Journal of Alzheimer's Disease - Volume 97, issue 4

Authors: Heikkinen, Anna-Leena | Paajanen, Teemu I. | Hänninen, Tuomo | Tikkanen, Veera | Hublin, Christer | Koivisto, Anne M. | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: Background: Although early-onset dementia (EOD) is associated with diagnostic challenges that differ from those of related to late-onset dementia, only limited studies have addressed the neuropsychological and health characteristics or specified the diagnoses underlying early-onset cognitive impairment in a real-world clinical setting. Objective: To investigate the neuropsychological profiles, etiologies, and comorbidities of an unselected cohort of memory clinic patients (≤65 years at symptom onset). Methods: The patients’ (n  = 210) diagnoses were determined based on comprehensive diagnostic workup. Medical comorbidities and neuropsychological profiles were compared between clinically relevant patient groups, namely early-onset dementia (n  = 55), mild cognitive …impairment due to vascular or suspected neurodegenerative (MCI-n, n  = 35) or non-neurodegenerative (MCI-o, n  = 106) etiologies, and subjective cognitive decline (n  = 14). Results: The most prevalent diagnoses were Alzheimer’s disease (AD, 14%) and depression (11%). Multiple prior medical conditions were common (67%); however, EOD patients had fewer other diagnoses (p  = 0.008) than MCI-o patients. Compared to other groups, EOD patients had more severe deficits (p  < 0.001) on immediate and delayed memory, processing speed, symptom awareness, and global cognition. AD patients had weaker memory retention ability but less behavioral symptoms than frontotemporal dementia (FTD) patients (p ≤0.05). Depression was associated with better immediate memory, symptom awareness, and global cognition than AD and FTD (p  < 0.05). Conclusions: EOD is associated with more severe and widespread neuropsychological deficits but fewer prior medical diagnoses than nondegenerative etiologies of cognitive impairment. AD and depression are common etiologies and the neuropsychological profiles are partly overlapping; however, memory, symptom awareness and global cognitive impairment measures may help in the differential diagnosis. Show more

Keywords: Alzheimer’s disease, cognition, dementia, depression, frontotemporal dementia, multimorbidity

DOI: 10.3233/JAD-230877

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1765-1776, 2024

Authors: Filiou, Renée-Pier | Brambati, Simona Maria | Lussier, Maxime | Bier, Nathalie

Article Type: Research Article

Abstract: Background: Executive functions (EF) are central to instrumental activities of daily living (IADL). A novel approach to the assessment of the impact of EF difficulties on IADL may be through the speech acts produced when performing IADL-inspired tasks in a laboratory-apartment. Speech acts may act as a window to the difficulties encountered during task performance. Objective: We aim to 1) qualitatively describe the speech acts produced by participants with mild neurocognitive disorder (mild NCD) and healthy controls (HC) as they performed 4 IADL-inspired tasks in a laboratory-apartment, and to then 2) compare their use in both …groups. Methods: The participants’ performance was videotaped, and speech acts produced were transcribed. Qualitative description of all speech acts was performed, followed by a deductive-inductive pattern coding of data. Statistical analyses were performed to further compare their use by mild NCD participants and HC. Results: Twenty-two participants took part in the study (n mild NCD = 11; n HC = 11). Meta-categories of data emerged from pattern coding: strategies, barriers, reactions, and consequences. Mild NCD participants used significantly more strategies and barriers than did HC. They were more defensive of their performance, and more reactive to their difficulties than HC. Mild NCD participants’ verification of having completed all tasks was less efficient than controls. Conclusions: An assessment of speech acts produced during the performance of IADL-inspired tasks in a laboratory-apartment may allow to detect changes in the use of language which may reflect EF difficulties linked to cognitive decline. Show more

Keywords: Activities of daily living, Alzheimer’s disease, executive function, neurocognitive disorders, speech

DOI: 10.3233/JAD-230031

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1777-1792, 2024

Authors: Harris, Janna L. | Wang, Xiaowan | Christian, Sarah K. | Novikova, Lesya | Kalani, Anuradha | Hui, Dongwei | Ferren, Sadie | Barbay, Scott | Ortiz, Judit Perez | Nudo, Randolph J. | Brooks, William M. | Wilkins, Heather M. | Chalise, Prabhakar | Michaelis, Mary Lou | Michaelis, Elias K. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Background: Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer’s disease (AD). Objective: To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association. Methods: We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1–5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and …tangle burden. Results: In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate. Conclusions: As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect. Show more

Keywords: Aging, Alzheimer’s disease, brain, mitochondria, traumatic brain injury

