Risk Factor For Alzheimer's Disease Research Articles

Anti-CMV IgG Seropositivity is Associated with Plasma Biomarker Evidence of Amyloid-β Accumulation.

Some human studies have identified infection with cytomegalovirus (CMV), a member of the alpha herpesvirus family, as a risk factor for Alzheimer's disease and related dementias (ADRD). To our knowledge, no studies have evaluated associations of CMV seropositivity with plasma biomarkers of ADRD risk in middle-aged adults. In participants recruited for an exercise study, we evaluated cross-sectional associations of CMV seropositivity with: Aβ42/Aβ40 ratio, a low ratio suggestive of central nervous system Aβ accumulation; glial fibrillary acidic protein (GFAP), a measure of neuroinflammation; and neurofilament light (NfL), a measure of neurodegeneration. Anti-CMV IgG was quantified by ELISA. Plasma ADRD biomarkers were quantified using the ultrasensitive SIMOA assay. We used linear regression to evaluate associations of CMV seropositivity with the ADRD biomarkers, adjusting for age, sex, and race (n = 303; Age = 55.7±9.2 years). For ADRD biomarkers significantly associated with CMV seropositivity, we evaluated continuous associations of anti-CMV IgG levels with the ADRD biomarkers, excluding CMV seronegative participants. 53% of participants were CMV seropositive. CMV seropositivity was associated with a lesser Aβ42/Aβ40 ratio (β=-3.02e-03 95% CI [-5.97e-03, -7.18e-05]; p = 0.045). In CMV seropositive participants, greater anti-CMV IgG levels were associated with a lesser Aβ42/Aβ40 ratio (β=-4.85e-05 95% CI[-8.45e-05, -1.25e-05]; p = 0.009). CMV seropositivity was not associated with plasma GFAP or NfL in adjusted analyses. CMV seropositivity was associated with a lesser plasma Aβ42/Aβ40 ratio. This association may be direct and causally related to CMV neuro-cytotoxicity or may be indirect and mediated by inflammatory factors resulting from CMV infection burden and/or the immune response.

Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β-catenin.

Elevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated β-catenin and Kelch-like ECH-associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the β-catenin-WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of β-catenin. Hcy-upregulated KEAP1 competed with β-catenin to bind to WTX. Knockdown of both β-catenin and KEAP1 attenuated Hcy-induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1-β-catenin pathway in Hcy-induced neuronal-like senescence and uncover a promising target for AD treatment.

Stable Variable Selection Method with Shrinkage Regression Applied to the Selection of Genetic Variants Associated with Alzheimer’s Disease

In this work, we aimed to establish a stable and accurate procedure with which to perform feature selection in datasets with a much higher number of predictors than individuals, as in genome-wide association studies. Due to the instability of feature selection where many potential predictors are measured, a variable selection procedure is proposed that combines several replications of shrinkage regression models. A weighted formulation is used to define the final predictors. The procedure is applied for the investigation of single nucleotide polymorphism (SNP) predictors associated with Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Furthermore, the two following data scenarios are investigated: one that solely considers the set of SNPs, and another with the covariates of age, sex, educational level, and ε4 allele of the Apolipoprotein E (APOE4) genotype. The SNP rs2075650 and the APOE4 genotype are provided as risk factors for Alzheimer’s disease, which is in line with the literature, and another four new SNPs are indicated, thus cultivating new hypotheses for in vivo analyses. These experiments demonstrate the potential of the new method for stable feature selection.

Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. We summarized the current evidence from several aspects and further quantified these associations. We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Dissecting Alzheimer's Disease Risk in Asian American Elders: A Classification and Regression Tree Approach.

Alzheimer's disease (AD) poses a growing public health challenge, particularly with an aging population. While extensive research has explored the relationships between AD, socio-demographic factors, and cardiovascular risk factors, a notable gap exists in understanding these connections within the Asian American elderly population. This study aims to address this gap by employing the Classification and Regression Tree (CART) approach to investigate the intricate interplay of socio-demographic variables, cardiovascular risk factors, sleep patterns, prior antidepressant use, and AD among Asian American elders. Data from the 2017 Uniform Data Set, provided by the National Alzheimer's Coordinating Center, were analyzed, focusing on a sample of Asian American elders (n = 4,343). The analysis utilized the Classification and Regression Tree (CART) approach. CART analysis identified critical factors, including levels of independence, specific age thresholds (73.5 and 84.5 years), apnea, antidepressant use, and body mass index, as significantly associated with AD risk. These findings have far-reaching implications for future research, particularly in examining the roles of gender, cultural nuances, socio-demographic factors, and cardiovascular risk elements in AD within the Asian American elderly population. Such insights can inform tailored interventions, improved healthcare access, and culturally sensitive policies to address the complex challenges posed by AD in this community.

