Journal of Alzheimer's Disease - Volume 92, issue 2

Authors: Khezri, Mohammad Rafi | Ghasemnejad-Berenji, Morteza | Moloodsouri, Donya

Article Type: Article Commentary

Abstract: One of the main players in apoptosis during Alzheimer’s disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer’s disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer’s disease.

Keywords: Alzheimer’s disease, apoptosis, caspase-3, PI3K/AKT

DOI: 10.3233/JAD-221157

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 391-393, 2023

Authors: Panyard, Daniel J. | Deming, Yuetiva K. | Darst, Burcu F. | Van Hulle, Carol A. | Zetterberg, Henrik | Blennow, Kaj | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Carlsson, Cynthia M. | Johnson, Sterling C. | Asthana, Sanjay | Engelman, Corinne D. | Lu, Qiongshi

Article Type: Research Article

Abstract: Background: Our understanding of the pathophysiology underlying Alzheimer’s disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. Objective: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. Methods: We built 13 tissue-specific AD PRS and studied the scores’ relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. …Results: The AD PRS model that was most predictive of AD diagnosis (even without APOE ) was the liver AD PRS: n  = 1,115; odds ratio = 2.15 (1.67–2.78), p  = 3.62×10–9 . The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ42 :Aβ40 ratio, p  = 3.53×10–6 ) and the phosphorylated tau:amyloid-β ratio (p  = 1.45×10–5 ). Conclusion: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, functional annotation, liver, polygenic risk score

DOI: 10.3233/JAD-220599

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 395-409, 2023

Authors: Tandon, Raghav | Levey, Allan I. | Lah, James J. | Seyfried, Nicholas T. | Mitchell, Cassie S.

Article Type: Research Article

Abstract: Background: The complex and not yet fully understood etiology of Alzheimer’s disease (AD) shows important proteopathic signs which are unlikely to be linked to a single protein. However, protein subsets from deep proteomic datasets can be useful in stratifying patient risk, identifying stage dependent disease markers, and suggesting possible disease mechanisms. Objective: The objective was to identify protein subsets that best classify subjects into control, asymptomatic Alzheimer’s disease (AsymAD), and AD. Methods: Data comprised 6 cohorts; 620 subjects; 3,334 proteins. Brain tissue-derived predictive protein subsets for classifying AD, AsymAD, or control were identified and validated with …label-free quantification and machine learning. Results: A 29-protein subset accurately classified AD (AUC = 0.94). However, an 88-protein subset best predicted AsymAD (AUC = 0.92) or Control (AUC = 0.92) from AD (AUC = 0.98). AD versus Control: APP, DHX15, NRXN1, PBXIP1, RABEP1, STOM, and VGF. AD versus AsymAD: ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PRKAR1B. AsymAD versus Control: APP, C4A, DMXL1, EXOC2, PITPNB, RABEP1, and VGF. Additional predictors: DNAJA3, PTBP2, SLC30A9, VAT1L, CROCC, PNP, SNCB, ENPP6, HAPLN2, PSMD4, and CMAS. Conclusion: Biomarkers were dynamically separable across disease stages. Predictive proteins were significantly enriched to sugar metabolism. Show more

Keywords: Alzheimer’s disease, biomarkers, machine learning, metabolism, proteomics, recursive feature elimination

DOI: 10.3233/JAD-220683

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 411-424, 2023

Authors: Beydoun, Hind A. | Beydoun, May A. | Maldonado, Ana I. | Fanelli-Kuczmarski, Marie T. | Weiss, Jordan | Evans, Michele K. | Zonderman, Alan B.

Article Type: Research Article

Abstract: Background: Cross-sectional studies have linked cognition to allostatic load (AL) which reflects multisystem dysregulation from life course exposure to stressors. Objective: To examine baseline and changes in AL and their relationships with 11 cognitive function test scores, while exploring health disparities according to sex and race. Methods: Longitudinal [Visit 1 (2004–2009) and Visit 2 (2009–2013)] data were analyzed from 2,223 Healthy Aging in Neighborhoods of Diversity across the Life Span participants. We calculated AL total score using cardiovascular, metabolic, and inflammatory risk indicators, and applied group-based trajectory modeling to define AL change. Results: Overall …and stratum-specific relationships were evaluated using mixed-effects linear regression models that controlled for socio-demographic, lifestyle, and health characteristics. Baseline AL was significantly associated with higher log-transformed Part A Trail Making Test score [Loge (TRAILS A)] (β = 0.020, p  = 0.004) and increasing AL was associated with higher Benton Visual Retention Test score [BVRT] (β = 0.35, p  = 0.002) at baseline, in models that controlled for age, sex, race, poverty status, education, literacy, smoking, drug use, the 2010 healthy eating index and body mass index. Baseline AL and AL change were not related to change in cognitive function between visits. There were no statistically significant interaction effects by sex or race in fully-adjusted models. Conclusion: At baseline, AL was associated with worse attention or executive functioning. Increasing AL was associated with worse non-verbal memory or visuo-constructional abilities at baseline. AL was not related to change in cognitive function over time, and relationships did not vary by sex or race. Show more

Keywords: Adults, allostatic load, cognitive function, health disparities, longitudinal study

DOI: 10.3233/JAD-220888

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 425-443, 2023

Authors: Teoh, Nicole Shu Ning | Gyanwali, Bibek | Lai, Mitchell K.P. | Chai, Yuek Ling | Chong, Joyce R. | Chong, Eddie Jun Yi | Chen, Christopher | Tan, Chuen Seng | Hilal, Saima

