Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Sanders, Owen Davis

Article Type: Review Article

Abstract: Oxidative stress, inflammation, and amyloid-β are Alzheimer’s disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch’s postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients’ brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently …in preclinical AD and AD patients’ hippocampal neurons, and in AD patients’ neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents’ brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1β, and interferon-β. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons and/or inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients’ blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mice’s hippocampi triggered antiviral interferon-β secretion; interferon-β injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patient’s Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized. Show more

Keywords: Cell-free nucleic acids, deoxyribonuclease I, mitochondrial DNA, neuroinflammatory diseases, oxidative stress, ribonucleases, wounds and injuries

DOI: 10.3233/ADR-220047

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1-19, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Research Article

Abstract: Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer’s disease (AD) is driven by intraneuronal amyloid-β (i Aβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived i Aβ activates, upon reaching a critical threshold, the AβPP-independent i Aβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only i …Aβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived i Aβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived i Aβ-activated self-sustaining mechanism producing a yet undefined deleterious “substance X” (s X) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the i Aβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD. Show more

Keywords: Age-related cognitive decline, Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0, amyloid-β protein precursor, BACE1 and BACE2 activators, intraneuronal amyloid-β

DOI: 10.3233/ADR-220079

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 21-35, 2023

Authors: Rosenbloom, Michael H. | Barclay, Terry

Article Type: Short Communication

Abstract: Prodromal Alzheimer’s disease (AD) is a neurodegenerative condition typically progressing to dementia within 3 years. We describe a case of a mild cognitive impairment (MCI) patient with biomarker evidence for amyloidosis, tau, and neurodegeneration who had minimal changes in clinical phenotype during an 11-year period. AD biomarkers were obtained with cerebrospinal fluid analysis and amyloid PET imaging, both of which supported a biological diagnosis of AD. However, the patient’s neuropsychological profile remained stable over 11 years except for mild memory-retrieval changes. This case provides evidence that MCI with supportive AD biomarkers may have an atypically minimal progression.

Keywords: Biomarkers, cognitive reserve, longitudinal progression, prodromal AD

DOI: 10.3233/ADR-220065

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 37-40, 2023

Authors: Zingel, Rebecca | Jacob, Louis | Smith, Lee | Konrad, Marcel | Kostev, Karel

Article Type: Research Article

Abstract: Background: To date, no large study has examined the relationship between psoriasis and dementia in Germany. Objective: The aim of this study was to assess the association between psoriasis and the risk of all-cause dementia in patients followed in general practices in Germany. Methods: This retrospective cohort study is based on longitudinal data from the IQVIATM Disease Analyzer database and included patients with an initial diagnosis of psoriasis between January 1995 and December 2014 in 1,173 general practices in Germany. Patients without psoriasis were matched individually (1:1) to psoriasis patients using propensity scores. The main …outcome of the study was the cumulative incidence of dementia diagnoses within up to 15 years of the index date. Univariate Cox proportional regression models were used to assess the relationship between psoriasis or psoriatic arthritis and dementia. Results: The present study included 10,583 patients with a diagnosis of psoriasis and 10,583 controls without psoriasis. After 15 years of follow-up, 22.0% of the psoriasis patients and 19.1% (p  < 0.001) of the non-psoriasis patients developed dementia. The incidence rate of dementia in 1,000 person-years was 15.0 in psoriasis patients and 11.9 in the non-psoriasis cohort. Psoriasis was significantly associated with a dementia risk (HR: 1.24; 95% CI: (1.14–1.35); p  < 0.001). The association was stronger in patients with PsA (HR: 1.35; 95% CI: (0.98–1.86)) but this was not significant (p  = 0.070). Conclusion: The present study found a positive association between psoriasis and all-cause dementia in patients in general practices in Germany. Show more

Keywords: Dementia, Germany, psoriasis, psoriatic arthritis, retrospective cohort study

DOI: 10.3233/ADR-220060

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 41-49, 2023

Authors: Lin, Ni-Hsuan | Goh, Angela | Lin, Shyh-Horng | Chuang, Kai-An | Chang, Chih-Hsuan | Li, Ming-Han | Lu, Chu-Hsun | Chen, Wen-Yin | Wei, Pei-Hsuan | Pan, I-Hong | Perng, Ming-Der | Wen, Shu-Fang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of Ganoderma lucidum (Antler form), Nelumbo nucifera Gaertn., Ziziphus jujuba Mill., and Dimocarpus longan, with the ability of its various components to confer resilience to …cognitive deficits. Objective: To evaluate the potential of Bugu-M on amyloid-β (Aβ) toxicity and its in vitro mechanisms and on in vivo cognitive function. Methods: We illustrated the effect of Bugu-M on Aβ25–35 -evoked toxicity as well as its possible mechanisms to diminish the pathogenesis of AD in rat cortical neurons. For cognitive function studies, 2-month-old female 3×Tg-AD mice were administered 400 mg/kg Bugu-M for 30 days. Behavioral tests were performed to assess the efficacy of Bugu-M on cognitive impairment. Results: In primary cortical neuronal cultures, Bugu-M mitigated Aβ-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Conclusion: Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, axon, cognition, dementia, herbal, mild cognitive impairment, natural product, prevention, synapse

DOI: 10.3233/ADR-220056

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 51-76, 2023

Authors: Naeser, Margaret A. | Martin, Paula I. | Ho, Michael D. | Krengel, Maxine H. | Bogdanova, Yelena | Knight, Jeffrey A. | Hamblin, Michael R. | Fedoruk, Andrea E. | Poole, Luke G. | Cheng, ChiaHsin | Koo, BangBon

Article Type: Research Article

Abstract: Background: Chronic traumatic encephalopathy, diagnosed postmortem (hyperphosphorylated tau), is preceded by traumatic encephalopathy syndrome with worsening cognition and behavior/mood disturbances, over years. Transcranial photobiomodulation (tPBM) may promote improvements by increasing ATP in compromised/stressed cells and increasing local blood, lymphatic vessel vasodilation. Objective: Aim 1: Examine cognition, behavior/mood changes Post-tPBM. Aim 2: MRI changes - resting-state functional-connectivity MRI: salience, central executive, default mode networks (SN, CEN, DMN); magnetic resonance spectroscopy, cingulate cortex. Methods: Four ex-players with traumatic encephalopathy syndrome/possible chronic traumatic encephalopathy, playing 11– 16 years, received In-office, red/near-infrared tPBM to scalp, 3x/week for 6 weeks. Two …had cavum septum pellucidum. Results: The three younger cases (ages 55, 57, 65) improved 2 SD (p  < 0.05) on three to six neuropsychological tests/subtests at 1 week or 1 month Post-tPBM, compared to Pre-Treatment, while the older case (age 74) improved by 1.5 SD on three tests. There was significant improvement at 1 month on post-traumatic stress disorder (PTSD), depression, pain, and sleep. One case discontinued narcotic pain medications and had reduced tinnitus. The possible placebo effect is unknown. At 2 months Post-tPBM, two cases regressed. Then, home tPBM was applied to only cortical nodes, DMN (12 weeks); again, significant improvements were seen. Significant correlations for increased SN functional connectivity (FC) over time, with executive function, attention, PTSD, pain, and sleep; and CEN FC, with verbal learning/memory, depression. Increased n-acetyl-aspartate (NAA) (oxygen consumption, mitochondria) was present in anterior cingulate cortex (ACC), parallel to less pain and PTSD. Conclusion: After tPBM, these ex-football players improved. Significant correlations of increased SN FC and CEN FC with specific cognitive tests and behavior/mood ratings, plus increased NAA in ACC support beneficial effects from tPBM. Show more

Keywords: Chronic traumatic encephalopathy, dementia, depression, neurodegenerative, pain, photobiomodulation, post-traumatic stress disorder, sleep, traumatic brain injury, traumatic encephalopathy syndrome