RNA m6A Methylation and Alzheimer's Disease: Current Evidence and Future Perspectives

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by the pathological accumulation of b-amyloid and neurofibrillary tangles. Despite substantial progress in both basic and clinical research on AD, the detailed mechanism of AD pathogenesis is still elusive. RNA N6-methyladenosine methylation (m6A) is the most predominant post-transcriptional modification on eukaryotic mRNA, prominently enriched in the mammalian brain. Notably, m6A-modified RNA showed significant changes during the development of AD, indicating an important role of this modification in AD pathogenesis. Aim: In this study, we aim to provide a summary of recent advances highlighting the indispensable role of m6A in AD pathogenesis. Result: From the perspective of m6A modification, we review our current understanding of the association between RNA m6A machinery and the risk factors of AD, as well as its involvement in various pathophysiological hallmarks of AD. We also discuss the main obstacles in current studies about m6A in AD pathogenesis and the corresponding caveats and solutions to them. Conclusion: This review emphasizes the significance of investigating m6A in the context of AD and highlights the considerable potential for m6A to emerge as a novel therapeutic target for AD.

Cumulative Anticholinergic Burden and its Predictors among Older Adults with Alzheimer's Disease Initiating Cholinesterase Inhibitors.

Cumulative anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. However, concomitant use of cholinesterase inhibitors (ChEIs) and anticholinergic burden can nullify the benefit of the treatment and worsen Alzheimer's disease (AD). A literature gap exists regarding the extent of the cumulative anticholinergic burden and associated risk factors in AD. Therefore, this study evaluated the prevalence and predictors of cumulative anticholinergic burden among patients with AD initiating ChEIs. A retrospective longitudinal cohort study was conducted using the Medicare claims data involving parts A, B, and D from 2013 to 2017. The study sample included older adults (65 years and older) diagnosed with AD and initiating ChEIs (donepezil, rivastigmine, or galantamine). The cumulative anticholinergic burden was calculated based on the Anticholinergic Cognitive Burden scale and patient-specific dosing using the defined daily dose over the 1 year follow-up period after ChEI initiation. Incremental anticholinergic burden levels were dichotomized into moderate-high (sum of standardized daily anticholinergic exposure over a year (TSDD) score ≥ 90) versus low-no (score 0-89). The Andersen Behavioral Model was used as the conceptual framework for selecting the predictors under the predisposing, enabling, and need categories. A multivariable logistic regression model was used to evaluate the predictors of high-moderate versus low-no cumulative anticholinergic burden. A multinomial logistic regression model was also used to determine the factors associated with patients having moderate and high burdens compared to low/no burdens. The study included 222,064 older adults with AD with incident ChEI use (mean age 82.24 ± 7.29, 68.9% females, 83.6% White). Overall, 80.48% had some anticholinergic burdenduring the follow-up, with 36.26% patients with moderate (TSDD scores 90-499), followed by 24.76% high (TSDD score > 500), and 19.46% with low (TSDD score 1-89) burden categories. Predisposing factors such as age; African American, Asian, or Hispanic race; and need factors included comorbidities such as dyslipidemia, syncope, delirium, fracture, pneumonia, epilepsy, and claims-based frailty index were less likely to be associated with the moderate-high anticholinergic burden. The factors that increased the odds of moderate-high burden were predisposing factors such as female sex; enabling factors such as dual eligibility and diagnosis year; and need factors such as baseline burden, behavioral and psychological symptoms of dementia, depression, insomnia, urinary incontinence, irritable bowel syndrome, anxiety, muscle spasm, gastroesophageal reflux disease, heart failure, and dysrhythmia.Most of these findings remained consistent with multinomial logistic regression. CONCLUSION: Four out of five older adults with AD had some level of anticholinergic burden, with over 60% having moderate-high anticholinergic burden. Several predisposing, enabling, and need factors were associated with the cumulative anticholinergic burden. The study findings suggest a critical need to minimize the cumulative anticholinergic burden to improve AD care.