DOI: 10.3233/JAD-231237

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1793-1806, 2024

Authors: Dai, Yulin | Hsu, Yu-Chun | Fernandes, Brisa S. | Zhang, Kai | Li, Xiaoyang | Enduru, Nitesh | Liu, Andi | Manuel, Astrid M. | Jiang, Xiaoqian | Zhao, Zhongming

Article Type: Research Article

Abstract: Background: The progressive cognitive decline, an integral component of Alzheimer’s disease (AD), unfolds in tandem with the natural aging process. Neuroimaging features have demonstrated the capacity to distinguish cognitive decline changes stemming from typical brain aging and AD between different chronological points. Objective: To disentangle the normal aging effect from the AD-related accelerated cognitive decline and unravel its genetic components using a neuroimaging-based deep learning approach. Methods: We developed a deep-learning framework based on a dual-loss Siamese ResNet network to extract fine-grained information from the longitudinal structural magnetic resonance imaging (MRI) data from the Alzheimer’s Disease …Neuroimaging Initiative (ADNI) study. We then conducted genome-wide association studies (GWAS) and post-GWAS analyses to reveal the genetic basis of AD-related accelerated cognitive decline. Results: We used our model to process data from 1,313 individuals, training it on 414 cognitively normal people and predicting cognitive assessment for all participants. In our analysis of accelerated cognitive decline GWAS, we identified two genome-wide significant loci: APOE locus (chromosome 19 p13.32) and rs144614292 (chromosome 11 p15.1). Variant rs144614292 (G > T) has not been reported in previous AD GWA studies. It is within the intronic region of NELL1 , which is expressed in neurons and plays a role in controlling cell growth and differentiation. The cell-type-specific enrichment analysis and functional enrichment of GWAS signals highlighted the microglia and immune-response pathways. Conclusions: Our deep learning model effectively extracted relevant neuroimaging features and predicted individual cognitive decline. We reported a novel variant (rs144614292) within the NELL1 gene. Show more

Keywords: Alzheimer’s disease, cognitive decline, deep learning, genome-wide association study, neuroimaging

DOI: 10.3233/JAD-231020

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1807-1827, 2024

Authors: Vermeulen, Robin Jeanna | Roudijk, Bram | Govers, Tim Martin | Rovers, Maroeska Mariet | Olde Rikkert, Marcel Gerardus Maria | Wijnen, Ben Franciscus Martinus

Article Type: Research Article

Abstract: Background: The increasing interest in early identification of people at risk of developing dementia, has led to the development of numerous models aimed at estimating the likelihood of progression from mild cognitive impairment (MCI) to dementia. It is important to study both the need for and possible outcomes related with such prediction models, including the impact of risk predictions on perceived quality of life (QoL). Objective: This study aimed to quantify the impact that receiving a risk prediction on progression from MCI to dementia has on QoL. Methods: A Discrete Choice Experiment (DCE) and Time Trade …Off (TTO) study were performed. Participants completed choice tasks related to dementia prognosis while imagining having MCI. We collected DCE data by an online survey, and TTO data via videoconferencing interviews. DCE data were analyzed using a mixed multinomial logit model and were anchored to a health state utility scale using mean observed TTO valuations. Results: 296 people participated in the DCE and 42 in the TTO. Moderate and high predicted dementia risks were associated with decrements in utility (–0.05 and –0.18 respectively), compared to no prognostic information. Low predicted risk was associated with an increase in utility (0.06), as well as the availability of medication or lifestyle interventions (0.05 and 0.13 respectively). Conclusions: This study shows a significant impact of dementia risk predictions on QoL and highlights the importance of caution when sharing information about expected MCI disease courses. Show more

Keywords: Alzheimer’s disease, dementia, health state utility, mild cognitive impairment, prognosis, quality of life, risk assessment

DOI: 10.3233/JAD-231037

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1829-1840, 2024

Authors: Vestin, Erika | Boström, Gustaf | Olsson, Jan | Elgh, Fredrik | Lind, Lars | Kilander, Lena | Lövheim, Hugo | Weidung, Bodil

Article Type: Research Article

Abstract: Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer’s disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ɛ4 carriership interaction. Methods: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001–2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical …records. Cox proportional-hazards regression models were applied. Results: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p  = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD. Show more

Keywords: Aged 80 and over, Alzheimer disease, apolipoprotein E, cognitive disorder, cohort study, cytomegalovirus, dementia, Herpes simplex, human herpesvirus 1, neurocognitive disorder