DOI: 10.3233/ADR-220022

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 77-105, 2023

Authors: Okahara, Kazunori | Ohsawa, Makoto | Haruta-Tsukamoto, Ayaka | Miyoshi, Ryoei | Funahashi, Hideki | Fukutani, Yasuhiro | Makita, Setsuko | Matsuo, Hisae | Ishida, Yasushi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and dementia have increasingly been conceived of as “complex diseases of aging”, determined by multiple, simultaneous, interacting pathophysiological processes. The condition known as frailty is a phenotype of aging and its comprehensive pathophysiology is thought to be closely related to the incidence of mild cognitive impairment (MCI) and the exacerbation of dementia. Objective: This study aimed to investigate the effect of the multicomponent drug, ninjin’yoeito (NYT), on frailty in MCI and mild AD patients. Methods: This study was an open-label trial. A total of 14 patients, including 9 with MCI and 5 …with mild AD, were enrolled. Among them, 11 were frail while 3 were prefrail. NYT (6–9 g/day) was administered orally for 24 weeks, and assessments were carried out at baseline (week 0), and at 4, 8, 16, and 24 weeks. Results: In the primary endpoint, significant early improvements were observed in the anorexia scores according to the Neuropsychiatric Inventory after four weeks of treatment with NYT. The Cardiovascular Health Study score was significantly improved, and no frailty was observed after 24 weeks. The fatigue visual analog scale scores also significantly improved. The Clinical Dementia Rating and the Montreal Cognitive Assessment scores remained at baseline levels during the NYT treatment period. Conclusion: The results suggest that NYT may be effective in the treatment of frailty, especially for anorexia and fatigue, in both MCI and mild AD patients, which would be beneficial for the prognosis of dementia. Show more

Keywords: Alzheimer’s disease, anorexia, dementia, fatigue, frailty, Kampo, mild cognitive impairment, Ninjin’yoeito

DOI: 10.3233/ADR-220074

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 107-117, 2023

Authors: Dubey, Souvik | Das, Shambaditya | Ghosh, Ritwik | Dubey, Mahua Jana | Chakraborty, Arka Prava | Roy, Dipayan | Das, Gautam | Dutta, Ajitava | Santra, Arindam | Sengupta, Samya | Benito-León, Juliàn

Article Type: Research Article

Abstract: Background: Cognitive postscripts of COVID-19, codenamed as ‘cognitive COVID’ or ‘brain fog,’ characterized by multidomain cognitive impairments, are now being reckoned as the most devastating sequelae of COVID-19. However, the impact on the already demented brain has not been studied. Objective: We aimed to assess the cognitive functioning and neuroimaging following SARS-CoV-2 infection in patients with pre-existing dementia. Methods: Fourteen COVID-19 survivors with pre-existing dementia (four with Alzheimer’s disease, five with vascular dementia, three with Parkinson’s disease dementia, and two with the behavioral variant of frontotemporal dementia) were recruited. All these patients had detailed cognitive and …neuroimaging evaluations within three months before suffering from COVID-19 and one year later. Results: Of the 14 patients, ten required hospitalization. All developed or increased white matter hyperintensities that mimicked multiple sclerosis and small vessel disease. There was a significant increase in fatigue (p  = 0.001) and depression (p  = 0.016) scores following COVID-19. The mean Frontal Assessment Battery (p < 0.001) and Addenbrooke’s Cognitive Examination (p  = 0.001) scores also significantly worsened. Conclusion: The rapid progression of dementia, the addition of further impairments/deterioration of cognitive abilities, and the increase or new appearance of white matter lesion burden suggest that previously compromised brains have little defense to withstand a new insult (i.e., ‘second hit’ like infection/dysregulated immune response, and inflammation). ‘Brain fog’ is an ambiguous terminology without specific attribution to the spectrum of post-COVID-19 cognitive sequelae. We propose a new codename, i.e. ‘FADE-IN MEMORY’ (i.e., Fatigue, decreased Fluency, Attention deficit, Depression, Executive dysfunction, slowed INformation processing speed, and subcortical MEMORY impairment). Show more

Keywords: Cognitive impairment, COVID-19, dementia, post-COVID-19

DOI: 10.3233/ADR-220090

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 119-128, 2023

Authors: Leccese, Deborah | Cornacchini, Sara | Nacmias, Benedetta | Sorbi, Sandro | Bessi, Valentina

Article Type: Short Communication

Abstract: Recent studies have speculated a link between Creutzfeldt-Jakob disease (CJD) and COVID-19, following the description of CJD cases after COVID-19 infection. We report the case of a 71-year-old female patient who developed neuropsychiatric and neurological symptoms after COVID-19 infection and was later diagnosed with CJD. Cerebrospinal fluid (CSF) total tau levels were slightly increased. She resulted prion protein gene (PRNP) M129V heterozygous. We aim to emphasize the role of the polymorphism at codon 129 of PRNP gene on the clinical phenotype and duration of CJD, and the CSF total tau levels that likely correlate with the rate of disease progression.

Keywords: Cerebrospinal fluid total tau, COVID-19 infection, Creutzfeldt-Jakob disease, prion disease, SARS-CoV-2

DOI: 10.3233/ADR-220095

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 129-134, 2023

Authors: Mozersky, Jessica | Solomon, Erin D. | Baldwin, Kari | Wroblewski, Matthew | Parsons, Meredith | Goodman, Melody | DuBois, James M.

Article Type: Research Article

Abstract: Background: Older adults are at increased risk of cognitive impairments including Alzheimer’s disease dementia. Legally authorized representatives (LARs) can provide informed consent when a participant is no longer able to, but little is known about barriers to incorporating them in research. Objective: Explore reasons for not asking and documenting participant decisions to appoint LARs among researchers conducting clinical intervention trials studying older adults or individuals with cognitive impairments. Methods: Mixed method design consisting of a survey (N  = 1,284) and qualitative interviews (N  = 40) regarding barriers to incorporating LARs. Participants were principal investigators and clinical research coordinators. …Results: 37% (N  = 469) had not asked and documented participant decisions about appointing LARs in the prior year. They had significantly lower confidence in resources available to incorporate LARs and lower positive attitudes compared to their counterparts who had done so. The majority (83%) had no trials studying individuals with cognitive impairments and reported LARs were not applicable. A minority (17%) had at least one trial studying individuals with cognitive impairments and reported being unaware of LARs. Qualitative findings indicate discomfort broaching a sensitive topic especially with individuals who are not yet impaired. Conclusion: Resources and education to increase awareness and knowledge of LARs are needed. Researchers studying older adults should, at minimum, have the knowledge and resources to incorporate LARs when necessary. Stigma and discomfort discussing LARs will need to be overcome, as early proactive discussions before a participant loses decisional capacity could enhance participant autonomy and facilitate recruitment and retention of older adults to research. Show more

Keywords: Clinical research, cognitive impairments, informed consent, legally authorized representatives, older adults, proxy, research ethics, surrogate

DOI: 10.3233/ADR-220103

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 135-149, 2023

Authors: Tolea, Magdalena I. | Camacho, Simone | Cohen, Iris R. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Greater mindfulness, the practice of awareness and living in the moment without judgement, has been linked to positive caregiving outcomes in dementia caregivers and its impact attributed to greater decentering and emotion regulation abilities. Whether the impact of these mindfulness-based processes varies across caregiver subgroups is unclear. Objective: Analyze cross-sectional associations between mindfulness and caregiver psychosocial outcomes, considering different caregiver and patient characteristics. Methods: A total of 128 family caregivers of persons living with Alzheimer’s disease and related disorders were assessed on several mindfulness measures (i.e., global; decentering, positive emotion regulation, negative emotion regulation) and …provided self-reported appraisals of caregiving experience; care preparedness; confidence, burden, and depression/anxiety. Bivariate relationships between mindfulness and caregiver outcomes were assessed with Pearson’s correlations and stratified by caregiver (women versus men; spouse versus adult child) and patient (mild cognitive impairment (MCI) versus Dementia; AD versus dementia with Lewy bodies; low versus high symptom severity) characteristics. Results: Greater mindfulness was associated with positive outcomes and inversely associated with negative outcomes. Stratification identified specific patterns of associations across caregiver groups. Significant correlations were found between all mindfulness measures and caregiving outcomes in male and MCI caregivers while the individual mindfulness component of positive emotion regulation was significantly correlated to outcomes in most caregiver groups. Conclusion: Our findings support a link between caregiver mindfulness and improved caregiving outcomes and suggest directions of inquiry into whether the effectiveness of dementia caregiver-support interventions may be improved by targeting specific mindfulness processes or offering a more inclusive all-scope approach depending on individual caregiver or patient characteristics. Show more

Keywords: Caregiver burden, caregivers, dementia, emotional regulation, informal care, mindfulness

DOI: 10.3233/ADR-220069

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 151-164, 2023

Authors: Roberts, Blaine R. | Laffoon, Scott B. | Roberts, Anne M. | Porter, Tenielle | Fowler, Chris | Masters, Colin L. | Dratz, Edward A. | Laws, Simon M.

