Journal of Alzheimer's Disease - Volume 91, issue 4

Authors: Huque, Hamidul | Eramudugolla, Ranmalee | Chidiac, Benjamin | Ee, Nicole | Ehrenfeld, Lauren | Matthews, Fiona E. | Peters, Ruth | Anstey, Kaarin J.

Article Type: Systematic Review

Abstract: Background: Despite rising interest in sex differences in dementia, it is unclear whether sex differences in dementia incidence and prevalence are apparent globally. Objective: We examine sex differences in incidence and prevalence of Any dementia, Alzheimer’s disease (AD), and vascular dementia (VaD), and evaluate whether country-level indicators of gender inequality account for differences. Methods: Systematic review with meta-analysis was used to obtain estimates of incidence and prevalence of Any dementia, AD, and VaD using random effects meta-analysis, and population-based studies with clinical or validated dementia measures. Meta-regression was used to evaluate how country-specific factors of life …expectancy, education, and gender differences in development, unemployment, and inequality indices influenced estimates. Results: We identified 205 eligible studies from 8,731 articles, representing 998,187 participants across 43 countries. There were no sex differences in the incidence of Any dementia, AD, or VaD, except in the 90+ age group (women higher). When examined by 5-year age bands, the only sex difference in prevalence of Any dementia was in the 85+ group and there was no sex difference in VaD. AD was more prevalent in women at most ages. Globally, the overall prevalence of dementia in adults 65 + was higher for women (80.22/1000, 95% CI 62.83–97.61) than men (54.86/1000, 95% CI 43.55–66.17). Meta-regression revealed that sex differences in Any dementia prevalence were associated with gender differences in life expectancy and in education. Conclusion: Globally, there are no sex differences in age-specific dementia incidence, but prevalence of AD is higher in women. Country-level factors like life expectancy and gender differences in education may explain variability in sex differences. Show more

Keywords: Alzheimer’s disease, dementia, gender differences, incidence, prevalence, sex differences

DOI: 10.3233/JAD-220724

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1231-1241, 2023

Authors: Harrington, Karra D. | Vasan, Shradha | Kang, Jee eun | Sliwinski, Martin J. | Lim, Michelle H.

Article Type: Systematic Review

Abstract: Background: Loneliness has been highlighted as a risk factor for dementia. However, the nature of the relationship between loneliness and cognitive function prior to onset of dementia is unclear. Objective: The aim of this systematic review and meta-analysis was to examine the relationship between loneliness and cognitive function in samples screened for dementia at study commencement. Methods: Five electronic databases (PubMed, PsycNET, Web of Science, EBSCOhost, Scopus) were searched from inception to August 31, 2021. A narrative review and random-effects meta-analysis were conducted on studies meeting search criteria. PROSPERO registration number: CRD42020155539. Results: The …sixteen studies that met inclusion criteria involved 30,267 individuals, with mean age ranging from 63.0 to 84.9 years. Studies varied in dementia screening criteria, measurement of loneliness and cognitive function, and statistical modeling approach. The narrative review indicated that loneliness was associated with poorer global cognition, episodic memory, working memory, visuospatial function, processing speed, and semantic verbal fluency. Results of the meta-analysis indicated that loneliness was negatively associated with global cognitive function (overall r  = –0.08; 95% CI = –0.14, –0.02; n  = 6). Due to lack of sufficient data and heterogeneity between studies, we were unable to explore associations with other cognitive domains or longitudinal associations. Conclusion: Loneliness is associated with subtle impairment across multiple cognitive domains in older adults who were screened for dementia. Better characterization of this relationship will provide important information about how loneliness contributes to the clinical and pathological sequalae of AD and be informative for risk reduction and early detection strategies. Show more

Keywords: Alzheimer disease, cognition, dementia, loneliness

DOI: 10.3233/JAD-220832

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1243-1259, 2023

Authors: Fischer, Michael Hén Forbord | Zibrandtsen, Ivan Chrilles | Høgh, Peter | Musaeus, Christian Sandøe

