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INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex‐specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female‐specific elevation in glycerophosphorylcholine and N‐acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)‐17 signaling, C‐type lectin receptor, interferon signaling, and Toll‐like receptor pathways. We pinpointed distinct microglia‐specific immunometabolism endophenotypes (i.e., lipid‐ and amino acid‐specific IL‐10 and IL‐17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate‐mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. Highlights: Sex‐specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression.Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin‐10 pathway activity.Female AD subjects showed a shift in glutamate‐mediated cell‐cell communications between excitatory neurons to microglia and astrocyte. [ABSTRACT FROM AUTHOR]

Introduction Late onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women. Hypothesis We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women. Methods We studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed. Result Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men. Conclusion Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD. Significance statement Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes. [ABSTRACT FROM AUTHOR]

Purpose: To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Materials and Methods: Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. Results: The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Conclusion: Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI. [ABSTRACT FROM AUTHOR]

Sex is an important factor to consider when evaluating memory with older adults. This present study aimed to examine sex differences in memory within a clinical sample of older adults (N = 1084). Raw learning and recall scores on the Hopkins Verbal Learning Test, Revised (HVLT-R) and Brief Visuospatial Memory Test, Revised (BVMT-R) were compared between sexes within the entire sample and cohorts stratified by age. Within the entire sample, women outperformed men in HVLT-R learning and recall, and there were no sex differences in BVMT-R performance. These sex differences, however, were absent or reversed for those with impaired HVLT-R performance and functional deficits, indicating that women retain an early advantage in verbal memory, which is lost with greater indication of disease severity. These findings indicate that women retain an advantage in verbal learning and memory, at least before significant levels of impairment, within a sample of older adults seen at an outpatient neurology clinic, which may have implications for diagnosing memory disorders. [ABSTRACT FROM AUTHOR]

Women are more likely to have Alzheimer's disease (AD) and decline more rapidly once diagnosed despite greater verbal memory early in the disease compared to men—an advantage that has been termed "memory reserve." Resting state functional MRI (fMRI) investigations demonstrate interactions between sex and AD risk factors in default mode network (DMN) connectivity, a network of brain regions showing progressive dysfunction in AD. Separate work suggests connectivity of left prefrontal cortex (PFC) may correlate with more general cognitive reserve in healthy aging. It is unknown whether left prefrontal functional connectivity with anterior and posterior default mode network (aDMN, pDMN) might differ by sex in AD. This study employed group independent component analysis (ICA) to analyze resting state fMRI data from 158 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline diagnoses of normal cognition or early mild cognitive impairment (eMCI). pDMN and aDMN were defined on a subject-specific basis; prefrontal areas were selected from the Brodmann atlas (BA 6, 44, 8, and 9). Moderation regression analyses examined whether sex and amyloid PET positivity (A+/–) moderated effects of apolipoprotein ε4 (APOE ε 4) on connectivity between left PFC, aDMN, and pDMN; and between aDMN and pDMN. Significant analyses were followed up with partial correlations assessing relationship of connectivity to verbal memory on the Rey Auditory Verbal Learning Test (RAVLT), and with preliminary analyses within NC and eMCI groups separately. Results showed no sex moderation of effects of A+ and APOE ε 4 on left prefrontal/DMN connectivity in the full sample. However, sex significantly moderated impact of A+ and APOE ε 4 on connectivity between aDMN and pDMN (p < 0.01). Women with an APOE allele (ε4+) and A+ showed greater aDMN/pDMN connectivity than their ε4- counterparts. No significant results were observed in men. Subgroup analyses suggested the aDMN/pDMN finding was true for those with NC, not eMCI. Partial correlations controlling for age and education showed increased aDMN/pDMN connectivity related to better verbal learning in women (p < 0.01) and not men (p = 0.18). In women at risk for AD or in early symptomatic stages who also have evidence of amyloid burden, stronger aDMN/pDMN connectivity may support verbal learning. [ABSTRACT FROM AUTHOR]