Article Type: Short Communication

Abstract: After age, polymorphisms of the Apolipoprotein E (APOE ) gene are the biggest risk factor for the development of Alzheimer’s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ɛ 2, ɛ 3, and ɛ 4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ɛ 4 (Q222K) mutation did not form dimers or complexes observed for apoE ɛ 2 & ɛ …3 proteins. Show more

Keywords: Alzheimer’s disease, APOE, biomarkers, 2D PAGE, mutation, plasma, proteogenomics

DOI: 10.3233/ADR-220075

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 165-172, 2023

Authors: Ehtezazi, Touraj | Rahman, Khalid | Davies, Rhys | Leach, Andrew G.

Article Type: Review Article

Abstract: Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has …been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments. Show more

Keywords: Alzheimer’s disease, blocking NMDA receptors, blood-brain barrier, declining cognitive function, liver dysfunction, serum bile acids

DOI: 10.3233/ADR-220071

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 173-211, 2023

Authors: Sinclair, Lindsey I. | Lawton, Michael A. | Palmer, Jennifer C. | Ballard, Clive G.

Article Type: Research Article

Abstract: Background: Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective: We aimed to characterize depression in AD and to identify risk factors. Methods: We used data from three large dementia focused cohorts: ADNI (n  = 665 with AD, 669 normal cognition), NACC (n  = 698 with AD, 711 normal cognition), and BDR (n  = 757 with AD). Depression ratings were available using the GDS …and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03–15.03). Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor. Show more

Keywords: Alzheimer’s disease, dementia, depression, depressive disorder

DOI: 10.3233/ADR-239000

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 213-225, 2023

Authors: Mendez, Mario F. | Nasir, Imaad

Article Type: Short Communication

Abstract: The differentiation of semantic variant primary progressive aphasia from dementia and Alzheimer’s disease can be difficult, particularly when the semantic anomia is pronounced. This report describes a patient who presented with complaints of memory loss and proved to have prominent semantic loss of all types of nouns, common and proper, concrete and abstract, yet continued to live independently and maintain his activities of daily living. The evaluation was consistent for semantic variant primary progressive aphasia with degradation of semantic knowledge and focal anterior temporal atrophy and hypometabolism. This report summarizes the literature and discusses the differential diagnosis of this disorder …from Alzheimer’s disease and related dementias. Show more

Keywords: Alzheimer’s disease, face recognition, semantic dementia, semantic variant primary progressive aphasia, surface dyslexia

DOI: 10.3233/ADR-230010

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 227-234, 2023

Authors: Tsamou, Maria | Kalligerou, Faidra | Ntanasi, Eva | Scarmeas, Nikolaos | Skalicky, Susanna | Hackl, Matthias | Roggen, Erwin L.

Article Type: Research Article

Abstract: Background: Late-onset or sporadic Alzheimer’s disease (sAD) is a neurodegenerative disease leading to cognitive impairment and memory loss. The underlying pathological changes take place several years prior to the appearance of the first clinical symptoms, however, the early diagnosis of sAD remains obscure. Objective: To identify changes in circulating microRNA (miR) expression in an effort to detect early biomarkers of underlying sAD pathology. Methods: A set of candidate miRs, earlier detected in biofluids from subjects at early stage of sAD, was linked to the proposed tau-driven adverse outcome pathway for memory loss. The relative expression of …the selected miRs in serum of 12 cases (mild cognitive impairment, MCI) and 27 cognitively normal subjects, recruited within the ongoing Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) study, was measured by RT-qPCR. Data on the protein levels of amyloid-β (Aβ42 ) and total/phosphorylated tau (t-tau/p-tau), in cerebrospinal fluid (CSF), and the cognitive z-scores of the participants were also retrieved. Results: Each doubling in relative expression of 13 miRs in serum changed the odds of either having MCI (versus control), or having pathological Aβ42 or pathological Aβ42 and tau (versus normal) proteins in their CSF, or was associated with the global composite z-score. Conclusion: These candidate human circulating miRs may be of great importance in early diagnosis of sAD. There is an urgent need for confirming these proposed early predictive biomarkers for sAD, contributing not only to societal but also to economic benefits. Show more

Keywords: Alzheimer’s disease, early diagnosis, microRNA, mild cognitive impairment

DOI: 10.3233/ADR-230001

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 235-248, 2023

Authors: Schmicker, Marlen | Frühling, Insa | Menze, Inga | Glanz, Wenzel | Müller, Patrick | Noesselt, Toemme | Müller, Notger G.

Article Type: Research Article

Abstract: Background: Patients with subjective cognitive decline (SCD) report memory deterioration and are at an increased risk of converting to Alzheimer’s disease (AD) although psychophysical testing does not reveal any cognitive deficit. Objective: Here, gustatory function is investigated as a potential predictor for an increased risk of progressive cognitive decline indicating higher AD risk in SCD. Methods: Measures of smell and taste perception as well as neuropsychological data were assessed in patients with subjective cognitive decline (SCD): Subgroups with an increased likelihood of the progression to preclinical AD (SCD+) and those with a lower likelihood (SCD–) were …compared to healthy controls (HC), patients with mild cognitive impairment and AD patients. The Sniffin’ Sticks test contained 12 items with different qualities and taste was measured with 32 taste stripes (sweet, salty, bitter, sour) of different concentration. Results: Only taste was able to distinguish between HC/SCD– and SCD+ patients. Conclusion: This study provides a first hint of taste as a more sensitive marker than smell for detecting preclinical AD in SCD. Longitudinal observation of cognition and pathology are necessary to further evaluate taste perception as a predictor of pathological objective decline in cognition. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic marker, early diagnosis, subjective cognitive decline, taste

DOI: 10.3233/ADR220092

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 249-262, 2023

Authors: Panegyres, Peter K. | Robins, Peter

Article Type: Research Article

Abstract: Background: Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer’s disease (AD). Objective: To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Methods: Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the …Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher’s Exact Test. Results: Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Conclusion: Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele. Show more

Keywords: Alzheimer’s disease, brain amyloid, sporadic, young onset dementia

DOI: 10.3233/ADR-220110

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 263-270, 2023

Authors: Knoll, Kelly | Rhee, Yeong | Hamm, Jeremy M. | Hammer, Kimberly D.P. | Heimbuch, Halli | Holloway, Jeremy | Jurivich, Donald | Lahr, Peyton | McGrath, Brenda | Parker, Kelly | Robinson-Lane, Sheria | Stover, Emily | Tomkinson, Grant R. | McGrath, Ryan

