Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

Background Whether psychological resilience correlates with neurocognitive performance is largely unknown. Therefore, we assessed association between neurocognitive performance and resilience in individuals with a history of childhood abuse or trauma exposure. Methods In this cross-sectional study of 226 highly traumatized civilians, we assessed neurocognitive performance, history of childhood abuse and other trauma exposure, and current depressive and PTSD symptoms. Resilience was defined as having ≥ 1 trauma and no current depressive or PTSD symptoms; non-resilience as having ≥ 1 trauma and current moderate/severe depressive or PTSD symptoms. Results The nonresilient group had a higher percentage of unemployment (p = 0.002) and previous suicide attempts (p <0.0001) than the resilient group. Both groups had comparable education and performance on verbal reasoning, nonverbal reasoning, and verbal memory. However, the resilient group performed better on nonverbal memory (p=0.016) with an effect size of 0.35. Additionally, more severe childhood abuse or other trauma exposure was significantly associated with non-resilience. Better nonverbal memory was significantly associated with resilience even after adjusting for severity of childhood abuse, other trauma exposure, sex, and race using multiple logistic regression (adjusted OR=1.2; p=0.017). Conclusions We examined resilience as absence of psychopathology despite trauma exposure in a highly traumatized, low socioeconomic, urban population. Resilience was significantly associated with better nonverbal memory, a measure of ability to code, store, and visually recognize concrete and abstract pictorial stimuli. Nonverbal memory may be a proxy for emotional learning, which is often dysregulated in stress-related psychopathology, and may contribute to our understanding of resilience.

Background Influences of resilience on the presence and severity of depression following trauma exposure are largely unknown. Hence, we examined effects of resilience on depressive symptom severity in individuals with past childhood abuse and/or other trauma exposure. Methods In this cross-sectional study of 792 adults, resilience was measured with the Connor–Davidson Resilience Scale, depression with the Beck Depression Inventory (BDI), childhood abuse with the Childhood Trauma Questionnaire, and other traumas with the Trauma Events Inventory. Results Multiple linear regression modeling with depression severity (BDI score) as the outcome yielded 4 factors: childhood abuse (β=2.5, p<0.0001), other trauma (β=3.5, p<0.0001), resilience (β=−0.5, p<0.0001), and other trauma×resilience interaction term (β=−0.1, p=0.0021), all of which were significantly associated with depression severity, even after adjusting for age, sex, race, education, employment, income, marital status, and family psychiatric history. Childhood abuse and trauma exposure contributed to depressive symptom severity while resilience mitigated it. Conclusions Resilience moderates depressive symptom severity in individuals exposed to childhood abuse or other traumas both as a main effect and an interaction with trauma exposure. Resilience may be amenable to external manipulation and could present a potential focus for treatments and interventions.

INTRODUCTION: Growing evidence indicates fine particulate matter (PM 2.5 ) as risk factor for Alzheimer's' disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as potential mediator of this association. METHODS: We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors' residential traffic-related PM 2.5 exposure 1, 3 and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs. RESULTS: PM 2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-six CpG sites were identified as mediators of the association between PM 2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation. DISCUSSION: Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM 2.5 and AD.

Background: Depression has been associated with a higher risk of Alzheimer's disease (AD) in several prospective studies; however, mechanisms underlying this association remain unclear. Methods: We examined genetic correlation between depression and AD using linkage disequilibrium score regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study results. Subsequently, cis and trans quantitative trait locus analyses for the depression genome-wide association study signals were performed to resolve the genetic signals to specific DNA methylation sites, brain transcripts, and proteins. These transcripts and proteins were then examined for associations with AD and its endophenotypes. Finally, the associations between depression polygenic risk score and AD endophenotypes were examined. Results: We detected a significant genetic correlation between depression and AD, suggesting that they have a shared genetic basis. Furthermore, we found that depression had a causal role in AD through Mendelian randomization but did not find evidence for a causal role of AD on depression. Moreover, we identified 75 brain transcripts and 28 brain proteins regulated by the depression genome-wide association study signals through quantitative trait locus analyses. Of these, 46 transcripts and seven proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, thus implicating them in AD. In addition, we found that a higher depression polygenic risk score was associated with a faster decline of episodic memory over time. Conclusions: Depression appears to have a causal role in AD, and this causal relationship is likely driven, in part, by the 53 brain transcripts and proteins identified in this study.

