Journal of Alzheimer's Disease - Volume 89, issue 4

Authors: Miao, Ya | Cui, Liang | Li, Junpeng | Chen, Yixin | Xie, Xiangqing | Guo, Qihao

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a degenerative disease of the central nervous system with insidious onset and chronic progression. The pathogenesis of AD is complex, which is currently considered to be the result of the interaction between genetic and environmental factors. The APOE ɛ4 is the strongest genetic risk factor for sporadic AD and a risk factor for progression from mild cognitive impairment (MCI) to AD. So far, no effective drugs have been found for the progression of MCI. However, the effects of nonpharmacological interventions such as nutrition, cognitive, and physical exercises on early AD have received increasing attention. We …followed up cognitive assessment scales, Aβ-PET and MRI examination of a patient with MCI for 4 years, who carried APOE ɛ4 homozygous with a clear family history. After 4 years of multi-domain lifestyle interventions including nutrition, socialization, and physical exercises, the patient’s cognitive function, especially memory function, improved significantly. Intracerebral amyloid deposition was decreased, and hippocampal atrophy improved. Based on this case, this study reviewed and discussed the interaction of APOE ɛ4 with the environment in AD research in recent years, as well as the impact and mechanisms of non-pharmaceutical multi-domain lifestyle interventions on MCI or early AD. Both the literature review and this case showed that multi-domain lifestyle interventions may reduce the risk of disease progression by reducing Aβ deposition in the brain and other different pathologic mechanisms, which offers promise in brain amyloid-positivity or APOE ɛ4 carriers. Show more

Keywords: Alzheimer’s disease, APOE, diet, genetic risk effect, mild cognitive impairment, nutrition, physical activities, social contacts

DOI: 10.3233/JAD-220374

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1131-1142, 2022

Authors: Yoshida, Kazufumi | Seo, Michael | Luo, Yan | Sahker, Ethan | Cipriani, Andrea | Leucht, Stefan | Iwatsubo, Takeshi | Efthimiou, Orestis | Furukawa, Toshiaki A.

Article Type: Research Article

Abstract: Background: Patient characteristics may predict the progression of Alzheimer’s disease (AD) and may moderate the effects of donepezil. Objective: To build a personalized prediction model for patients with AD and to estimate patient-specific treatment effects of donepezil, using individual patient characteristics. Methods: We systematically searched for all double-masked randomized controlled trials comparing oral donepezil and pill placebo in the treatment of AD and requested individual participant data through its developer, Eisai. The primary outcome was cognitive function at 24 weeks, measured with the Alzheimer’s Disease Assessment Scale-cognitive component (ADAS-cog). We built a Bayesian meta-analytical prediction model …for patients receiving placebo and we performed an individual patient data meta-analysis to estimate patient-level treatment effects. Results: Eight studies with 3,156 participants were included. The Bayesian prediction model suggested that more severe cognitive and global function at baseline and younger age were associated with worse cognitive function at 24 weeks. The individual participant data meta-analysis showed that, on average, donepezil was superior to placebo in cognitive function (ADAS-cog scores, –3.2; 95% Credible Interval (CrI) –4.2 to –2.1). In addition, our results suggested that antipsychotic drug use at baseline might be associated with a lower effect of donepezil in ADAS-cog (2.0; 95% CrI, –0.02 to 4.3). Conclusion: Although our results suggested that donepezil is somewhat efficacious for cognitive function for most patients with AD, use of antipsychotic drugs may be associated with lower efficacy of the drug. Future research with larger sample sizes, more patient covariates, and longer treatment duration is needed. Show more

Keywords: Alzheimer’s disease, cognition, donepezil, effect modifier, meta-analysis, prognosis