Viral Infections, Are They a Trigger and Risk Factor of Alzheimer's Disease?

Alzheimer's Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD such as the lytic replication and axonal transport of HSV-1, the various mechanisms of ZIKV neurotropism through the human protein Musashi-1 (MSI1), and the spread of SARS-CoV-2 through the transfer of the virus through the BBB endothelial cells to glial cells and then to neurons via transsynaptic transfer. We will also explore beyond these mere associations by carefully analyzing the potential mechanisms by which these viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, the dysregulation of immune responses, and the impact on protein processing (Aβ42 and hyperphosphorylated tau). Controversies and challenges of the virus-AD relationship emerge as we tease out these potential mechanisms. Looking forward, we emphasize future directions, such as distinct questions and proposed experimentations to explore, that the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development while encouraging further discussion.

Molecular Mechanisms Linking Osteoarthritis and Alzheimer's Disease: Shared Pathways, Mechanisms and Breakthrough Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease mostly affecting the elderly population. It is characterized by cognitive decline that occurs due to impaired neurotransmission and neuronal death. Even though deposition of amyloid beta (Aβ) peptides and aggregation of hyperphosphorylated TAU have been established as major pathological hallmarks of the disease, other factors such as the interaction of genetic and environmental factors are believed to contribute to the development and progression of AD. In general, patients initially present mild forgetfulness and difficulty in forming new memories. As it progresses, there are significant impairments in problem solving, social interaction, speech and overall cognitive function of the affected individual. Osteoarthritis (OA) is the most recurrent form of arthritis and widely acknowledged as a whole-joint disease, distinguished by progressive degeneration and erosion of joint cartilage accompanying synovitis and subchondral bone changes that can prompt peripheral inflammatory responses. Also predominantly affecting the elderly, OA frequently embroils weight-bearing joints such as the knees, spine and hips leading to pains, stiffness and diminished joint mobility, which in turn significantly impacts the patient's standard of life. Both infirmities can co-occur in older adults as a result of independent factors, as multiple health conditions are common in old age. Additionally, risk factors such as genetics, lifestyle changes, age and chronic inflammation may contribute to both conditions in some individuals. Besides localized peripheral low-grade inflammation, it is notable that low-grade systemic inflammation prompted by OA can play a role in AD pathogenesis. Studies have explored relationships between systemic inflammatory-associated diseases like obesity, hypertension, dyslipidemia, diabetes mellitus and AD. Given that AD is the most common form of dementia and shares similar risk factors with OA-both being age-related and low-grade inflammatory-associated diseases, OA may indeed serve as a risk factor for AD. This work aims to review literature on molecular mechanisms linking OA and AD pathologies, and explore potential connections between these conditions alongside future prospects and innovative treatments.

Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer’s risk

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer’s disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher β-amyloid (Aβ) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aβ load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.

Deciphering the Association of Epstein-Barr Virus and Its Glycoprotein M Peptide with Neuropathologies in Mice.

The reactivation of ubiquitously present Epstein-Barr virus (EBV) is known to be involved with numerous diseases, including neurological ailments. A recent in vitro study from our group unveiled the association of EBV and its 12-amino acid peptide glycoprotein M146-157 (gM146-157) with neurodegenerative diseases, viz., Alzheimer's disease (AD) and multiple sclerosis. In this study, we have further validated this association at the in vivo level. The exposure of EBV/gM146-157 to mice causes a decline in the cognitive ability with a concomitant increase in anxiety-like symptoms through behavioral assays. Disorganization of hippocampal neurons, cell shrinkage, pyknosis, and apoptotic appendages were observed in the brains of infected mice. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were found to be elevated in infected mouse brain tissue samples, whereas TNF-α exhibited a decline in the serum of these mice. Further, the altered levels of nuclear factor-kappa B (NF-kB) and neurotensin receptor 2 affirmed neuroinflammation in infected mouse brain samples. Similarly, the risk factor of AD, apolipoprotein E4 (ApoE4), was also found to be elevated at the protein level in EBV/gM146-157 challenged mice. Furthermore, we also observed an increased level of myelin basic protein in the brain cortex. Altogether, our results suggested an integral connection of EBV and its gM146-157 peptide to the neuropathologies.