Introduction: Tests of visuospatial function are often administered in comprehensive neuropsychological evaluations. These tests are generally considered assays of parietal lobe function; however, the neural correlates of these tests, using modern imaging techniques, are not well understood. In the current study we investigated the relationship between three commonly used tests of visuospatial function and lobar cortical thickness in each hemisphere. Method: Data from 374 patients who underwent a neuropsychological evaluation and MRI scans in an outpatient dementia clinic were included in the analysis. We examined the relationships between cortical thickness, as assessed with Freesurfer, and performance on three tests: Judgment of Line Orientation (JoLO), Block Design (BD) from the Fourth edition of the Wechsler Adult Intelligence Scale, and Brief Visuospatial Memory Test-Revised Copy Trial (BVMT-R-C) in patients who showed overall average performance on these tasks. Using a series of multiple regression models, we assessed which lobe’s overall cortical thickness best predicted test performance. Results: Among the individual lobes, JoLO performance was best predicted by cortical thickness in the right temporal lobe. BD performance was best predicted by cortical thickness in the right parietal lobe, and BVMT-R-C performance was best predicted by cortical thickness in the left parietal lobe. Conclusions: Performance on constructional tests of visuospatial function appears to correspond best with underlying cortical thickness of the parietal lobes, while performance on visuospatial judgment tests appears to correspond best to temporal lobe thickness. Future research using voxel-wise and connectivity techniques and including more diverse samples will help further understanding of the regions and networks involved in visuospatial tests. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) impacts men and women differently, but the effect of sex on predementia stages is unclear. The objective of this study was to examine whether sex moderates the impact of florbetapir positron emission tomography (PET) amyloid positivity (A+) on verbal learning and memory performance and hippocampal volume (HV) in normal cognition (NC) and early mild cognitive impairment (eMCI). Methods: Seven hundred forty-two participants with NC and participants with eMCI from the Alzheimer's Disease Neuroimaging Initiative (second cohort [ADNI2] and Grand Opportunity Cohort [ADNI-GO]) were included. All had baseline florbetapir PET measured, and 526 had screening visit HV measured. Regression moderation models were used to examine whether A+ effects on Rey Auditory Verbal Learning Test learning and delayed recall and right and left HV (adjusted for total intracranial volume) were moderated by diagnosis and sex. Age, cognition at screening, education, and apolipoprotein E ε4 carrier status were controlled. Results: Women with A+, but not those with florbetapir PET amyloid negative (A-),eMCI showed poorer learning. For women with NC, there was no relationship of A+ with learning. In contrast, A+ men trended toward poorer learning regardless of diagnosis. A similar trend was found for verbal delayed recall: Women with A+, but not A-, eMCI trended toward reduced delayed recall; no effects were observed for women with NC or for men. Hippocampal analyses indicated that women with A+, but not those with A-, eMCI, trended toward smaller right HV; no significant A+ effects were observed for women with NC. Men showed similar, though nonsignificant, patterns of smaller right HV in A+ eMCI, but not in men with A- eMCI or NC. No interactive effects of sex were noted for left HV. Conclusions: Women with NC showed verbal learning and memory scores robust to A+, and women with A+ eMCI lost this advantage. In contrast, A+ impacted men's scores less significantly or not at all, and comparably across those with NC and eMCI. Sex marginally moderated the relationship of A+ and diagnosis with right HV, such that women with NC showed no A+ effect and women with A+ eMCI lost that advantage in neural integrity; the pattern in men was less clear. These findings show that women with A+ eMCI (i.e., prodromal AD) have differential neural and cognitive decline, which has implications for considering sex in early detection of AD and development of therapeutics. [ABSTRACT FROM AUTHOR]

Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied., Competing Interests: Declaration of interests J.B.L. has received consulting fees from Vaxxinity and grant support from GE Healthcare and serves on a data safety monitoring board for Eisai., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial., Objective: To develop a new composite score to improve the prediction of outcome change., Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression., Results: The new AD composite S core with variable S election (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs., Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages., Competing Interests: JC has provided consultation to Acadia, Actinogen, Alkahest, AlphaCognition, Aprinoia, AriBio, Biogen, BioVie, Cassava, Cerecin, Corium, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, GAP Innovations, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, SynapseBio, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. All other authors have nothing to disclose., (© 2024 – The authors. Published by IOS Press.)

Introduction: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood., Methods: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort., Results: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism., Discussion: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD., Highlights: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data., Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features., Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women)., Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status., Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.

Purpose of Review: Poor cognitive aging and dementia pose a significant public health burden, and women face unique risks compared to men. Recent research highlights the role of genetics, menopause, chronic disease, and lifestyle in risk and resilience in women's cognitive aging. This work suggests avenues for clinical action at midlife that may change the course of brain health in aging., Recent Findings: Studies indicate women's risk for poor cognitive aging relates in part to hormone changes at menopause, a time when memory, brain structure and function, and Alzheimer's pathology may be observed in women and not men. Medical and lifestyle risks including diabetes, hypertension, and low physical activity also contribute to women's unique risks. At the same time, literature on resilience suggests women may benefit from lifestyle and chronic disease intervention, possibly more than men. Current studies emphasize the importance of interacting genetic and lifestyle risks, and effects of social determinants of health., Summary: Women have greater risk than men for poor cognitive aging; however, by treating the whole person, including genetics, lifestyle, and social environment, clinicians have an opportunity to support healthy cognitive aging in women and reduce the future public health burden of dementia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes., Method: Archival records from 1617 older adults (M age = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4 th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants ( n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes., Results: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes ( r 's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures., Conclusions: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance., Competing Interests: Disclosure statement S.J.B, M.J.A, L.D., J.Z.K.C., E.T.R. and J.M. have no competing interests to declare. C.C.F. is a consultant for CorTechs Labs, in addition to his research appointment at the University of California, San Diego. L.K.M. holds stocks in CorTechs Labs. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board. He also receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. J.B.B has served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly and holds stock options in CorTechs Labs, Inc., Impact Biomedicines, and Human Longevity, Inc. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies., (Copyright © 2021. Published by Elsevier Inc.)