A key feature of posttraumatic stress disorder (PTSD) is a disruption of hypothalamic-pituitary-adrenal (HPA) axis feedback sensitivity and cortisol levels. Despite known diurnal rhythmicity of cortisol, there has been little exploration of the circadian timing of the index trauma and consequent cortisol release. Stress-related glucocorticoid pulses have been shown to shift clocks in peripheral organs but not the suprachiasmatic nucleus, uncoupling the central and peripheral clocks. A sample of 425 participants was recruited in the Emergency Department following a DSM-IV-TR Criterion A trauma. The Zeitgeber time of the trauma was indexed in minutes since sunrise, which was hypothesized to covary with circadian blood cortisol levels (high around sunrise and decreasing over the day). Blood samples were collected M(SD)= 4.0(4.0) hours post-trauma. PTSD symptoms six months post-trauma were found to be negatively correlated with trauma time since sunrise (r(233) = −0.15, p = 0.02). The effect remained when adjusting for sex, age, race, clinician-rated severity, education, pre-trauma PTSD symptoms, and time of the blood draw (β = -0.21, p = 0.00057). Cortisol levels did not correlate with blood draw time, consistent with a masking effect of the acute stress response obscuring the underlying circadian rhythm. Interactions between trauma time and expression of NPAS2 (punadjusted=0.042) and TIMELESS (punadjusted=0.029) predicted six-month PTSD symptoms. The interaction of trauma time and cortisol concentration was significantly correlated with the expression of PER1 (padjusted=0.029). The differential effect of time of day on future symptom severity suggests a role of circadian effects in PTSD development, potentially through peripheral clock disruption.

Objective APOE is a strong risk factor for Alzheimer's disease (AD) and associated with higher low-density lipoprotein cholesterol (LDL-C) levels. Moreover, LDL-C is associated with the development of clinically ascertained AD; however, whether this association is present with the underlying neuropathological manifestations of AD or whether it is independent of the effect of APOE is unknown and is the focus of this paper. Methods Individuals in the Religious Orders Study/Memory and Ageing Project cohorts with longitudinal measures of blood lipids and detailed autopsies were studied. We modelled the relationship between blood lipids and 12 age-related brain pathologies using a linear mixed model adjusted for potential confounding factors and stratified by APOE genotype with overall significance determined by meta-Analysis. Blood lipids considered were LDL-C, high-density lipoprotein cholesterol and triglycerides. Brain pathologies included AD pathology measured by silver staining (Braak stage, a modified Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score and global AD pathology) and immunohistochemistry (beta-Amyloid and neurofibrillary tangles) as well as cerebral microinfarct, cerebral macroinfarct, cerebral amyloid angiopathy, cerebral atherosclerosis, hippocampal sclerosis, TDP-43 cytoplasmic inclusions and Lewy bodies. Results 559 participants (69.1% female) had complete data for analysis. They were followed for a median of 7 years and a median of 3 years prior to dementia onset. LDL-C was associated with all measures of AD neuropathology (neurofibrillary tangles, beta-Amyloid, Braak stage, modified CERAD score and global AD pathology) and cerebral amyloid angiopathy independent of APOE after adjusting for age, sex, cholesterol-lowering medication use, body mass index, smoking and education at false discovery rate (FDR) p-value <0.05. Conclusions These findings implicate LDL-C in the pathophysiology of AD independent of APOE and suggest LDL-C is a modifiable risk factor for AD.

INTRODUCTION: Higher fine particulate matter (PM 2.5 ) exposure has been found to be associated with Alzheimer's disease (AD). PM 2.5 has been hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. A major genetic risk factor of AD, the apolipoprotein E ( APOE ) gene, has also been hypothesized to modify the association between PM 2.5 and AD. However, little prior research exisits to support these hypotheses. Therefore, this paper aims to investigate the association between traffic-related PM 2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. METHODS: Brain tissue donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (ADRC) who died before 2020 (n=224) were assessed for AD pathology including Braak Stage, Consortium to Establish a Registry for AD (CERAD) score, and the combined AD neuropathologic change (ABC score). Traffic-related PM 2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250m. One-, 3-, and 5-year average PM 2.5 concentrations prior to death were matched to participants home address. We assessed the association between traffic-related PM 2.5 and AD hallmark pathology, as well as effect modification by APOE genotype, using adjusted ordinal logistic regression models. RESULTS: Traffic-related PM 2.5 was significantly associated with CERAD score for the 1-year exposure window (OR: 1.92; 95% CI: 1.12, 3.30), and the 3-year exposure window (OR: 1.87; 95%-CI: 1.01, 3.17). PM 2.5 had harmful, but non-significant associations on Braak Stage and ABC score. The strongest associations between PM 2.5 and neuropathology markers were among those without APOE ε 4 alleles (e.g., for CERAD and 1-year exposure window, OR: 2.31; 95% CI: 1.36, 3.94), though interaction between PM 2.5 and APOE genotype was not statistically significant. CONCLUSIONS: Our study found traffic-related PM 2.5 exposure was associated with CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM 2.5 affects Aβ deposition in the brain. This association was particularly strong among donors without APOE ε 4 alleles. Future studies should further investigate the biological mechanisms behind this assocation.

