A long-standing question is how to best use brain morphometric and genetic data to distinguish AD patients from cognitively normal (CN) subjects and to predict those who will progress from mild cognitive impairment (MCI) to AD. Here we use a neural network (NN) framework on both magnetic resonance imaging-derived quantitative structural brain measures and genetic data to address this question. We tested the effectiveness of NN models in classifying and predicting AD. We further performed a novel analysis of the NN model to gain insight into the most predictive imaging and genetics features, and to identify possible interactions between features that affect AD risk. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and included baseline structural MRI data and single nucleotide polymorphism (SNP) data for 138 AD patients, 225 CN subjects, and 358 MCI patients. We found that NN models with both brain and SNP features as predictors perform significantly better than models with either alone in classifying AD and CN subjects, with an area under the receiver operating characteristic curve (AUC) of 0.992, and in predicting the progression from MCI to AD (AUC=0.835). The most important predictors in the NN model were the left middle temporal gyrus volume, the left hippocampus volume, the right entorhinal cortex volume, and the APOE ε4 risk allele. Further, we identified interactions between the right parahippocampal gyrus and the right lateral occipital gyrus, the right banks of the superior temporal sulcus and the left posterior cingulate, and SNP rs10838725 and the left lateral occipital gyrus. Our work shows the ability of NN models to not only classify and predict AD occurrence, but also to identify important AD risk factors and interactions among them.

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Background: APOE 4 and sex have been linked to increased risk for conversion to Alzheimer's disease (AD). However, the relationship between APOE 4 gene dose, sex, and AD biomarkers remains understudied. Objective: To investigate the effect of APOE 4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOE 4 dose modifies AD risk differently in MCI women and men. Methods: We examined cross-sectional AD biomarkers for participants with MCI (n = 930, 55-96 years old) from three large aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOE 4 alleles and stratified by sex. Results: Across all participants, number of APOE 4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOE 4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOE 4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOE 4 alleles. Women with 2 APOE 4 alleles had poorer memory between 65-69 and poorer global cognition between 70-74 compared to men with 2 APOE 4 alleles. # Last authorship.

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD.

Our pilot study demonstrates high prevalence of exercise-induced ST-segment depression in asymptomatic, middle-aged, overweight women. Peripheral vascular endothelial dysfunction did not predict Ex-ECG ST-segment depression. Further work is needed to investigate the utility of vascular endothelial testing and Ex-ECG for IHD diagnostic and management purposes in women.

Deletion of the OCD-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.

Background: The polymorphic alleles of apolipoprotein E (APOE) are the main determining factors in the Alzheimer's disease (AD) risk. Among the APOE alleles, E4 allele carriers are at the highest risk for Alzheimer's disease compared to E3 and E2 allele carriers. Even though the risk between Alzheimer's disease and E4 allele are high, some differences in their association were found among different ethnic groups. Moreover, previous studies have reported that the presence of E4 is associated with increased risk for both early onset AD and late onset AD (LOAD). The purpose of our study is to elucidate the direct implications of E4 in the LOAD among Korean population. Methods: The study consisted of 723 normal subjects and 650 AD patients from the Korean population. The two groups were further divided as 258 male and 465 female in the control group and 239 male and 411 female in the AD group respectively. The individuals aged above 65 were included to check the association with LOAD. Blood samples collected from those groups were SNP genotyped. Results: Comparison between the individuals with APOE genotypes have showed the risk of AD and the risk association was dramatically increased for the people with E4/E4 (OR ¼ 64.73), E3/E4 (OR ¼ 2.77), E2/E4 (OR ¼ 2.31), E2/E2 (OR ¼ 1.54), E2/E3 (OR ¼ 1.00) with reference to the commonly found E3/E3 allele (OR ¼ 1.00). In addition, the incidence ratio of AD for E4 carriers were found relatively high compared to the other APOE alleles. Conclusions: The results revealed that E4 carriers are at the highest risk for AD among Korean population and resembling the strong association of E4 with LOAD. In a previous study, the increased risk of E4/E4 was also observed among Japanese (OR ¼ 33.1), Caucasian (OR ¼ 12.5) and African-American (OR ¼ 5.7). Similarly, in this study, the E4/E4 allele exhibited the increased risk for AD. Moreover, the incidence ratio of AD for E4 carriers were also significantly high in both male and female population compared to the other APOE allele carriers.

Background: Current guidelines do not endorse exercise electrocardiography (Ex-ECG) screening in asymptomatic adults due to poor diagnostic accuracy for clinical coronary artery disease (CAD), however Ex-ECG combined with other variables paradoxically has strong prognostic accuracy for cardiovascular mortality. Ex-ECG ST segment depression “false positive” results are common in women, who have higher rates of vascular dysfunction such as Raynaud’s and migraines compared to men. We hypothesized that ST segment depression indicates endothelial vascular dysfunction, which is known to predict an adverse prognosis. To test this hypothesis, we evaluated the relationship between Ex-ECG and peripheral endothelial vascular function in asymptomatic women. Methods: Asymptomatic women with no cardiac risk factors and normal resting ECG underwent maximal Bruce protocol Ex-ECG testing (GE Healthcare). Computer-generated Ex-ECG ST segment values were independently verified by 2 cardiologists. Based on established methods, endothelial vascular function was assessed by calculating reactive hyperemia index (RHI) using peripheral vascular testing (Endopat, Itamar). As established previously, RHI <1.68 is abnormal and indicates endothelial vascular dysfunction. Results: Among 35 women, mean age 54±8 years and BMI 24±4, there were 5 (14%) women with abnormal RHI. Women with abnormal RHI had a greater (more abnormal) ST/HR slope, a trend toward greater peak ST depression, and achieved lower METs than women with normal RHI (Table 1). Conclusion: Among asymptomatic women, endothelial vascular dysfunction was associated with abnormal Ex-ECG results characterized by greater ST/HR slope, greater ST depression, and lower exercise capacity. These findings suggest that “false positive” ST-segment depression in the absence of clinical CAD in women may be explained by endothelial vascular dysfunction. Our study further suggests that endothelial vascular dysfunction may explain the Ex-ECG diagnostic/prognostic paradox.