Article Type: Research Article

Abstract: Background: Instrumental activities of daily living (IADL) are neuropsychological-driven tasks that are linked to cognitive dysfunction. Examining population-based IADL deficits may reveal insights for the presence of these impairments in the United States. Objective: This investigation sought to evaluate the prevalence and trends of IADL impairments in Americans. Methods: A secondary analysis of data from the 2006–2018 waves of the Health and Retirement Study was conducted. The overall unweighted analytic sample included 29,764 Americans aged≥50 years. Respondents indicated their ability to perform six IADLs: manage money, manage medications, use a telephone, prepare hot meals, shop for …groceries, and use a map. Persons reporting difficulty or an inability to complete an individual IADL were considered as having a task-specific impairment. Similarly, those indicating difficulty or an inability to perform any IADL were classified as having an IADL impairment. Sample weights were utilized to generate nationally-representative estimates. Results: Having an impairment in using a map (2018 wave: 15.7% (95% confidence interval (CI): 15.0–16.4) had the highest prevalence in individual IADLs regardless of wave examined. The overall prevalence of IADL impairments declined during the study period (p  < 0.001) to 25.4% (CI: 24.5–26.2) in the 2018 wave. Older Americans and women had a consistently higher prevalence of IADL impairments compared to middle-aged Americans and men, respectively. The prevalence of IADL impairments was also highest among Hispanics and non-Hispanic Blacks. Conclusion: IADL impairments have declined over time. Continued surveillance of IADLs may help inform cognitive screening, identify subpopulations at risk of impairment, and guide relevant policy. Show more

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, dementia, mass screening

DOI: 10.3233/ADR-220107

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 271-278, 2023

Authors: Fisher, Daniel W. | Tulloch, Jessica | Yu, Chang-En | Tsuang, Debby

Article Type: Research Article

Abstract: Background: Pathological amyloid-β and α -synuclein are associated with a spectrum of related dementias, ranging from Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) to Parkinson disease dementia (PDD). While these diseases share clinical and pathological features, they also have unique patterns of pathology. However, epigenetic factors that contribute to these pathological differences remain unknown. Objective: In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. Methods: We employed an Illumina Infinium 850k array and …RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. Results: We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Conclusion: Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, dementia, DNA methylation, Lewy bodies, Lewy body disease, Parkinson’s disease, RNA-seq, transcriptome

DOI: 10.3233/ADR220114

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 279-297, 2023

Authors: O’Caoimh, Rónán | Molloy, D. William

Article Type: Research Article

Abstract: Background: Short cognitive screening instruments (CSI) are required to identify cognitive impairment in busy outpatient clinics. While the Six Item Cognitive Impairment Test (6CIT) is commonly used, its accuracy in those with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) and against more widely-used CSIs is less well established. Objective: To examine the diagnostic accuracy of the 6CIT against the Montreal Cognitive Assessment (MoCA) and Quick Mild Cognitive Impairment (Qmci ) screen across the cognitive spectrum in a memory clinic population. Methods: In total, 142 paired assessments were available (21 with SCD, 32 MCI, and …89 with dementia). Consecutive patients underwent a comprehensive assessment and were screened using the 6CIT, Qmci , and MoCA. Accuracy was determined from the area under receiver operating characteristic curves (AUC). Results: The median age of patients was 76 (±11) years; 68% were female. The median 6CIT score was 10/28 (±14). The 6CIT was strongly, negatively, and statistically significantly correlated with the Qmc i (r  = –0.84) and MoCA (r  = –0.86). The 6CIT had good accuracy for separating cognitive impairment (MCI or dementia) from SCD, (AUC:0.88; 0.82–0.94), similar to the MoCA (AUC:0.92; 0.87–0.97, p  = 0.308), but statistically lower than the Qmci (AUC:0.96; 0.94–0.99, p  = 0.01). The 6CIT was faster to administer, median time 2.05 minutes versus 4.38 and 9.5 for the Qmci and MoCA, respectively. Conclusion: While the Qmci was more accurate than the 6CIT, the shorter administration time of the 6CIT, suggests it may be useful when assessing or monitoring cognitive impairment in busy memory clinics, though larger samples are required to evaluate. Show more

Keywords: Cognitive screening, diagnostic accuracy, memory clinic, Six Item Cognitive Impairment Test, Montreal Cognitive Assessment, Quick Mild Cognitive Impairment screen

DOI: 10.3233/ADR220117

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 299-306, 2023

Authors: Nakanishi, Miharu | Ogawa, Asao | Sakai, Mai | Yoshii, Hatsumi | Miyashita, Mitsuhiro | Yamasaki, Syudo | Nishida, Atsushi

Article Type: Short Communication

Abstract: This study examined the longitudinal association between dementia, activity participation, the coronavirus disease 2019 pandemic period, and 1-year mental health changes. We obtained data from the National Health and Aging Trends Study in the United States. We included 4,548 older adult participants of two or more survey rounds between 2018 and 2021. We identified baseline dementia status, and assessed depressive symptoms and anxiety at baseline and follow-up. Dementia and poor activity participation were independently associated with an increased prevalence of depressive symptoms and anxiety. Dementia care and support should address emotional and social needs under continued public health restrictions.

Keywords: Activity participation, Alzheimer’s disease, anxiety, COVID-19, dementia, depression

DOI: 10.3233/ADR-230019

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 307-315, 2023

Authors: Morrison-Koechl, Jill | Fearon, Danielle O. | Fernandes, Myra A. | Tyas, Suzanne L.

Article Type: Research Article

Abstract: Background: Risk factors for dementia, such as Alzheimer’s disease, are complex and span a lifetime. Exploring novel factors, such as characteristics of writing, may provide insight into dementia risk. Objective: To investigate the association between emotional expressivity and risk of dementia in the context of a previously identified risk factor, written language skills. Methods: The Nun Study recruited 678 religious sisters aged 75 + years. Of these, 149 U.S.-born participants had archived autobiographies handwritten at a mean age of 22 years. The autobiographies were scored for frequency of emotion word usage and language skills (e.g., idea density). The …association of emotional expressivity and a four-level composite variable (combining high/low emotional expressivity and high/low idea density) with dementia was assessed using logistic regression models adjusted for age, education, and apolipoprotein E. Results: Within the composite variable, odds of dementia increased incrementally, with opposing effects of emotional expressivity across the two idea density levels. Compared to the referent category (low emotional expressivity/high idea density), the risk of dementia increased in those with high emotional expressivity/high idea density (OR = 2.73, 95% CI = 1.05–7.08), while those with low emotional expressivity/low idea density had the highest risk (OR = 18.58, 95% CI = 4.01–86.09). Conclusion: Dementia risk is better captured by inclusion of multiple measures relating to characteristics of writing. Emotional expressivity may be protective when individuals are at increased risk due to poor written language skills (i.e., low idea density), but detrimental when not at risk (i.e., high idea density). Our findings indicate that emotional expressivity is a contextually-dependent novel risk factor for dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, emotions, language, life course perspective, logistic models, longitudinal studies, risk factors

DOI: 10.3233/ADR-220106

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 317-326, 2023

Authors: Schramm, Sara | Krizanovic, Nela | Roggenbuck, Ulla | Jöckel, Karl-Heinz | Herring, Arne | Keyvani, Kathy | Jokisch, Martha

Article Type: Research Article

Abstract: Background: Blood kallikrein-8 is supposed to be a biomarker for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), a precursor of AD dementia. Little is known about the association of kallikrein-8 and non-AD type dementias. Objective: To investigate whether blood kallikrein-8 is elevated in individuals with non-amnestic MCI (naMCI), which has a higher probability to progress to a non-AD type dementia, compared with cognitively unimpaired (CU) controls. Methods: We measured blood kallikrein-8 at ten-year follow-up (T2) in 75 cases and 75 controls matched for age and sex who were participants of the population-based Heinz Nixdorf …Recall study (baseline: 2000–2003). Cognitive performance was assessed in a standardized manner at five (T1) and ten-year follow-up. Cases were CU or had subjective cognitive decline (SCD) at T1 and had naMCI at T2. Controls were CU at both follow-ups. The association between kallikrein-8 (per 500 pg/ml increase) and naMCI was estimated using conditional logistic regression: odds ratios (OR) and 95% confidence intervals (95% CI) were determined, adjusted for inter-assay variability and freezing duration. Results: Valid kallikrein-8 values were measured in 121 participants (45% cases, 54.5% women, 70.5±7.1 years). In cases, the mean kallikrein-8 was higher than in controls (922±797 pg/ml versus 884±782 pg/ml). Kallikrein-8 was not associated with having naMCI compared to being CU (adjusted; OR: 1.03 [95% CI: 0.80–1.32]). Conclusion: This is the first population-based study that shows that blood kallikrein-8 tends not to be elevated in individuals with naMCI compared with CU. This adds to the evidence of the possible AD specificity of kallikrein-8. Show more