Using Focus Groups to Explore Older Black Men's Perception of Dietary Interventions.

Older Black men are underrepresented in research despite being disproportionately affected by Alzheimer's disease (AD) and cardiovascular (CV) risk factors related to AD compared with non-Hispanic Whites. Although dietary interventions have shown promise to reduce modifiable CV risk factors related to AD, Black Americans have lower adherence likely due to lack of cultural considerations. Using a noninterventional convergent parallel mixed-methods approach, this study examined the cultural contexts that inform perceptions of dietary interventions among older Midwestern Black men. All participants completed an online demographic and dietary habit survey prior to focus group discussions. Two focus group discussion sessions were conducted with a total of 10 cognitively normal Black men aged 55 years and older. Survey data were analyzed using a frequency analysis and qualitative data were analyzed using a six-step thematic analysis process. Most men indicated having hypertension (N = 7, 77.8%) and currently not following a dietary eating pattern (N = 8, 88.9%). Emerging themes identified included (1) knowledge of dementia, (2) perceptions of dietary interventions, (3) barriers impacting participation in dietary interventions, and (4) overcoming barriers to engage Black men in dietary interventions. Findings from this study should inform the design of future dietary interventions for AD prevention to enhance participation among older Black men.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults

BackgroundFunctional decline associated with dementia, including in Alzheimer’s disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).MethodsWe retrospectively analyzed records on 1310 participants from the ADNI database for the multivariate analysis. We used longitudinal measures of Mini-Mental State Examination (MMSE) scores in participants, who were cognitively normal, or having AD, or other cognitive deficits to investigate the trajectories of cognitive changes. Multiple linear regression, linear mixed models and latent class analyses were conducted to investigate the association of the SNP rs6859 with MMSE.ResultsThe regression coefficient per one allele dose of the SNP rs6859 was independently associated with MMSE in both cross-sectional (-2.23, p < 0.01) and linear mixed models (-2.26, p < 0.01) analyses. The latent class model with three distinct subgroups (class 1: stable and gradual decline, class 2: intermediate and late decline, and class 3: lowest and irregular) performed best in the posterior classification, 42.67% (n = 559), 21.45% (n = 281), 35.88% (n = 470) were classified as class 1, class 2, and class 3. In the heterogeneous linear mixed model, the regression coefficient per one allele dose of rs6859 – A risk allele was significantly associated with MMSE class 1 and class 2 memberships and related decline; Class 1 (-2.28, 95% CI: -4.05, -0.50, p < 0.05), Class 2 (-5.56, 95% CI: -9.61, -1.51, p < 0.01) and Class 3 (-0.37, 95% CI: -1.62, 0.87, p = 0.55).ConclusionsThis study found statistical evidence supporting the classification of three latent subclass groups representing complex MMSE trajectories in the ADNI cohort. The SNP rs6859 can be suggested as a candidate genetic predictor of variation in modeling MMSE trajectory, as well as for identifying latent classes with higher baseline MMSE. Functional studies may help further elucidate this relationship.

Comparative analysis of multimodal biomarkers for amyloid-beta positivity detection in Alzheimer's disease cohorts.

Efforts to develop cost-effective approaches for detecting amyloid pathology in Alzheimer's disease (AD) have gained significant momentum with a focus on biomarker classification. Recent research has explored non-invasive and readily accessible biomarkers, including magnetic resonance imaging (MRI) biomarkers and some AD risk factors. In this comprehensive study, we leveraged a diverse dataset, encompassing participants with varying cognitive statuses from multiple sources, including cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and our in-house Dementia Disease Initiation (DDI) cohort. As brain amyloid plaques have been proposed as sufficient for AD diagnosis, our primary aim was to assess the effectiveness of multimodal biomarkers in identifying amyloid plaques, using deep machine learning methodologies. Our findings underscore the robustness of the utilized methods in detecting amyloid beta positivity across multiple cohorts. Additionally, we investigated the potential of demographic data to enhance MRI-based amyloid detection. Notably, the inclusion of demographic risk factors significantly improved our models' ability to detect amyloid-beta positivity, particularly in early-stage cases, exemplified by an average area under the ROC curve of 0.836 in the unimpaired DDI cohort. These promising, non-invasive, and cost-effective predictors of MRI biomarkers and demographic variables hold the potential for further refinement through considerations like APOE genotype and plasma markers.

