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The publisher apologizes for erroneously omitting part of the footnote for Table 2. This has now been corrected both online and in print.

Objectives: To empirically expand the existing subtypes of mild cognitive impairment (MCI) by incorporating information on neuropsychiatric and functional features, and to assess whether cerebrovascular disease (CVD) risk factors are associated with any of these subgroups.Design: Latent class analysis using 1,655 patients with MCI.Setting: Participants in the Uniform Data Set (UDS) from 29 National Institutes of Health-supported Alzheimer's Disease Centers.Participants: Patients with a consensus diagnosis of MCI from each center and with a Mini-Mental State Examination score of 22 or greater.Measurements: UDS cognitive battery, Neuropsychiatric Inventory Questionnaire, and Functional Assessment Questionnaire administered at initial visit.Results: Seven empirically based subgroups of MCI were identified: 1) minimally impaired (relative frequency, 12%); 2) amnestic only (16%); 3) amnestic with functional and neuropsychiatric features (16%); 4) amnestic multidomain (12%); 5) amnestic multidomain with functional and neuropsychiatric features (12%); 6) functional and neuropsychiatric features (15%); and 7) executive function and language impairments (18%). Two of these subgroups with functional and neuropsychiatric features were at least 3.8 times more likely than the minimally impaired subgroup to have a Rosen-Hachinski score of 4 or greater, an indicator of probable CVD.Conclusions: Findings suggest that there are several distinct phenotypes of MCI characterized by prominent cognitive features, prominent functional features, and neuropsychiatric features or a combination of all three. Subgroups with functional and neuropsychiatric features are significantly more likely to have CVD, which suggests that there may be distinct differences in disease etiology from the other phenotypes. [ABSTRACT FROM AUTHOR]

Objective: Recent evidence suggests that high molecular weight soluble oligomeric Abeta (oAbeta) assemblies (also known as Abeta-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oAbeta/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of Abeta-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAbeta/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes.Methods: We produced and histologically characterized single transgenic mice overexpressing APP(E693Q) or APP(E693Q) X PS1DeltaE9 bigenic mice. APP(E693Q) mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for Abetatotal, Abeta40, Abeta42, and oAbeta/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oAbeta/ADDL ELISA, we assigned individual APP(E693Q) mice to either an undetectable oAbeta/ADDLs group or a readily detectable oAbeta/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task.Results: Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/Abeta, although only APP(E693Q) X PS1Delta9 bigenic mice developed amyloid plaques. The APP(E693Q) mice did not develop amyloid plaques at any age studied, up to 30 months. APP(E693Q) mice were tested for spatial learning and memory, and only 12-month-old APP(E693Q) mice with readily detectable oAbeta/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates.Interpretation: These data suggest that cerebral oAbeta/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human Abeta assemblies. ANN NEUROL 2010. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) often presages development of Alzheimer's disease (AD). We recently completed a cross-sectional study to test the hypothesis that a combination of a brief cognitive screening instrument (Mini-Cog) with a functional scale (Functional Activities Questionnaire; FAQ) would accurately identify individuals with MCI and undiagnosed dementia. The Mini-Cog consists of a clock drawing task and 3-item recall, and takes less than 5 minutes to administer. The FAQ is a 30-item questionnaire completed by an informant. In addition to the Mini-Cog and FAQ, a traditional cognitive test battery was administered, and two neurologists and a neuropsychologist determined a consensus diagnosis of Normal, MCI, or Dementia. A classification tree algorithm was used to pick optimal cutpoints, and, using these cutpoints, the combined Mini-Cog and FAQ (MC-FAQ) predicted the consensus diagnosis with an accuracy of 83% and a weighted kappa of 0.81. When the population was divided into Normal and Abnormal, the sensitivity, specificity and positive predictive value were 89%, 90%, and 95%, respectively. The MC-FAQ discriminates individuals with MCI from cognitively normal individuals and those with dementia, and its ease of administration makes it an attractive screening instrument to aid detection of cognitive impairment in the elderly. [ABSTRACT FROM AUTHOR]