DOI: 10.3233/JAD-220263

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1143-1157, 2022

Authors: Guo, Rong | Ou, Ya-Nan | Hu, He-Ying | Ma, Ya-Hui | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between osteoarthritis (OA) and risk of dementia and cognitive impairment (CIM) has long been debated; however, uncertainties still persist. Objective: The aim of our present meta-analysis and systematic review was to roundly illuminate the association between OA and the risk of dementia and CIM. Methods: We identified relevant studies by searching PubMed, Embase, and Web of Science up to October 2021. The relative risk (RR) or odds ratio (OR) with 95% confidence interval (CI) were aggregated using random-effects methods. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. Publication bias …was explored using funnel plot. Results: Of 21,925 identified literatures, 8 were eligible for inclusion in the systematic review and 19 observational studies involving 724,351 individuals were included in the meta-analysis. The risk of developing dementia and CIM among OA patients was demonstrated in 11 prospective studies (RR = 1.42, 95% CI = 1.07–1.86, I2  = 98.9%, p  < 0.001), 2 retrospective cohort studies (RR = 1.35, 95% CI = 1.19–1.52, I2  = 61.0%, p  = 0.109), 3 retrospective case-control studies (OR = 1.21, 95% CI = 0.96–1.53, I2  = 95.2%, p  < 0.001), and 4 cross-sectional studies (OR = 1.51, 95% CI = 1.09–2.09, I2  = 75.8%, p  = 0.006). Meta-regression analyses did not find any valid moderators. Heterogeneity in subgroup analyses for population age, OA location, year of publication, outcome type, adjusted for BMI, depression, and comorbidity decreased to zero. No significant evidence of publication bias was found. Conclusion: OA associated with an increased risk of dementia and CIM. Effective interventions in OA patients may decrease new incidence of dementia or CIM. Show more

Keywords: Dementia, meta-analysis, osteoarthritis, systematic review

DOI: 10.3233/JAD-220568

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1159-1172, 2022

Authors: Sánchez-de-Lara-Sánchez, Sofía | Sánchez-Pérez, Ana María

Article Type: Systematic Review

Abstract: Background: In recent years, the existence of the gut-brain axis and the impact of intestinal microbiota on brain function has received much attention. Accumulated evidence has prompted the postulation of the infectious hypothesis underlying or facilitating neurodegenerative diseases, such as Alzheimer’s disease. Under this hypothesis, intervention with probiotics could be useful at a preventive and therapeutic level. Objective: The objective of this systematic review is to reveal a benefit of improved cognitive function following the use of probiotics in individuals with mild cognitive impairment. Methods: We searched bibliographic databases and analyzed in detail the evidence …and methodological quality of five recent randomized, double-blind, placebo-controlled clinical trials using the Cochrane Tool and the SIGN checklist. Results: Overall, and with satisfactory methodological quality, the evaluated studies support the use of probiotics as a weapon to slow the progression of cognitive decline in subjects with mild cognitive impairment. The reviewed literature also indicates that maximum benefit of probiotics is found in subjects with incipient cognitive dysfunction and has no effect in those with advanced disease or absence of disease. Conclusion: These results support the intervention with probiotics, especially as a preventive approach. However, caution is required in the interpretation of the results as microbiota has not been evaluated in all studies, and further large-scale research with a prolonged study period is necessary to ensure the translatability of the results into real practice. Show more

Keywords: Alzheimer’s disease, brain-gut axis, cognitive dysfunction, gastrointestinal microbiome, probiotics

DOI: 10.3233/JAD-220615

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1173-1191, 2022

Authors: Ahulló-Fuster, Mónica Alba | Ortiz, Tomás | Varela-Donoso, Enrique | Nacher, Juan | Sánchez-Sánchez, M. Luz

Article Type: Research Article

Abstract: The progressive aging of the population will notably increase the burden of those diseases which leads to a disabling situation, such as Alzheimer’s disease (AD) and ophthalmological diseases that cause a visual impairment (VI). Eye diseases that cause a VI raise neuroplastic processes in the parietal lobe. Meanwhile, the aforementioned lobe suffers a severe decline throughout AD. From this perspective, diving deeper into the particularities of the parietal lobe is of paramount importance. In this article, we discuss the functions of the parietal lobe, review the parietal anatomical and pathophysiological peculiarities in AD, and also describe some of the changes …in the parietal region that occur after VI. Although the alterations in the hippocampus and the temporal lobe have been well documented in AD, the alterations of the parietal lobe have been less thoroughly explored. Recent neuroimaging studies have revealed that some metabolic and perfusion impairments along with a reduction of the white and grey matter could take place in the parietal lobe during AD. Conversely, it has been speculated that blinding ocular diseases induce a remodeling of the parietal region which is observable through the improvement of the integration of multimodal stimuli and in the increase of the volume of this cortical region. Based on current findings concerning the parietal lobe in both pathologies, we hypothesize that the increased activity of the parietal lobe in people with VI may diminish the neurodegeneration of this brain region in those who are visually impaired by oculardiseases. Show more

Keywords: Aging, Alzheimer’s disease, blindness, dementia, metabolism, neurodegeneration, neuroplasticity, parietal lobe, visual impairment

DOI: 10.3233/JAD-220498

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1193-1202, 2022

Authors: Morrow, Christopher B. | Chaney, Grace-Anna S. | Capuzzi, Daniel | Bakker, Arnold | Onyike, Chiadi U. | Kamath, Vidyulata

Article Type: Short Communication

Abstract: Hyperorality is a distinctive feature of the behavioral variant of frontotemporal dementia (bvFTD), but little is known about its significance in early-stage disease. This study examined the cognitive and psychiatric symptom profiles associated with hyperorality, using data from subjects with early-stage bvFTD enrolled in Alzheimer’s Disease Research Centers. We found that hyperorality was not associated with cognitive performance, but was associated with psychosis, elation, and disinhibition. Hyperorality may share neurobiology with a subset of early psychiatric symptoms, a finding which could help identify targets for future treatment.