Keywords: Alzheimer’s disease, biomarker, dementia, Heinz Nixdorf Recall study, kallikrein-8, mild cognitive impairment, neurodegeneration, neuropsin

DOI: 10.3233/ADR-220073

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 327-337, 2023

Authors: den Hoedt, Sandra | Dorst-Lagerwerf, Kristien Y. | de Vries, Helga E. | Rozemuller, Annemieke J.M. | Scheltens, Philip | Walter, Jochen | Sijbrands, Eric J.G. | Martinez-Martinez, Pilar | Verhoeven, Adrie J.M. | Teunissen, Charlotte E. | Mulder, Monique T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD. Methods: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n  = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n  = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels …in CSF were determined by immunoassay. Results: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p  = 0.042), SM(d18:1/18:0) (p  = 0.026), and Aβ42 (p  < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r  > 0.49; p  < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r  = 0.50; p  = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p  = 0.028), but negatively in SCD patients (p  = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r < –0.47; p  < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p  = 0.048 and 0.047, respectively). Conclusion: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, Apolipoprotein E4, ceramides, cerebrospinal fluid, cognitive dysfunction, lipoproteins, sphingolipids

DOI: 10.3233/ADR220072

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 339-354, 2023

Authors: Pais, Marcos V. | Forlenza, Orestes V. | Diniz, Breno S.

Article Type: Review Article

Abstract: Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive assays such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in the determination of plasma biomarkers of Alzheimer’s disease (AD). Despite the significant variability, many studies have established in-house cut-off values for the most promising available biomarkers. We first reviewed the most used laboratory methods and assays to measure plasma AD biomarkers. Next, we review studies focused on the diagnostic performance of these biomarkers to identify AD cases, predict cognitive decline in pre-clinical AD cases, and differentiate AD cases …from other dementia. We summarized data from studies published until January 2023. A combination of plasma Aβ42/40 ratio, age, and APOE status showed the best accuracy in diagnosing brain amyloidosis with a liquid chromatography–mass spectrometry (LC–MS) assay. Plasma p-tau217 has shown the best accuracy in distinguishing Aβ-PET+ from Aβ-PET–even in cognitively unimpaired individuals. We also summarized the different cut-off values for each biomarker when available. Recently developed assays for plasma biomarkers have undeniable importance in AD research, with improved analytical and diagnostic performance. Some biomarkers have been extensively used in clinical trials and are now clinically available. Nonetheless, several challenges remain to their widespread use in clinical practice. Show more

Keywords: Alzheimer’s disease, amyloid-β , GFAP, NfL protein, plasma biomarkers, phosphorylated tau

DOI: 10.3233/ADR-230029

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 355-380, 2023

Authors: Das, Tushar Kanti | Ganesh, Bhanu Priya | Fatima-Shad, Kaneez

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are …the disruption of neuronal circuitry at different levels of cellular signaling, leading to the death of neurons and glial cells in the brain. Therefore, it is necessary to find out the common molecular mechanisms of these two diseases to understand their etiological connections. Here, we summarized the most common signaling cascades including autotoxicity, ApoE4, insulin signaling, inflammation, mTOR-autophagy, notch signaling, and microbiota-gut-brain axis, present in both AD and IS. These targeted signaling pathways reveal a better understanding of AD and IS and could provide a distinguished platform to develop improved therapeutics for these diseases. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, excitotoxicity, glucose, insulin, ischemic stroke, microbiota-gut-brain axis, mTOR-autophagy, Notch signaling, PI3K/Akt

DOI: 10.3233/ADR-220108

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 381-398, 2023

Authors: Won, Junyeon | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Despite growing evidence regarding the association between exercise training (ET) and functional brain network connectivity, little is known about the effects of ET on large-scale within- and between-network functional connectivity (FC) of core brain networks. Objective: We investigated the effects of ET on within- and between-network functional connectivity of the default mode network (DMN), frontoparietal network (FPN), and salience network (SAL) in older adults with intact cognition (CN) and older adults diagnosed with mild cognitive impairment (MCI). The association between ET-induced changes in FC and cognitive performance was examined. Methods: 33 older adults (78.0±7.0 years; …16 MCI and 17 CN) participated in this study. Before and after a 12-week walking ET intervention, participants underwent a graded exercise test, Controlled Oral Word Association Test (COWAT), Rey Auditory Verbal Learning Test (RAVLT), a narrative memory test (logical memory; LM), and a resting-state fMRI scan. We examined the within (W ) and between (B ) network connectivity of the DMN, FPN, and SAL. We used linear regression to examine associations between ET-related changes in network connectivity and cognitive function. Results: There were significant improvements in cardiorespiratory fitness, COWAT, RAVLT, and LM after ET across participants. Significant increases in DMNW and SALW , and DMN-FPNB , DMN-SALB , and FPN-SALB were observed after ET. Greater SALW and FPN-SALB were associated with enhanced LM immediate recall performance after ET in both groups. Conclusion: Increased within- and between-network connectivity following ET may subserve improvements in memory performance in older individuals with intact cognition and with MCI due to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive function, exercise training, functional connectivity, mild cognitive impairment, neural network, older adults, physical activity

DOI: 10.3233/ADR-220062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 399-413, 2023

Authors: Benichou Haziot, Carla | Birak, Kulbir Singh

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, yet it currently lacks effective treatment due to its complex etiology. The pathological changes in AD have been linked to the neurotoxic immune responses following aggregation of Aβ and phosphorylated tau. The gut microbiota (GM) is increasingly studied for modulating neuroinflammation in neurodegenerative diseases and in vivo studies emerge for AD. This critical review selected 7 empirical preclinical studies from 2019 onwards assessing therapy approaches targeting GM modulating microglia neuroinflammation in AD mouse models. Results from probiotics, fecal microbiota transplantation, and drugs were compared and contrasted, including for cognition, neuroinflammation, …and toxic aggregation of proteins. Studies consistently reported significant amelioration or prevention of cognitive deficits, decrease in microglial activation, and lower levels of pro-inflammatory cytokines, compared to AD mouse models. However, there were differences across papers for the brain regions affected, and changes in astrocytes were inconsistent. Aβ plaques deposition significantly decreased in all papers, apart from Byur dMar Nyer lNga Ril Bu (BdNlRB ) treatment. Tau phosphorylation significantly declined in 5 studies. Effects in microbial diversity following treatment varied across studies. Findings are encouraging regarding the efficacy of study but information on the effect size is limited. Potentially, GM reverses GM derived abnormalities, decreasing neuroinflammation, which reduces AD toxic aggregations of proteins in the brain, resulting in cognitive improvements. Results support the hypothesis of AD being a multifactorial disease and the potential synergies through multi-target approaches. The use of AD mice models limits conclusions around effectiveness, as human translation is challenging. Show more

Keywords: Alzheimer’s disease, brain-gut axis, dysbiosis, fecal microbiota transplantation, microglia, neurodegenerative diseases, probiotics, therapeutics

DOI: 10.3233/ADR-220097

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 415-431, 2023

Authors: Silva, Rosa | Bobrowicz-Campos, Elzbieta | Santos-Costa, Paulo | Cardoso, Remy | Bernardo, Joana | Santana, Elaine | Almeida, Inês | Loureiro, Ricardo | Cardoso, Daniela | Apóstolo, João