Background: Conflicting results have been reported on the association of plasma total homocysteine (tHcy) and cholesterol levels in Alzheimer disease (AD). The objective of this study was to determine the relationship between cognitive performance and plasma levels of tHcy and its biological determinants folate and vitamin B12, and lipids in clinically diagnosed AD patients. Methods: A cross-sectional database review was performed on two separate groups of patients (n = 191). Mini-Mental State Exam (MMSE) scores, plasma levels of tHcy, vitamin B12, folate, cholesterol, and triglycerides were analyzed. Results: The MMSE scores were inversely correlated with age, plasma levels of tHcy and LDL cholesterol. However, only the inverse relationship between MMSE scores and LDL cholesterol levels persisted after adjustment for age, sex, and status of statin treatment. Plasma tHcy levels increased significantly with age and were inversely related to vitamin B12 and folate levels, which modified the relationship between MMSE scores and plasma tHcy levels. Conclusions: The plasma tHcy levels appeared to relate more to aging than to cognition. Cognitive performance was inversely associated with plasma LDL cholesterol levels in AD patients. Our findings provide further evidence that high LDL cholesterol levels may play a role in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

This study investigated the relationship between the vascular comorbidities (VCs) of hypertension and hypercholesterolemia and the cognitive phenotype of Alzheimer disease (AD). Seventy-four AD patients underwent objective measurement of blood pressure and serum cholesterol levels, and they received a detailed neuropsychologic evaluation examining attention, memory, language, visuomotor/visuospatial skills, and executive functioning. Multiple regression analyses controlling for demographic variables, overall cognitive status, and the presence of diabetes/cardiac disease indicated that an increase in the number of VCs, but not their severity, was associated with poorer verbal and visual recall, visuoconstructive and spatial analysis, verbal reasoning, and set shifting. The findings demonstrate that VCs are associated with specific aspects of cognitive functioning in AD patients. The mechanisms likely involve the effects of VCs on cerebrovascular disease including white matter disruption. The results highlight the importance of controlling these risk factors in patients who carry the diagnosis of AD. [ABSTRACT FROM AUTHOR]

Dopamine afferents from the mesencephalon appear to play a critical role in the normal development and cognitive functions of multiple areas of the primate cerebral cortex. In some regions, such as the prefrontal and motor cortices, dopamine innervation changes substantially during postnatal development. However, little is known about the postnatal maturation of dopamine afferents to the primate rostral entorhinal cortex, a periallocortical region that receives a dense dopamine innervation in adults. In this study, we used immunocytochemical techniques and antibodies against tyrosine hydroxylase and the dopamine transporter to examine the postnatal development of dopamine axons in the rostral subdivision of macaque monkey entorhinal cortex. Within animals, the axons labeled with each antibody did not differ in overall density or laminar distribution. Across development, the density of dopamine axons in layers I and VI did not change appreciably. In contrast, the density of labeled exons in layer III significantly increased by a factor of three between birth and 5-7 months of age. The timing of this change differs substantially from that observed in prefrontal cortex, where peak dopamine innervation occurs between 2 and 3 years of age. These findings, in concert with other data, suggest that developmental changes in the dopamine innervation of cortical regions may parallel the functional maturation of those areas. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. In addition to idiopathic disease, AD is also associated with autosomal dominant inheritance, which causes a familial form of AD (FAD). Some instances of FAD have been linked to mutations in the beta-amyloid protein precursor (APP). Although there are numerous mouse AD models available, few rat AD models, which have several advantages over mice, have been generated.Results: Fischer 344 rats expressing human APP driven by the ubiquitin-C promoter were generated via lentiviral vector infection of Fischer 344 zygotes. We generated two separate APP-transgenic rat lines, APP21 and APP31. Serum levels of human amyloid-beta (Abeta)40 were 298 pg/ml for hemizygous and 486 pg/ml for homozygous APP21 animals. Serum Abeta42 levels in APP21 homozygous rats were 135 pg/ml. Immunohistochemistry in brain showed that the human APP transgene was expressed in neurons, but not in glial cells. These findings were consistent with independent examination of enhanced green fluorescent protein (eGFP) in the brains of eGFP-transgenic rats. APP21 and APP31 rats expressed 7.5- and 3-times more APP mRNA, respectively, than did wild-type rats. Northern blots showed that the human APP transgene, driven by the ubiquitin-C promoter, is expressed significantly more in brain, kidney and lung compared to heart and liver. A similar expression pattern was also seen for the endogenous rat APP. The unexpected similarity in the tissue-specific expression patterns of endogenous rat APP and transgenic human APP mRNAs suggests regulatory elements within the cDNA sequence of APP.Conclusion: This manuscript describes the generation of APP-transgenic inbred Fischer 344 rats. These are the first human AD model rat lines generated by lentiviral infection. The APP21 rat line expresses high levels of human APP and could be a useful model for AD. Tissue-specific expression in the two transgenic rat lines and in wild-type rats contradicts our current understanding of APP gene regulation. Determination of the elements that are responsible for tissue-specific expression of APP may enable new treatment options for AD. [ABSTRACT FROM AUTHOR]