Article Type: Systematic Review

Abstract: Background: Magnitude-squared coherence (MSCOH) is an electroencephalography (EEG) measure of functional connectivity. MSCOH has been widely applied to investigate pathological changes in patients with Alzheimer’s disease (AD). However, significant heterogeneity exists between the studies using MSOCH. Objective: We systematically reviewed the literature on MSCOH changes in AD as compared to healthy controls to investigate the clinical utility of MSCOH as a marker of AD. Methods: We searched PubMed, Embase, and Scopus to identify studies reporting EEG MSCOH used in patients with AD. The identified studies were independently screened by two researchers and the data was extracted, …which included cognitive scores, preprocessing steps, and changes in MSCOH across frequency bands. Results: A total of 35 studies investigating changes in MSCOH in patients with AD were included in the review. Alpha coherence was significantly decreased in patients with AD in 24 out of 34 studies. Differences in other frequency bands were less consistent. Some studies showed that MSCOH may serve as a diagnostic marker of AD. Conclusion: Reduced alpha MSCOH is present in patients with AD and MSCOH may serve as a diagnostic marker. However, studies validating MSCOH as a diagnostic marker are needed. Show more

Keywords: Alzheimer’s disease, coherence, electroencephalography, functional connectivity

DOI: 10.3233/JAD-220508

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1261-1272, 2023

Authors: Itzhaki, Ruth F.

Article Type: Article Commentary

Abstract: Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of …AD. Show more

Keywords: Alzheimer’s disease, COVID-10, herpes simplex virus type 1, infections, reactivation, vaccinations

DOI: 10.3233/JAD-220955

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1273-1276, 2023

Authors: Eiser, Arnold R. | Fulop, Tamas

Article Type: Article Commentary

Abstract: In this commentary, we offer an overview of the several environmental and metabolic factors that have been identified as contributing to the development of Alzheimer’s disease (AD). Many of these factors involve extracranial organ systems including immune system dysfunction accompanied by neuroinflammation (inflammaging), gastrointestinal dysbiosis, insulin resistance, and hepatic dysfunction. A variety of microbial factors including mouth flora, viruses, and fungi appear to play a significant role. There is a role for the colonic microbiome becoming dysbiotic and producing toxic metabolites. Declining hepatic function contributes diminished neuronal precursors and reduces toxin elimination. Environmental toxins especially metals play an important role …in impairing the blood-brain barrier and acting synergistically with biotoxins and other toxic chemicals. Prevention and treatment of AD appears to require measuring several of these biomarkers and implementing corrective actions regarding such toxicants and correcting metabolic dysfunction at early or preclinical stages of this disorder. Show more

Keywords: Alzheimer’s disease, biotoxins, dementia, dysbiosis, environmental exposure, metabolism, neuroinflammation

DOI: 10.3233/JAD-221078

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1277-1281, 2023

Authors: Rahkonen, Atte | Taipale, Heidi | Koponen, Marjaana | Hartikainen, Sirpa | Tolppanen, Anna-Maija | Tanskanen, Antti | Tiihonen, Miia

Article Type: Research Article

Abstract: Background: Use of pharmacological treatments is one possible modifiable risk factor for cognitive disorders. Objective: To investigate if the use of muscle relaxants is associated with the risk of Alzheimer’s disease (AD). Methods: The study was performed in a nested case-control design. Altogether 70,718 community-dwelling residents of Finland who received AD diagnosis in 2005–2011 were included as cases (the MEDALZ study). Each case was matched with four controls without AD by age, sex, and region of residence (N  = 282,858). Data was extracted from Prescription register (1995–2012), Special Reimbursement register (1972–2012), and Hospital Discharge register (1972–2012). Drug …use periods were modeled with PRE2DUP-method. Defined daily dose (DDD) was used to quantify the use. Analyses were conducted for any muscle relaxant use, and drug specific analyses were done for orphenadrine and tizanidine. A five-year lag window prior to the diagnosis was used, and results analyzed with conditional logistic regression. Results: The use of any muscle relaxant was associated with the risk of AD, aOR (95% CI) 1.04 (1.02–1.07). Stronger associations were observed with longer use (>366 days, aOR 1.12 (1.03–1.21)) than shorter use (1–365 days aOR, 1.04 (1.02–1.06)) compared to non-users. Dose-response was not observed. Tizanidine was not associated with AD, whereas cumulative exposure of orphenadrine (≥101 DDDs) was associated with the risk of AD, aOR 1.19 (1.07–1.32). Conclusion: Muscle relaxant use was associated with the risk of AD and higher exposure to orphenadrine showed increased risk. Further studies on higher doses and longer durations of use are warranted. Show more

Keywords: Alzheimer’s disease, dementia, muscle relaxant, orphenadrine, tizanidine

DOI: 10.3233/JAD-220409

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1283-1290, 2023

Authors: Huie, Emily Z. | Escudero, Anthony | Saito, Naomi | Harvey, Danielle | Nguyen, My-Le | Lucot, Katherine L. | LaGrande, Jayne | Mungas, Dan | DeCarli, Charles | Lamar, Melissa | Schneider, Julie A. | Kapasi, Alifiya | Rissman, Robert A. | Teich, Andrew F. | Dugger, Brittany N.