Several common psychiatric and neurodegenerative diseases share epidemiologic risk; however, whether they share pathophysiology is unclear and is the focus of our investigation. Using 25 GWAS results and LD score regression, we find eight significant genetic correlations between psychiatric and neurodegenerative diseases. We integrate the GWAS results with human brain transcriptomes (n = 888) and proteomes (n = 722) to identify cis- and trans- transcripts and proteins that are consistent with a pleiotropic or causal role in each disease, referred to as causal proteins for brevity. Within each disease group, we find many distinct and shared causal proteins. Remarkably, 30% (13 of 42) of the neurodegenerative disease causal proteins are shared with psychiatric disorders. Furthermore, we find 2.6-fold more protein-protein interactions among the psychiatric and neurodegenerative causal proteins than expected by chance. Together, our findings suggest these psychiatric and neurodegenerative diseases have shared genetic and molecular pathophysiology, which has important ramifications for early treatment and therapeutic development.

Alzheimer's disease (AD) progresses through a lengthy asymptomatic period during which pathological changes accumulate prior to development of clinical symptoms. As disease-modifying treatments are developed, tools to stratify risk of clinical disease will be required to guide their use. In this study, we examine the relationship of AD biomarkers in healthy middle-aged individuals to health history, family history, and neuropsychological measures and identify cerebrospinal fluid (CSF) biomarkers to stratify risk of progression from asymptomatic to symptomatic AD. CSF from cognitively normal (CN) individuals (N=1149) in the Emory Healthy Brain Study were assayed for Aβ 42 , total Tau (tTau), and phospho181-Tau (pTau), and a subset of 134 cognitively normal, but biomarker-positive, individuals were identified with asymptomatic AD (AsymAD) based on a locally-determined cutoff value for ratio of tTau to Aβ 42 . These AsymAD cases were matched for demographic features with 134 biomarker-negative controls (CN/BM-) and compared for differences in medical comorbidities and family history. Dyslipidemia emerged as a distinguishing feature between AsymAD and CN/BM- groups with significant association with personal and family history of dyslipidemia. A weaker relationship was seen with diabetes, but there was no association with hypertension. Examination of the full cohort by median regression revealed a significant relationship of CSF Aβ 42 (but not tTau or pTau) with dyslipidemia and diabetes. On neuropsychological tests, CSF Aβ 42 was not correlated with performance on any measures, but tTau and pTau were strongly correlated with visuospatial perception and visual episodic memory. In addition to traditional CSF AD biomarkers, a panel of AD biomarker peptides derived from integrating brain and CSF proteomes were evaluated using machine learning strategies to identify a set of 8 peptides that accurately classified CN/BM- and symptomatic AD CSF samples with AUC of 0.982. Using these 8 peptides in a low dimensional t-distributed Stochastic Neighbor Embedding analysis and k-Nearest Neighbor (k=5) algorithm, AsymAD cases were stratified into "Control-like" and "AD-like" subgroups based on their proximity to CN/BM- or AD CSF profiles. Independent analysis of these cases using a Joint Mutual Information algorithm selected a set of 5 peptides with 81% accuracy in stratifying cases into AD-like and Control-like subgroups. Performance of both sets of peptides was evaluated and validated in an independent data set from the Alzheimer's Disease Neuroimaging Initiative. Based on our findings, we conclude that there is an important role of lipid metabolism in asymptomatic stages of AD. Visuospatial perception and visual episodic memory may be more sensitive than language-based abilities to earliest stages of cognitive decline in AD. Finally, candidate CSF peptides show promise as next generation biomarkers for predicting progression from asymptomatic to symptomatic stages of AD.