Keywords: Cognition, early-stage dementia, frontotemporal dementia, hyperorality, neuropsychiatric symptoms, neuropsychological profile

DOI: 10.3233/JAD-220443

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1203-1209, 2022

Authors: Berdyński, Mariusz | Ludwiczak, Jan | Barczak, Anna | Barcikowska-Kotowicz, Maria | Kuźma-Kozakiewicz, Magdalena | Dunin-Horkawicz, Stanisław | Żekanowski, Cezary | Borzemska, Beata

Article Type: Research Article

Abstract: Background: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). Objective: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. Methods: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n  = 14 Alzheimer’s disease, n  = 8 frontotemporal dementia, n  = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of …TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. Results: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer’s disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. Conclusion: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer’s disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, behavioral variant of frontotemporal dementia, compound heterozygosity, TREM2, TYROBP, variant burden

DOI: 10.3233/JAD-220210

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1211-1219, 2022

Authors: Ooi, Suyi | Patel, Sheila K. | Eratne, Dhamidhu | Kyndt, Christopher | Reidy, Natalie | Lewis, Courtney | Lee, Sarah C.M. | Darby, David | Brodtmann, Amy

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. Objective: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. Methods: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. Results: Fifty participants were studied: bvFTD = 20, semantic variant FTD (svFTD) = 11, non-fluent variant FTD (nfvFTD) = 9, FTD with motor …neuron disease (MND) = 4, phFTD = 2, slow progressors = 3, FTD mimic = 1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p  = 0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). Conclusion: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily absence of neurodegeneration, and therefore appears limited in distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility. Show more

Keywords: Biomarker, frontotemporal dementia, neurofilament light, phenocopy, primary progressive aphasia

DOI: 10.3233/JAD-220272

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1221-1231, 2022

Authors: Nidadavolu, Lolita S. | Feger, Danielle | Wu, Yuqiong | Grodstein, Francine | Gross, Alden L. | Bennett, David A. | Walston, Jeremy D. | Oh, Esther S. | Abadir, Peter M.

Article Type: Research Article

Abstract: Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at …or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty. Show more

Keywords: Cell-free DNA, cell death, cognitive dysfunction, dementia, frailty

DOI: 10.3233/JAD-220301

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1233-1240, 2022

Authors: Creavin, Sam | Fish, Mark | Bayer, Antony | Gallacher, John | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Background: The merit of using baseline cognitive assessments in mid-life to help interpret cross-sectional cognitive tests scores in later life is uncertain. Objective: Evaluate how accuracy for diagnosing dementia is enhanced by comparing cross-sectional results to a midlife measure. Methods: Cohort study of 2,512 men with repeated measures of Mini-Mental State Examination (MMSE) over approximately 10 years. Index test MMSE at threshold of 24 indicating normal, as a cross-sectional measure and in combination with decline in MMSE score from mid-life. Reference standard consensus clinical diagnosis of dementia by two clinicians according to Diagnostic and Statistical Manual …of Mental Disorders, Fourth Edition (DSM-IV). Results: 1,150 men participated at phase 4 of whom 75 had dementia. A cross-sectional MMSE alone produced a sensitivity of 60% (50% to 70%) and specificity 95% (94% to 97%) with a threshold of≥24 points indicating normal. For lower-scoring men in late life, with cross sectional scores of < 22, combining cross-sectional AND a three-point or more decline over time had a sensitivity of 52% (39% to 64%) and specificity 99% (99% to 100%). For higher-scoring men in later life, with cross sectional scores < 26 combining cross-sectional OR decline of at least three points had a sensitivity of 98% (92% to 100%) and specificity 38% (32% to 44%). Conclusion: It may be helpful in practice to formally evaluate cognition in mid-life as a baseline to compare with if problems develop in future, as this may enhance diagnostic accuracy and classification of people in later life. Show more

Keywords: Cohort studies, cognitive dysfunction, dementia, epidemiologic studies, neurocognitive disorders, sensitivity and specificity

DOI: 10.3233/JAD-220345

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1241-1248, 2022