Article Type: Systematic Review

Abstract: Background: In a society increasingly committed to promoting an active life in the community, new resources are needed to respond to the needs of citizens with Alzheimer’s disease and other forms of dementia. The potential of several individual cognitive interventions to be provided by caregivers has been explored in the literature. Objective: To synthesize the best available evidence on the effectiveness of caregiver-provided individual cognitive interventions in older adults with dementia. Methods: Systematic review of experimental studies on individual cognitive interventions for older adults with dementia. An initial search of MEDLINE and CINAHL was undertaken. Another …search for published and unpublished studies was performed on major healthcare-related online databases in March 2018 and updated in August 2022. This review considered studies that included older adults with dementia, aged 60 years and over. All studies that met the inclusion criteria were assessed for methodological quality using a JBI standardized critical appraisal checklist. Data were extracted using a JBI data extraction form for experimental studies. Results: Eleven studies were included: eight randomized controlled trials and three quasi-experimental studies. Caregiver-provided individual cognitive interventions had several beneficial effects in cognitive domains, including memory, verbal fluency, attention, problem-solving, and autonomy in activities of daily living. Conclusion: These interventions were associated with moderate improvements in cognitive performance and benefits in activities of daily living. The findings highlight the potential of caregiver-provided individual cognitive interventions for older adults with dementia. Show more

Keywords: Alzheimer’s disease, caregivers, cognitive therapies, dementia, major neurocognitive disorder, older adults, systematic review

DOI: 10.3233/ADR-220115

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 433-459, 2023

Authors: Eaton, Jacqueline | Neller, Sarah | Fernandez Cajavilca, Moroni | Johnson, Julene K. | Ellington, Lee

Article Type: Short Communication

Abstract: Interventions that actively engage dementia caregivers show promise in reducing the negative outcomes of caregiving but lack optimization and systematic testing. The purpose of this manuscript is to describe an iterative process developed to refine an intervention to enhance active engagement. A three-stage review process with content experts was developed to refine activities in preparation for focus group feedback and pilot testing. We identified caregiving vignettes, reorganized engagement techniques, and optimized focus group activities for online delivery to promote caregiver access and safety. The framework developed from this process is included, along with a template to guide intervention refinement.

Keywords: Alzheimer’s disease, caregivers, dementia, intervention study, trial protocol

DOI: 10.3233/ADR-220096

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 461-467, 2023

Authors: Roveta, Fausto | Marcinnò, Andrea | Grassini, Alberto | Ferrandes, Fabio | Cermelli, Aurora | Boschi, Silvia | Gallone, Salvatore | Atzori, Cristiana | Imperiale, Daniele | Dentelli, Patrizia | Pasini, Barbara | Brusco, Alfredo | Rubino, Elisa | Rainero, Innocenzo

Article Type: Short Communication

Abstract: We describe a 52-year-old patient with a progressive visuospatial disorder and apraxia. Neuropsychological assessment, neuroradiological findings, and Alzheimer’s disease (AD) core biomarker assay on cerebrospinal fluid led to a diagnosis of posterior cortical atrophy due to AD. We performed a next generation sequencing dementia-gene panel and found the c.1301 C>T p.(Ala434Val) variant in the Presenilin1 (PSEN1) gene. The missense change affects the PAL (Pro433-Ala434-Leu435) motif critical for catalytic activity of the macromolecular γ -secretase complex. Evolutionary and integrated bioinformatic tools predicted a deleterious effect of the variant supporting its role in the AD pathogenesis.

Keywords: Alzheimer’s disease, case reports, genetics, posterior cortical atrophy

DOI: 10.3233/ADR230023

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 469-473, 2023

Authors: Milicic, Lidija | Porter, Tenielle | Vacher, Michael | Laws, Simon M.

Article Type: Review Article

Abstract: Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual’s biological age based on an algorithmically defined set …of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer’s disease. Show more

Keywords: Aging, Alzheimer’s disease, dementia, DNA methylation, epigenetics

DOI: 10.3233/ADR-220109

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 475-503, 2023

Authors: Ávila-Villanueva, Marina | Dolado, Alberto Marcos | Fernández-Blázquez, Miguel

Article Type: Review Article

Abstract: The development of Alzheimer’s disease (AD) follows three consecutive phases: namely preclinical, prodromal or mild cognitive impairment (MCI), and dementia. In addition, the preclinical phase can be divided into subphases related to the presence of biomarkers that appear at different points before the onset of MCI. Indeed, an early risk factor could promote the appearance of additional ones through a continuum. The presence of various risk factors may trigger specific biomarkers. In this review, we comment on how modifiable risk factors for AD may be reverted, thus correlating with a possible decrease in the specific biomarkers for the disease. Finally, …we discuss the development of a suitable AD prevention strategy by targeting modifiable risk factors, thereby increasing the level of “precision medicine” in healthcare systems worldwide. Show more

Keywords: Alzheimer’s disease continuum, modifiable risk factors, precision medicine, sleep disturbances

DOI: 10.3233/ADR220100

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 505-512, 2023

Authors: Torrealba, Eduardo | Aguilar-Zerpa, Norka | Garcia-Morales, Pilar | Díaz, Mario

Article Type: Review Article

Abstract: Despite advances in the detection of biomarkers and in the design of drugs that can slow the progression of Alzheimer’s disease (AD), the underlying primary mechanisms have not been elucidated. The diagnosis of AD has notably improved with the development of neuroimaging techniques and cerebrospinal fluid biomarkers which have provided new information not available in the past. Although the diagnosis has advanced, there is a consensus among experts that, when making the diagnosis in a specific patient, many years have probably passed since the onset of the underlying processes, and it is very likely that the biomarkers in use and …their cutoffs do not reflect the true critical points for establishing the precise stage of the ongoing disease. In this context, frequent disparities between current biomarkers and cognitive and functional performance in clinical practice constitute a major drawback in translational neurology. To our knowledge, the In-Out-test is the only neuropsychological test developed with the idea that compensatory brain mechanisms exist in the early stages of AD, and whose positive effects on conventional tests performance can be reduced in assessing episodic memory in the context of a dual-task, through which the executive auxiliary networks are ‘distracted’, thus uncover the real memory deficit. Furthermore, as additional traits, age and formal education have no impact on the performance of the In-Out-test . Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, early detection, hippocampal amnesia paradigm tests, mild cognitive impairment, prodromal Alzheimer’s disease, subjective memory complaints

DOI: 10.3233/ADR-220116

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 513-525, 2023

Authors: Bhattacharyya, Sumit | Tobacman, Joanne K.

Article Type: Research Article

Abstract: Background: Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer’s disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin …4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI. Objective: Reports about chondroitin sulfate, chondroitin sulfate proteoglycans, and chondroitin sulfatases in AD were reviewed. Methods: Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4 (CSPG4), and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays. Results: SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate, and iNOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified. Conclusion: Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse. Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD. Show more

Keywords: Alzheimer’s disease, arylsulfatase B, chondroitin sulfate, glycosaminoglycan, iNOS, lipid peroxidation, N-acetylgalactosamine-4-sulfatase, SAA, thiol

DOI: 10.3233/ADR-230028

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 527-534, 2023

Authors: Musaeus, Christian Sandøe | Gleerup, Helena Sophia | Hasselbalch, Steen Gregers | Waldemar, Gunhild | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: Studies have found a disruption of the blood-brain barrier (BBB) in patients with Alzheimer’s disease (AD), but there is little evidence of the changes in the BBB over time. The cerebrospinal fluid’s (CSF) protein concentration can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate the changes in Q-Alb in patients with AD over time. Methods: A total of 16 patients diagnosed with AD, who had at least two lumbar punctures performed, were …included in the current study. Results: The difference in Q-Alb over time did not show a significant change. However, Q-Alb increased over time if the time interval was > 1 year between the measurements. No significant associations between Q-Alb and age, Mini-Mental State Examination, or AD biomarkers were found. Conclusion: The increase in Q-Alb suggests that there is an increased leakage through the BBB, which may become more prominent as the disease progresses. This may be a sign of progressive underlying vascular pathology, even in patients with AD without major vascular lesions. More studies are needed to further understand the role of BBB integrity in patients with AD over time and the association with the progression of the disease. Show more