DOI: 10.3233/JAD-230718

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1841-1850, 2024

Authors: Sible, Isabel J. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer’s disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels. Objective: Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment. Methods: In this post hoc analysis of the SPRINT trial, 457 participants (n  = 206 in standard group, n  = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0–4.0) years …later to determine plasma AD biomarkers total tau and Aβ1–42 :Aβ1–40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV×time on AD biomarker levels. Results: Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p  = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: −0.02 [−0.19, 0.16], p  = 0.843). BPV was not associated with Aβ 1–42 :Aβ 1–40 ratio in either group. Mean BP was not associated with biomarkers. Conclusions: Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD. Show more

Keywords: Alzheimer’s disease, biomarkers, blood pressure variability, plasma, tau

DOI: 10.3233/JAD-230930

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1851-1860, 2024

Authors: Zhang, Xiaoyu | Haeri, Mohammad | Swerdlow, Russell H. | Wang, Ning

Article Type: Research Article

Abstract: Background: DNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei …extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains. Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients. Show more

Keywords: Alzheimer’s disease, DNA damage, double-strand DNA breaks, single-strand DNA breaks, TOP2B

DOI: 10.3233/JAD-231303

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1861-1875, 2024

Authors: Han, Yinlian | Yang, Mu | Tian, Min | Yang, Yang | Liu, Wen | Liu, Yiming

Article Type: Research Article

Abstract: Background: The aging global population has led to an increased burden of cognitive impairment in older adults. Objective: This study examined the relationship between fermented dairy intake and cognitive function in this population. Methods: Yogurt, cheese, and fermented dairy consumption were assessed through two 24-hour dietary recall interviews, categorized into low, medium, and high intake groups. Multivariate linear regression was employed to examine the relationship between fermented dairy intake and cognitive tests, including the Alzheimer’s Disease Word Learning Immediate Recall Test (CERAD-IRT), CERAD Delayed Recall Test (CERAD-DRT), Animal Fluency Test (AFT), Digit Symbol …Substitution Test (DSST), and global cognitive z-scores, adjusting for potential confounding factors. Results: The study comprised 2,462 participants (average age 69.34±6.75 years, 52.07% female). Among yogurt consumers, global cognition and AFT z-scores are notably higher than non-consumers. Conversely, individuals who consume cheese display significantly lower CERAD-DRT z-scores. Compared to participants not intake fermented dairy, consumers of fermented dairy show significantly higher AFT and DSST z-scores and lower CERAD-DRT z-scores. Moreover, when categorizing individuals based on their intake of fermented dairy, those with low and medium consumption show significantly higher AFT and DSST z-scores, as well as significantly lower CERAD-DRT z-scores compared to non-consumers. Conclusions: Our study suggests that moderate consumption of fermented dairy products is associated with better executive function and verbal fluency in the elderly. Show more

Keywords: Alzheimer’s disease, cognitive function, elderly, fermented dairy, NHANES, yogurt

DOI: 10.3233/JAD-230865

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1877-1887, 2024

Authors: Gephine, Lucas | Roux, Candice M. | Freret, Thomas | Boulouard, Michel | Leger, Marianne

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia and remains incurable. This age-related neurodegenerative disease is characterized by an early decline in episodic and spatial memory associated with progressive disruption of the hippocampal functioning. Recent clinical evidence suggests that impairment of the spatial pattern separation (SPS) function, which enables the encoding and storage of episodic spatial information, may be an indicator of the early stages of AD. Objective: The aim of our study was to characterize SPS performance at a prodromal stage in 5xFAD transgenic mouse model of AD. Methods: Behavioral performance of …male wild-type (WT) and 5xFAD mice (n  = 14 per group) was assessed from the age of 4 months in two validated paradigms of SPS function either based on spontaneous exploration of objects or on the use of a touchscreen system. Results: Compared with age-matched WT littermates, a mild deficit in SPS function was observed in the object recognition task in 5xFAD mice, whereas both groups showed similar performance in the touchscreen-based task. These results were observed in the absence of changes in locomotor activity or anxiety-like behavior that could have interfered with the tasks assessing SPS function. Conclusions: Our results indicate an early vulnerability of the SPS function in 5xFAD mice in the paradigm based on spontaneous exploration of objects. Our work opens up the possibility of examining the early neurobiological processes involved in the decline of episodic memory and may help to propose new therapeutic strategies in the context of AD. Show more

Keywords: Alzheimer’s disease, cognition disorders, transgenic mice

DOI: 10.3233/JAD-231112

Citation: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1889-1900, 2024