Article Type: Research Article

Abstract: Background: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. Objective: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. Methods: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood …assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. Results: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. Conclusion: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials. Show more

Keywords: Blood biomarker, cognitive decline, inflammation mediators, interleukin-6, interleukin-8, memory clinic

DOI: 10.3233/JAD-220971

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 445-455, 2023

Authors: Zhu, Carolyn W. | Gu, Yian | Kociolek, Anton J. | Fernandez, Kayri K. | Cosentino, Stephanie | Stern, Yaakov

Article Type: Research Article

Abstract: Background: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. Objective: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer’s disease (AD) or DLB and had autopsy confirmed diagnosis. Methods: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n  = 44, DLB: n  = 14) and also had autopsy-confirmed diagnoses of pure AD (n  = 32), mixed AD+Lewy body (LB) (n  = 5), or pure LB (n  = 11). Total …Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient’s cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. Results: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. Conclusion: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-LB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs. Show more

Keywords: Alzheimer’s disease, clinical diagnosis, cost of care, dementia with Lewy bodies, Medicare claims, pathology confirmed diagnosis

DOI: 10.3233/JAD-221021

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 457-466, 2023

Authors: van den Berg, Emma | Nilsson, Johanna | Kersten, Iris | Brinkmalm, Gunnar | de Kort, Anna M. | Klijn, Catharina J.M. | Schreuder, Floris H.B.M. | Jäkel, Lieke | Gobom, Johan | Portelius, Erik | Zetterberg, Henrik | Brinkmalm, Ann | Blennow, Kaj | Kuiperij, H. Bea | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. Objective: We therefore aimed to investigate synaptic dysfunction in CAA. Methods: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. Results: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in …the CSF of CAA patients compared with controls (p  = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p ≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n  = 6) were similar to AD patients, while levels in CAA/ATN- (n  = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). Conclusion: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral amyloid angiopathy, cerebrospinal fluid, synaptic pathology

DOI: 10.3233/JAD-220977

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 467-475, 2023

Authors: Ren, Jun-Rong | Wang, Zhen | Cheng, Yuan | He, Chen-Yang | Jian, Jie-Ming | Fan, Dong-Yu | Shen, Ying-Ying | Chen, Dong-Wan | Li, Hui-Yun | Yi, Xu | Zeng, Gui-Hua | Tan, Cheng-Rong | Shi, An-Yu | Chen, Li-Yong | Mao, Qing-Xiang | Wang, Yan-Jiang | Wang, Jun

Article Type: Research Article

Abstract: Background: The kidney-brain crosstalk has been involved in Alzheimer’s disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. Objective: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. Methods: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Results: We found higher plasma Klotho and …lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aβ42 , Aβ40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ42 . Conclusion: Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, estimated glomerular filtration rate, kidney-brain crosstalk, Klotho

DOI: 10.3233/JAD-221107

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 477-485, 2023

Authors: Ono, Rei | Sakurai, Takashi | Sugimoto, Taiki | Uchida, Kazuaki | Nakagawa, Takeshi | Noguchi, Taiji | Komatsu, Ayane | Arai, Hidenori | Saito, Tami

Article Type: Research Article

Abstract: Background: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease. Objective: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort. Methods: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their …close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC. Results: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61–5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele. Conclusion: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking. Show more

Keywords: Alzheimer’s disease, cause of death, frontotemporal lobar degeneration, Lewy bodies, mild cognitive impairment, mortality, prognostic factor, vascular dementia

DOI: 10.3233/JAD-221290

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 487-498, 2023

Authors: Kikuchi, Hiroyuki | Takahashi, Miki | Komatsu, Hiroaki | Axelsen, Paul H.

Article Type: Research Article

Abstract: Background: The extraction and quantification of amyloid-β (Aβ) peptides in brain tissue commonly uses formic acid (FA) to disaggregate Aβ fibrils. However, it is not clear whether FA can disaggregate post-translationally modified Aβ peptides, or whether it induces artifact by covalent modification during disaggregation. Of particular interest are Aβ peptides that have been covalently modified by 4-hydroxy-2-nonenal (HNE), an oxidative lipid degradation product produced in the vicinity of amyloid plaques that dramatically accelerates the aggregation of Aβ peptides. Objective: Test the ability of FA to disaggregate Aβ peptides modified by HNE and to induce covalent artifacts. …Methods: Quantitative liquid-chromatography-tandem-mass spectrometry of monomeric Aβ peptides and identify covalently modified forms. Results: FA disaggregated ordinary Aβ fibrils but also induced the time-dependent formylation of at least 2 residue side chains in Aβ peptides, as well as oxidation of its methionine side chain. FA was unable to disaggregate Aβ peptides that had been covalently modified by HNE. Conclusion: The inability of FA to disaggregate Aβ peptides modified by HNE prevents FA-based approaches from quantifying a pool of HNE-modified Aβ peptides in brain tissue that may have pathological significance. Show more

Keywords: Ascorbate, copper, deuterium-stabilized fatty acids, liposomes, mass spectrometry, mouse, oxidative stress, polyunsaturated

DOI: 10.3233/JAD-220940

Citation: Journal of Alzheimer's Disease, vol. 92, no. 2, pp. 499-511, 2023