Keywords: Albumin, Alzheimer’s disease, blood-brain barrier, cerebrospinal fluid, CSF/plasma albumin quotient, Q-Alb

DOI: 10.3233/ADR-230016

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 535-541, 2023

Authors: Thompson, Fintan | Russell, Sarah | Quigley, Rachel | Sagigi, Betty | Miller, Gavin | Esterman, Adrian | Harriss, Linton R. | Taylor, Sean | McDermott, Robyn | Strivens, Edward

Article Type: Research Article

Abstract: Background: Reducing the burden of dementia in First Nations populations may be addressed through developing population specific methods to quantify future risk of dementia. Objective: To adapt existing dementia risk models to cross-sectional dementia prevalence data from a First Nations population in the Torres Strait region of Australia in preparation for follow-up of participants. To explore the diagnostic utility of these dementia risk models at detecting dementia. Methods: A literature review to identify existing externally validated dementia risk models. Adapting these models to cross-sectional data and assessing their diagnostic utility through area under the receiver operating …characteristic curve (AUROC) analyses and calibration using Hosmer-Lemeshow Chi2 . Results: Seven risk models could be adapted to the study data. The Aging, Cognition and Dementia (AgeCoDe) study, the Framingham Heart Study (FHS), and the Brief Dementia Screening Indicator (BDSI) had moderate diagnostic utility in identifying dementia (i.e., AUROC >0.70) before and after points for older age were removed. Conclusion: Seven existing dementia risk models could be adapted to this First Nations population, and three had some cross-sectional diagnostic utility. These models were designed to predict dementia incidence, so their applicability to identify prevalent cases would be limited. The risk scores derived in this study may have prognostic utility as participants are followed up over time. In the interim, this study highlights considerations when transporting and developing dementia risk models for First Nations populations. Show more

Keywords: Alzheimer’s disease, Australia, dementia, diagnostic, First Nations, Indigenous, risk models

DOI: 10.3233/ADR-220093

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 543-555, 2023

Authors: Sehar, Ujala | Rawat, Priyanka | Choudhury, Moumita | Boles, Annette | Culberson, John | Khan, Hafiz | Malhotra, Keya | Basu, Tanisha | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and Alzheimer’s disease-related disorders (ADRD) are late-onset, age-related progressive neurodegenerative disorders, characterized by memory loss and multiple cognitive impairments. Current research indicates that Hispanic Americans are at an increased risk for AD/ADRD and other chronic conditions such as diabetes, obesity, hypertension, and kidney disease, and given their rapid growth in numbers, this may contribute to a greater incidence of these disorders. This is particularly true for the state of Texas, where Hispanics are the largest group of ethnic minorities. Currently, AD/ADRD patients are taken care by family caregivers, which puts a tremendous burden on family caregivers who …are usually older themselves. The management of disease and providing necessary/timely support for patients with AD/ADRD is a challenging task. Family caregivers support these individuals in completing basic physical needs, maintaining a safe living environment, and providing necessary planning for healthcare needs and end-of-life decisions for the remainder of the patient’s lifetime. Family caregivers are mostly over 50 years of age and provide all-day care for individuals with AD/ADRD, while also managing their health. This takes a significant toll on the caregiver’s own physiological, mental, behavioral, and social health, in addition to low economic status. The purpose of our article is to assess the status of Hispanic caregivers. We also focused on effective interventions for family caregivers of persons with AD/ADRD involving both educational and psychotherapeutic components, and a group format further enhances effectiveness. Our article discusses innovative methods and validations to support Hispanic family caregivers in rural West Texas. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease-related disorders, diabetes, family caregivers, Hispanics, obesity, psychotherapeutic components

DOI: 10.3233/ADR-220094

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 557-574, 2023

Authors: Wang, Hui Jue | Kusumo, Raphael W. | Kiss, Alex | Tennen, Gayla | Marotta, Giovanni | Viaje, Shirley | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Agitation is a disabling neuropsychiatric symptom of dementia. Pro re nata (PRN) injections of psychotropics can be administered for severe acute agitation, but little is known about the frequency of their actual use. Objective: Characterize actual use of injectable PRN psychotropics for severe acute agitation in Canadian long-term care (LTC) residents with dementia and compare use before and during the COVID-19 pandemic. Methods: Residents from two Canadian LTC facilities with orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018– May 1, 2019 (i.e., pre-COVID-19) and January 1, 2020– May 1, 2021 (i.e., COVID-19) …were identified. Electronic medical records were reviewed to document PRN injections of psychotropic medications and collect data on reason and demographic characteristics. Descriptive statistics were used to characterize frequency, dose, and indications of use, and multivariate regression models were used to compare use between time periods. Results: Of the 250 residents, 45 of 103 (44%) people in the pre-COVID-19 period and 85 of 147 (58%) people in the COVID-19 period with standing orders for PRN psychotropics received ≥1 injections. Haloperidol was the most frequently used agent in both time periods (74% (155/209 injections) pre-COVID-19; 81% (323/398 injections) during COVID-19). Residents in the COVID-19 period were almost two times more likely to receive injections compared with those in the pre-COVID-19 period (odds ratio = 1.96; 95% CI = 1.15–3.34; p  = 0.01). Conclusion: Our results suggest that use of PRN injections increased in LTC during the pandemic and contribute to the mounting evidence that agitation worsened during that time. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral symptoms, benzodiazepines, COVID-19, dementia, haloperidol, lorazepam, olanzapine, psychotropic drugs

DOI: 10.3233/ADR-230009

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 575-587, 2023

Authors: Ash, Sharon | Nevler, Naomi | Irwin, David J. | Shellikeri, Sanjana | Rascovsky, Katya | Shaw, Leslie | Lee, Edward B. | Trojanowski, John Q. | Grossman, Murray

Article Type: Research Article

Abstract: Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal …dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder. Show more

Keywords: Language, phonetics, primary progressive nonfluent aphasia, speech, verbal apraxia

DOI: 10.3233/ADR-220089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 589-604, 2023

Authors: Bussè, Cinzia | Zorzi, Giovanni | Pettenuzzo, Ilaria | Mozzetta, Stefano | Cagnin, Annachiara

Article Type: Short Communication

Abstract: Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer’s disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

Keywords: Alzheimer’s disease, dementia, frontotemporal dementia, learning, memory

DOI: 10.3233/ADR-230015

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 605-612, 2023

Authors: Ratis, Renan C. | Dacoregio, Maria I. | Simão-Silva, Daiane P. | Mateus, Rogério P. | Machado, Luciana P.B. | Bonini, Juliana S. | Silva, Weber Claudio Francisco Nunes da

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor. Objective: To investigate the association between APOE4 and BCHE-K as a risk factor for AD. Methods: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with …the meta-analysis data to verify if the effect found is not associated only with the E4 allele. Results: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558. Conclusion: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD. Show more

Keywords: Alzheimer’s disease, APOE, BaβAC, cholinesterase, dementia, genetics, odds ratio

