and AD groups. This pattern emerged primarily in connectivity between the precuneus and frontal regions. Conclusion We present distinct structural and functional brain imaging profiles for two AD‐risk groups; cognitively healthy, FH+ individuals, and individuals with aMCI. These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

BackgroundIndividuals with Alzheimer’s Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear.MethodsHere, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging.ResultsThe meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions.ConclusionOur findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.

BackgroundAccumulating evidence suggests that Alzheimer’s Disease (AD) plasma biomarkers aid in screening for at‐risk individuals, tracking disease progression, and monitoring response to interventions. Plasma amyloid‐β (Aβ) and phosphorylated tau (pTau) have shown promise in predicting cerebral deposition of Aβ, while neurofilament light chain (NfL) serves as a more global marker of neurodegeneration. However, blood collection protocols often differ, and it is important to confirm the relationship between blood biomarker values and established neuroimaging markers for AD neuropathology.MethodHere, we examined which blood biomarkers could predict clinician rating of cerebral amyloid status. We leveraged available clinical, cognitive, and neuroimaging data for 140 cognitively healthy older adults (65+, mean 72 ± 6.4) who participated in the Alzheimer’s Prevention Program (APP) study and had blood specimens available. Participants were assessed by a trained clinician and neuropsychometric test battery to exclude the presence of MCI or dementia syndromes. Cerebral amyloid burden was measured by Florbetapir (18F) positron emission tomography and images were rated by three trained clinicians as “elevated” or “non‐elevated”. Biomarkers were measured in plasma collected in acid citrate dextrose (ACD) tubes using a Quanterix Simoa® HD‐X platform, and included NfL, Aβ42, Aβ40, and p‐tau181.ResultPlasma Aβ42/40 ratio was significantly lower in the “elevated” group than in the “non‐elevated” group (p < 0.001), while NfL (p =0.008) and p‐tau 181 (p = 0.001) were both significantly higher. Aβ42/40 ratio was able to discriminate the rating groups in a ROC analysis with an AUC of 0.835, significantly outperforming p‐tau 181 (AUC = 0.640) and NfL (AUC = 0.572).ConclusionDespite collecting samples with ACD rather than the traditional EDTA as an anti‐coagulant, expected group differences were observed. Our results suggest that Aβ42/40 ratio is useful in discriminating clinician‐rated elevated cerebral amyloid status, which has important implications regarding disclosure of blood biomarker results from different collection protocols in the context of AD risk.