Article Type: Research Article

Abstract: Background: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer’s disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts. Objective: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer’s Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N = 1135: Hispanics/Latinos = 29, African Americans/Black Americans = 51, Asians/Asian Americans = 10, American Indians/Alaskan Natives = …2, non-Hispanic White = 1043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex were included. Methods: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender. Results: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p  = 0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p -values > 0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%). Conclusion: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD. Show more

Keywords: African American, Alzheimer’s disease, Asian, brain, cohort studies, Hispanic, Latino, minoritized groups, neuropathology

DOI: 10.3233/JAD-220558

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1291-1301, 2023

Authors: Lima, Marisa | Tábuas-Pereira, Miguel | Durães, João | Vieira, Daniela | Faustino, Pedro | Baldeiras, Inês | Santana, Isabel

Article Type: Research Article

Abstract: Background: Frontal-variant of Alzheimer’s disease (fvAD) was purposed for patients with AD pathology that, despite the typical amnestic presentation, show early and progressive deterioration of behavior and executive functions, closely resembling the behavioral-variant of frontotemporal dementia (bvFTD). This leads to a challenging differential diagnosis where neuropsychological evaluation and in vivo pathological evidence are essential. Objective: To evaluate the contribution of a comprehensive neuropsychological assessment (NP) battery in distinguishing between fvAD-dementia and bvFTD supported by cerebrospinal fluid (CSF) biomarkers. Methods: We included 40 patients with a baseline NP profile with prominent early executive and/or behavioral dysfunction, …who meet both diagnosis of bvFTD and fvAD-dementia, according to international criteria. All patients underwent comprehensive NP assessment and CSF-AD biomarker evaluation. Neuropsychological domains as well as clinical and sociodemographic features, and APOE genotype were compared between groups. Results: 21 patients (52.5%) met the biological criteria for AD (decreased Aβ42 together with increased T-tau or P-tau in CSF) and were therefore classified as fvAD (mean age was 64.57, with 47.6% female). There were no differences between groups regarding age/age-at-onset, gender, or educational level. Regarding neuropsychological profile, performances in language and memory functions were equivalent in both groups. Significant differences were found in visuo-constructional abilities (p  = 0.004), Trail Making Test A (p  < 0.001), and Raven’s Colored Progressive Matrices (p  = 0.019), with fvAD patients showing worst performances. Conclusion: In patients with an early prominent frontal profile, a higher impairment in attention and visuo-spatial functions, signaling additional right hemisphere fronto-parietal dysfunction, point towards a diagnosis of fvAD-dementia and may be useful in clinical practice. Show more

Keywords: ATN system, behavioral-variant frontotemporal dementia, cerebrospinal fluid biomarkers, frontal-variant Alzheimer’s disease, neuropsychological assessment

DOI: 10.3233/JAD-220897

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1303-1312, 2023

Authors: Liu, Che | Lee, Sang H. | Loewenstein, David A. | Galvin, James E. | Levin, Bonnie E. | McKinney, Alexander | Alperin, Noam

Article Type: Research Article

Abstract: Background: Lower cerebral blood flow (CBF) and excessive brain atrophy are linked to Alzheimer’s disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. Objective: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. Methods: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, …of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. Results: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485). Conclusion: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss. Show more

Keywords: Amnestic mild cognitive impairment, cerebral blood flow, cerebral perfusion, global cognition, memory, phase-contrast MRI

DOI: 10.3233/JAD-220734

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1313-1322, 2023

Authors: Sharma, Neelam | Banerjee, Rupkatha | Davis, Ronald L.

Article Type: Research Article

Abstract: Background: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer’s disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology. Objective: To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology. Methods: The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays. …Results: We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade. Conclusion: Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, bioenergetics, biogenesis, fission/fusion, mitophagy, MT dysfunction

DOI: 10.3233/JAD-220884

Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1323-1338, 2023