DOI: 10.3233/ADR-220084

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 613-625, 2023

Authors: Oh, Jean | Crockett, Rachel A. | Hsu, Chun-Liang | Dao, Elizabeth | Tam, Roger | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: As the aging population grows, there is an increasing need to develop accessible interventions against risk factors for cognitive impairment and dementia, such as cerebral small vessel disease (CSVD). The progression of white matter hyperintensities (WMHs), a key hallmark of CSVD, can be slowed by resistance training (RT). We hypothesize RT preserves white matter integrity and that this preservation is associated with improved cognitive and physical function. Objective: To determine if RT preserves regional white matter integrity and if any changes are associated with cognitive and physical outcomes. Methods: Using magnetic resonance imaging data from …a 12-month randomized controlled trial, we compared the effects of a twice-weekly 60-minute RT intervention versus active control on T1-weighted over T2-weighted ratio (T1w/T2w; a non-invasive proxy measure of white matter integrity) in a subset of study participants (N = 21 females, mean age = 69.7 years). We also examined the association between changes in T1w/T2w with two key outcomes of the parent study: (1) selective attention and conflict resolution, and (2) peak muscle power. Results: Compared with an active control group, RT increased T1w/T2w in the external capsule (p  = 0.024) and posterior thalamic radiations (p  = 0.013) to a greater degree. Increased T1w/T2w in the external capsule was associated with an increase in peak muscle power (p  = 0.043) in the RT group. Conclusion: By maintaining white matter integrity, RT may be a promising intervention to counteract the pathological changes that accompany CSVD, while improving functional outcomes such as muscle power. Show more

Keywords: Aged, Alzheimer’s disease, cerebral small vessel diseases, dementia, magnetic resonance imaging, randomized controlled trial, resistance training, white matter

DOI: 10.3233/ADR-220113

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 627-639, 2023

Authors: Cahan, Joshua G. | Vassar, Robert | Bonakdarpour, Borna

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42 ) and phosphorylated-tau help clinicians accurately diagnose Alzheimer’s disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Objective: Determine whether CSF biomarker levels aid prognostication of BPSD in AD. Methods: This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42 , total tau, phosphorylated tau, and amyloid-to-tau …index using a survival analysis approach. Results: Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p  = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. Conclusion: These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral and psychological symptoms of dementia, biomarkers, dementia, neurodegenerative disease

DOI: 10.3233/ADR-220064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 641-647, 2023

Authors: Saiyed, Nazia | Yilmaz, Ali | Vishweswariah, Sangeetha | Maiti, Amit K. | Ustun, Ilyas | Bartolone, Sarah | Brown-Hughes, Travonia | Thorpe Jr , Roland J. | Osentoski, Tammy | Ruff, Stacey | Pai, Amita | Maddens, Michael | Imam, Khaled | Graham, Stewart F.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia, accounting for 80% of all cases. Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. Early detection is crucial, as irreversible brain damage occurs before symptoms manifest. Objective: This study aimed to identify potential biomarkers for early detection of AD by analyzing urinary cytokine concentrations. We investigated 37 cytokines in AD, MCI, and cognitively normal individuals (NC), assessing their associations with AD development. Methods: Urinary cytokine concentrations were measured in AD (n  = 25), MCI (n  = 25), and NC (n  = 26) patients. …IL6ST and MMP-2 levels were compared between AD and NC, while TNFRSF8, IL6ST, and IL-19 were assessed in AD versus MCI. Diagnostic models distinguished AD from NC, and in-silico analysis explored molecular mechanisms related to AD. Results: Significant perturbations in IL6ST and MMP-2 concentrations were observed in AD urine compared to NC, suggesting their potential as biomarkers. TNFRSF8, IL6ST, and IL-19 differed significantly between AD and MCI, implicating them in disease progression. Diagnostic models exhibited promising performance (AUC: 0.59–0.79, sensitivity: 0.72–0.80, specificity: 0.56–0.78) in distinguishing AD from NC. In-silico analysis revealed molecular insights, including relevant non-coding RNAs, microRNAs, and transcription factors. Conclusion: This study establishes significant associations between urinary cytokine concentrations and AD and MCI. IL6ST, MMP-2, TNFRSF8, IL6ST, and IL-19 emerge as potential biomarkers for early detection of AD. In-silico analysis enhances understanding of molecular mechanisms in AD. Further validation and exploration of these biomarkers in larger cohorts are warranted to assess their clinical utility. Show more

Keywords: Alzheimer’s disease, biomarkers, cytokines, inflammation, mild cognitive impairment, urine

DOI: 10.3233/ADR-220081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 649-657, 2023

Authors: Roth, Sophie | Burnie, Nerida | Suridjan, Ivonne | Yan, Jessie T. | Carboni, Margherita

Article Type: Research Article

Abstract: Background: Diagnostic pathways for patients presenting with cognitive complaints may vary across geographies. Objective: To describe diagnostic pathways of patients presenting with cognitive complaints across 6 countries. Methods: This real-world, cross-sectional study analyzed chart-extracted data from healthcare providers (HCPs) for 6,744 patients across China, France, Germany, Spain, UK, and the US. Results: Most common symptoms at presentation were cognitive (memory/amnestic; 89.86%), followed by physical/behavioral (87.13%). Clinical/cognitive tests were used in > 95%, with Mini-Mental State Examination being the most common cognitive test (79.0%). Blood tests for APOE ɛ4/other mutations, or to rule out treatable causes, …were used in half of the patients. Clinical and cognitive tests were used at higher frequency at earlier visits, and amyloid PET/CSF biomarker testing at higher frequency at later visits. The latter were ordered at low rates even by specialists (across countries, 5.7% to 28.7% for amyloid PET and 5.0% to 27.3% for CSF testing). Approximately half the patients received a diagnosis (52.1% of which were Alzheimer’s disease [AD]). Factors that influenced risk of not receiving a diagnosis were HCP type (higher for primary care physicians versus specialists) and region (highest in China and Germany). Conclusion: These data highlight variability in AD diagnostic pathways across countries and provider types. About 45% of patients are referred/told to ‘watch and wait’. Improvements can be made in the use of amyloid PET and CSF testing. Efforts should focus on further defining biomarkers for those at risk for AD, and on dismantling barriers such low testing capacity and reimbursement challenges. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diagnosis, neurology, neuropsychological tests, standard of care, surveys and questionnaires

DOI: 10.3233/ADR230007

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 659-674, 2023

Authors: Fotuhi, Majid | Khorrami, Noah D. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss. Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks. Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, …Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression—as well as underwent quantitative EEG—at the beginning and the end of the program. Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested (p ≤0.0011; d z ≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD d z = 0.86; PCS d z = 0.83; memory d z = 1.09). Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field. Show more

Keywords: Alzheimer’s disease, attention-deficit/hyperactivity disorder, electroencephalography, memory, neurofeedback, post-concussion syndrome, rehabilitation, subjective cognitive decline, subjective cognitive impairment, traumatic brain injury

DOI: 10.3233/ADR-220091

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 675-697, 2023

Authors: Guarnera, Jade | Yuen, Eva | Macpherson, Helen

Article Type: Review Article

Abstract: Social concepts such as loneliness and social isolation are fairly new factors that have been recently gaining attention as to their involvement in changes in cognitive function and association with dementia. The primary aim of this narrative review was to describe the current understanding of how loneliness and social isolation influence cognitive aging and how they are linked to dementia. Studies have shown that there is an association between loneliness, social isolation, and reduced cognitive function, in older adults, across multiple cognitive domains, as well as a heightened risk of dementia. Numerous changes to underlying neural biomechanisms including cortisol secretion …and brain volume alterations (e.g., white/grey matter, hippocampus) may contribute to these relationships. However, due to poor quality research, mixed and inconclusive findings, and issues accurately defining and measuring loneliness and social isolation, more consistent high-quality interventions are needed to determine whether studies addressing loneliness and social isolation can impact longer term risk of dementia. This is especially important given the long-term impact of the COVID-19 pandemic on social isolation in older people is yet to be fully understood. Show more

Keywords: Aging, alzheimer’s disease, cognition, dementia, loneliness, social isolation

DOI: 10.3233/ADR-230011

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 699-714, 2023

Authors: Michaelian, Johannes C. | McCade, Donna | Hoyos, Camilla M. | Brodaty, Henry | Harrison, Fleur | Henry, Julie D. | Guastella, Adam J. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Individuals living with Alzheimer’s disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, …randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n  = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and ‘burden’ as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs. Show more

Keywords: Alzheimer’s disease, dementia, intranasal oxytocin, oxytocin nasal spray, social cognition

DOI: 10.3233/ADR-230013

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 715-729, 2023