Autosomal Dominant Alzheimer's Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice.

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.

HuM195 and its single-chain variable fragment increase Aβ phagocytosis in microglia via elimination of CD33 inhibitory signaling.

CD33 is a transmembrane receptor expressed on cells of myeloid lineage and regulates innate immunity. CD33 is a risk factor for Alzheimer's disease (AD) and targeting CD33 has been a promising strategy drug development. However, the mechanism of CD33's action is poorly understood. Here we investigate the mechanism of anti-CD33 antibody HuM195 (Lintuzumab) and its single-chain variable fragment (scFv) and examine their therapeutic potential. Treatment with HuM195 full-length antibody or its scFv increased phagocytosis of β-amyloid 42 (Aβ42) in human microglia and monocytes. This activation of phagocytosis was driven by internalization and degradation of CD33, thereby downregulating its inhibitory signal. HumM195 transiently induced CD33 phosphorylation and its signaling via receptor dimerization. However, this signaling decayed with degradation of CD33. scFv binding to CD33 leads to a degradation of CD33 without detection of the CD33 dimerization and signaling. Moreover, we found that treatments with either HuM195 or scFv promotes the secretion of IL33, a cytokine implicated in microglia reprogramming. Importantly, recombinant IL33 potentiates the uptake of Aβ42 in monocytes. Collectively, our findings provide unanticipated mechanistic insight into the role of CD33 signaling in both monocytes and microglia and define a molecular basis for the development of CD33-based therapy of AD.

Association of PM2.5 Exposure and Alzheimer Disease Pathology in Brain Bank Donors-Effect Modification by APOE Genotype.

Fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The APOE gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology and effect modification by APOE genotype, using adjusted ordinal logistic regression models. Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 APOE ε4 copy. Traffic-related PM2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. Our study found traffic-related PM2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects β-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.

Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS) to Assess Effects of Age, Sex, and Head Size on Interstitial Fluid Dynamics in Healthy Subjects.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS) is a novel MRI method for assessing brain interstitial fluid dynamics, potentially indexing glymphatic function. Failed glymphatic clearance is implicated in Alzheimer's disease (AD) pathophysiology. We assessed the contribution of age and female sex (strong AD risk factors) to DTI-ALPS index in healthy subjects. We also for the first time assessed the effect of head size. In accord with prior studies, we show reduced DTI-ALPS index with aging, and in men compared to women. However, head size may be a major contributing factor to this counterintuitive sex difference.

The Effects of PICALM rs3851179 and Age on Brain Atrophy and Cognition Along the Alzheimer's Disease Continuum.

Rs3851179, a variant of PICALM gene, and age are the risk factors of Alzheimer's disease (AD). AD is divided into early-onset AD (EOAD, < 65 years) and late-onset AD (LOAD, ≥ 65 years) by age. The purpose was to investigate the impact of different genotypes of PICALM rs3851179 on brain atrophy and cognitive decline across the AD continuum in different age groups. Four hundred seven cognitive normal (CN) controls, 362 mild cognitive impairment (MCI) patients, and 94 AD patients were enrolled to assess the interaction between AD continuum, age status, and PICALM on gray matter volume (GMV), global cognition, memory function, and executive function using full factorial ANCOVA (3 × 2 × 2). The interaction between AD continuum and PICALM significantly affected the GMV of the left putamen (PUT.L). rs3851179 A-allele carriers did not show a significant decrease in PUT.L GMV from CN to MCI to AD, while GG-allele carriers did. The interaction between AD continuum and age status was significant on GMV of the left angular gyrus (ANG.L) and right superior occipital gyrus (SOG.R). LOAD had higher GMV of ANG.L and SOG.R than EOAD. The interactive effects among AD continuum, age status, and PICALM were not significant on GMV but were significant on global cognition and executive function. The A-allele was found to have a protective effect on global cognition and executive function in EOAD, but not significantly so in LOAD. PICALM rs3851179 A-allele might alleviate the atrophy of PUT.L across the AD continuum than GG-allele. Age status did not affect the interaction between AD continuum and PICALM on brain atrophy. The ANG.L and SOG.R atrophied more severely in EOAD than in LOAD. Rs3851179 A-allele was protective for global cognition and executive function in EOAD.