Background: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found.Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons.Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003).Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.). [ABSTRACT FROM AUTHOR]

Background: Recent research has postulated that the activation of cGAS-STING-interferon signalling pathways could be implicated in the pathogenesis of Alzheimer's disease (AD). However, the precise types of interferons and related cytokines, both from the brain and periphery, responsible for cognitive impairment in patients with AD remain unclear., Methods: A total of 131 participants (78 [59.5%] female and 53 [40.5%] male; mean [SD] age, 61.5 [7.6] years) with normal cognition and cognitive impairment from the China Aging and Neurodegenerative Initiative cohort were included. CSF and serum IFNα-2a, IFN-β, IFN-γ, TNF-α, IL-6, IL-10, MCP-1and CXCL-10 were tested. The correlation between these interferons and related cytokines with AD core biomarkers in the CSF and plasma, cognition performance, and brain MRI measures were analysed., Results: We found that only CSF IFN-β levels were significantly elevated in Alzheimer's disease compared to normal cognition. Furthermore, CSF IFN-β levels were significantly associated with AD core biomarkers (CSF P-tau and Aβ42/Aβ40 ratio) and cognitive performance (MMSE and CDR score). Additionally, the CSF IFN-β levels were significantly correlated with the typical pattern of brain atrophy in AD (such as hippocampus, amygdala, and precuneus). In contrast, CSF IL-6 levels were significantly elevated in non-AD cognitively impaired patients compared to other groups. Moreover, CSF IL-6 levels were significantly associated with cognitive performance in non-AD individuals and correlated with the vascular cognitive impairment-related MRI markers (such as white matter hyperintensity)., Conclusion: Our findings demonstrate that distinct inflammatory molecules are associated with different cognitive disorders. Notably, CSF IFN-β levels are significantly linked to the pathology and cognitive performance of AD, identifying this interferon as a potential target for AD therapy., Competing Interests: Declarations. Ethics approval: This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of the USTC in Hefei, China (2019KY-26). All participants provided written informed consent for participating in the study. The Clinical Trial Number: (ChiCTR1900024777|| http://www.chictr.org.cn/ ) with the Clinical Trial Registry (July 27, 2019). Consent for publication: No applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The SARS-CoV-2 pandemic accelerated development of innovative methods for conducting research remotely via digital technologies. However, few studies have examined participant technological literacy skills or access as key social determinants of brain health in aging populations at risk of Alzheimer's disease and other dementias., Objective: To identify associations of sociodemographic and clinical characteristics, cognitive status and geolocation with digital technology access and skill within dementia research cohorts., Methods: A self-administered questionnaire surveyed digital access and literacy skills in persons enrolled across various studies conducted at Emory Goizueta Alzheimer's Disease Research Center. We investigated cognitive and sociodemographic characteristics, and neighborhood disadvantage related to these digital attributes., Results: Of 1860 participants (mean age: 65.3 years (SD:11.4)) surveyed, 71.6% were women, 87.1% Whites, 10.4% African Americans, and 46.9% had postgraduate-level education. Most participants had access to digital devices: desktop (53.7%), laptop (81.6%), tablet (71.6%), smartphone (94.6%), internet (82.0%), or videoconferencing (95.5%). Cognitively unimpaired participants had higher odds of digital access (OR:3.75; 95% CI:2.45-5.73) and skill (OR:1.22; 95% CI:1.14-1.30). Although Whites were likelier to have access (OR:1.36; 95% CI:1.01-1.82) than African Americans, no differences were found in skill between the two groups. Living in more disadvantaged neighborhoods was significantly associated with lower technology skills (OR:0.86; 95% CI:0.82-0.91)., Conclusions: Cognitive impairment, race, and neighborhood socioeconomic disadvantage are significant barriers which limit digital access and skill. Improving digital knowledge, skill-building, and geographic access may encourage research participation especially in geographically remote or disadvantaged areas and help narrow sociodemographic and racial disparities existing in dementia research., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits., Competing Interests: Competing interests: C.C. has received research support from GSK and Eisai. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of Circular Genomics and owns stocks in this company. D.J.P. is an employee of GSK and holds stock in GSK. M.d.C.M. has been an invited speaker at Eisai. M.d.C.M. is an associate editor at Alzheimer’s Research and Therapy. B.T. and P.J.V. are inventors on a patent (WO2020197399A1, owned by Stichting VUmc). C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly and performed contract research or received grants from AC Immune, Axon Neuroscience, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama and Vivoryon. She serves on editorial boards of Medidact Neurologie–Springer, Alzheimer’s Research and Therapy and Neurology: Neuroimmunology and Neuroinflammation and is an editor of the Neuromethods book (Springer). She had speaker contracts for Roche, Grifols and Novo Nordisk. The rest of the authors declare no competing interest., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within non-Hispanic White (NHW) populations. Here we provide an extensive survey of the proteomic landscape of AD across diverse racial/ethnic groups., Methods: Two cortical regions, from multiple centers, were harmonized by uniform neuropathological diagnosis. Among 998 unique donors, 273 donors self-identified as African American, 229 as Latino American, and 434 as NHW., Results: While amyloid precursor protein and the microtubule-associated protein tau demonstrated higher abundance in AD brains, no significant race-related differences were observed. Further proteome-wide and focused analyses (specific amyloid beta [Aβ] species and the tau domains) supported the absence of racial differences in these AD pathologies within the brain proteome., Discussion: Our findings indicate that the racial differences in AD risk and clinical presentation are not underpinned by dramatically divergent patterns in the brain proteome, suggesting that other determinants account for these clinical disparities., Highlights: We present a large-scale proteome (∼10,000 proteins) of DLPFC (998) and STG (244) across AD cases. About 50% of samples were from racially and ethnically diverse brain donors. Key AD proteins (amyloid and tau) correlated with CERAD and Braak stages. No significant race-related differences in amyloid and tau protein levels were observed in AD brains. AD-associated protein changes showed a strong correlation between the brain proteomes of African American and White individuals. This dataset advances understanding of ethnoracial-specific AD pathways and potential therapies., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers., Competing Interests: Declaration of interests C.C. has received research support from GSK and EISAI. C.C. is a member of the advisory board of Circular Genomics and owns stocks in these companies. C.C. is on the advisory board of ADmit. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Merck, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6). He receives compensation for serving as chief medical officer for MODAG GmbH and is a beneficiary of the phantom share program of MODAG GmbH. E.M. reports research support received from NIA (U01AG059798), Anonymous Foundation, GHR, Alzheimer Association, Eli Lilly Eisai, and Hoffmann-La Roche and paid consulting for Eli Lilly, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann-La Roche, Grifols, and Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer's disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches., Methods: We employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology., Results: Heparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181., Conclusion: These findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain., (© 2024. The Author(s).)