Despite having an initial verbal memory advantage over men, women have greater rates of Alzheimer's disease and more rapid cognitive decline once diagnosed. Moreover, although Alzheimer's disease is influenced by inflammation, which itself has known sex differences, no study has investigated whether sex differences in memory are moderated by peripheral inflammatory activity. To address this issue, we analyzed data from 109 individuals (50 women, M age  = 71.62, range = 55-87) diagnosed as cognitively normal, or having mild cognitive impairment or Alzheimer's disease dementia. We then followed the sample for 12 months, as part of a longitudinal study of aging and Alzheimer's disease. At baseline, we assessed levels of the inflammatory cytokines interleukin (IL)-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in plasma. At baseline and 12 months, we assessed verbal memory using the Rey Auditory Verbal Learning Test and nonverbal memory using the Brief Visuospatial Memory Test-Revised. As hypothesized, for the full sample, women exhibited stronger verbal (but not nonverbal) memory than men. In women, but not men, higher IL-1β at baseline related to poorer verbal learning across both time points and delayed recall at 12 months. The effect of sex on memory also differed by IL-1β level, with women exhibiting a memory advantage both at baseline and 12 months, but only for those with low-to-moderate IL-1β levels. Therefore, high peripheral inflammation levels may lead to a sex-specific memory vulnerability relevant for Alzheimer's disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cognitive decline and mood symptoms are common in Parkinson's disease (PD). Reductions in striatal dopaminergic binding have been associated with worse cognition and mood. We investigated whether this association persists throughout the disease progression in newly diagnosed PD. Four-year data from Parkinson's Progression Markers Initiative (PPMI) were used. Groups consisted of left and right limb dominantly affected PD patients, and controls. Longitudinal relationships between cognition, mood and striatal binding ratios were assessed by repeated measures correlations. Reduced binding was associated with general cognitive decline in controls, reduced processing speed and increased mood symptoms in PD. Anxiety was associated with striatum only in left limb dominantly affected PD. Dominantly affected limb side did not impact striatum and cognition association. There are longitudinal associations between striatum, processing speed and anxiety. Dopamine transporter availability imaging may have some prognostic value for cognition and mood in PD.

Objective: To evaluate the sex differences in cognitive course over 4 years in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls., Methods: Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson's Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared., Results: Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period)., Conclusions: Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

Alzheimer's disease (AD) is caused by a cascade of changes to brain integrity. Neuroimaging biomarkers are important in diagnosis and monitoring the effects of interventions. As memory impairments are among the first symptoms of AD, the relationship between imaging findings and memory deficits is important in biomarker research. The most established magnetic resonance imaging (MRI) finding is hippocampal atrophy, which is related to memory decline and currently used as a diagnostic criterion for AD. While the medial temporal lobes are impacted early by the spread of neurofibrillary tangles, other networks and regional changes can be found quite early in the progression. Atrophy in several frontal and parietal regions, cortical thinning, and white matter alterations correlate with memory deficits in early AD. Changes in activation and connectivity have been detected by functional MRI (fMRI). Task-based fMRI studies have revealed medial temporal lobe hypoactivation, parietal hyperactivation, and frontal hyperactivation in AD during memory tasks, and activation patterns of these regions are also altered in preclinical and prodromal AD. Resting state fMRI has revealed alterations in default mode network activity related to memory in early AD. These studies are limited in part due to the historic inclusion of patients who had suspected AD but likely did not have the disorder. Modern biomarkers allow for more diagnostic certainty, allowing better understanding of neuroimaging markers in true AD, even in the preclinical stage. Larger patient cohorts, comparison of candidate imaging biomarkers to more established biomarkers, and inclusion of more detailed neuropsychological batteries to assess multiple aspects of memory are needed to better understand the memory deficit in AD and help develop new biomarkers. This article reviews MRI findings related to episodic memory impairments in AD and introduces a new study with multimodal imaging and comprehensive neuropsychiatric evaluation to overcome current limitations.

We examined moderation effects of sex and diagnosis on the effect of positive florbetapir positron emission tomography (PET) amyloid-β (Aβ) scan (A+) on hippocampus subfield volumes in 526 normal control (NC) and early mild cognitive impairment (eMCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI2; ADNI-GO). Regression moderation models showed that women- but not men- with NC designation did not show reduced subiculum volumes despite A+. At the eMCI stage, A+ was detrimental across sexes. Findings were significant while accounting for the effects of age, cognition at screening, education, and APOE4 carrier status. These findings suggest that women with A+ have early neural resistance to Alzheimer's disease-related amyloid burden.

Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer's disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN.