Journal of Alzheimer's Disease - Volume 77, issue 2

Authors: Lamballais, Sander | Zijlmans, Jendé L. | Vernooij, Meike W. | Ikram, M. Kamran | Luik, Annemarie I. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Individual differences in the risk to develop dementia remain poorly understood. These differences may partly be explained through reserve, which is the ability to buffer cognitive decline due to neuropathology and age. Objective: To determine how much early and late–life cognitive reserve (CR) and brain reserve (BR) contribute to the risk of dementia. Methods: 4,112 dementia-free participants (mean age = 66.3 years) from the Rotterdam Study were followed up for on average 6.0 years. Early-life CR and BR were defined as attained education and intracranial volume, respectively. Late-life CR was derived through variance decomposition based on cognition. …Late-life BR was set as the total non-lesioned brain volume divided by intracranial volume. Results: Higher early-life CR (hazard ratio = 0.48, 95% CI = [0.21; 1.06]) but not early-life BR associated with a lower risk of incident dementia. Higher late-life CR (hazard ratio = 0.57, 95% CI = [0.48; 0.68]) and late-life BR (hazard ratio = 0.54, 95% CI = [0.43; 0.68]) also showed lower levels of dementia. Combining all proxies into one model attenuated the association between early-life CR and dementia (hazard ratio = 0.56, 95% CI = [0.25; 1.25]) whereas the other associations were unaffected. These findings were stable upon stratification for sex, age, and APOE ɛ 4. Finally, high levels of late-life CR and BR provided additive protection against dementia. Conclusion: The findings illustrate the importance of late-life over early-life reserve in understanding the risk of dementia, and show the need to study CR and BR conjointly. Show more

Keywords: Cognition, cognitive reserve, dementia, education, neuroimaging

DOI: 10.3233/JAD-200264

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 607-618, 2020

Authors: de Leeuw, Francisca A. | Honer, William G. | Schneider, Julie A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. Methods: We examined associations of α - and γ -tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a …SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. Results: Higher brain γ -tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p  < 0.001 to 0.003). When additionally adjusted for global Alzheimer’s disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α -tocopherol and presynaptic protein levels. Conclusion: In this cross-sectional study, we found higher brain γ -tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels. Show more

Keywords: Antioxidants, SNARE protein, tocopherols, vitamin E

DOI: 10.3233/JAD-200166

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 619-627, 2020

Authors: Hu, Li | Zhu, Shaoping | Peng, Xiaoping | Li, Kanglan | Peng, Wanjuan | Zhong, Yu | Kang, Chenyao | Cao, Xingxing | Liu, Zhou | Zhao, Bin

Article Type: Research Article

Abstract: Background: Excessive salt intake is considered as an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. Objective: To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Methods: Adult female C57BL/6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. …Results: The mice fed a HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β , IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. Conclusion: The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production. Show more

Keywords: Blood-brain barrier, cognition, gut microbiota, high-salt diet, microglia, short-chain fatty acids

DOI: 10.3233/JAD-200035

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 629-640, 2020

Authors: Junquera, Almudena | García-Zamora, Estefanía | Olazarán, Javier | Parra, Mario A. | Fernández-Guinea, Sara

Article Type: Research Article

Abstract: Background: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI) to dementia in Alzheimer’s clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). Objective: The present study analyzes the contributions of executive functions to predict MCI–dementia progression in ACS. Methods: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at …1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. Results: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI–dementia conversion, even after controlling for the severity of MCI at baseline (F (1, 68) = 116.25, p  = 0.000, R2  = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F (1, 68) = 5.09, p  = 0.955, R2  = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. Conclusion: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive dysfunction, executive function, longitudinal studies

DOI: 10.3233/JAD-200586

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 641-653, 2020

Authors: Caruso, Giulia | Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall , performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two …tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance. Objective: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia. Methods: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer’s disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs). Results: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance. Conclusion: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks. Show more

Keywords: Alzheimer’s disease, familiarity, frontotemporal dementia, recall, recognition, recollection

DOI: 10.3233/JAD-200126

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 655-666, 2020

Authors: Tan, Ji-Ping | Wang, Xiaoxiao | Lan, Xiaoyang | Li, Nan | Zhang, Shimin | Zhao, Yiming | Wang, Lu-Ning

Article Type: Research Article

Abstract: Background: Over time, improved cognitive abilities in elderly individuals lead to an overall increase in performance on widely used cognitive screening tests (e.g., Mini-Mental State Examination, MMSE) and impact screening efficacy. Objective: We aimed to examine the epoch effect on cognitive function measured using MMSE, in addition to the influence of demographic characteristics on MMSE. We also evaluated the ability of the MMSE in detecting dementia and examined the discrimination ability and measurement precision of the MMSE. Methods: In a cross-sectional survey, Chinese veterans aged ≥60 years were interviewed. Multiple linear regression analysis was applied to …explore the factors affecting the MMSE. The expected MMSE score was calculated to examine the epoch effect. The diagnostic accuracy of the MMSE was determined via receiver operating characteristic curve analyses. Item response theory methods were implemented using Stata 16.0. Results: The MMSE score increased with higher education and decreased with advancing age. The observed MMSE score in this study (26.9) was higher than the expected MMSE score (24.9). It demonstrated 78.3% /84.1% /89.9% sensitivity and 85.8% /79.5% /66.8% specificity in detecting dementia using the cut-off score 25/26/27. The MMSE showed reduced discrimination and provided little information for ability level of −1 and above. Conclusion: Improved cognitive ability over time may increase the performance on cognitive screening tests (e.g., MMSE). This impact of epoch in cognitive function emphasizes the importance of regularly updating cognitive screening tests. Show more

Keywords: Dementia, epoch effect, item response theory, Mini-Mental State Examination

DOI: 10.3233/JAD-200112

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 667-674, 2020

Authors: Fung, Susan | Smith, Carole L. | Prater, Katherine E. | Case, Amanda | Green, Kevin | Osnis, Leah | Winston, Chloe | Kinoshita, Yoshito | Sopher, Bryce | Morrison, Richard S. | Garden, Gwenn A. | Jayadev, Suman

Article Type: Research Article

Abstract: Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1 ), presenilin 2 (PSEN 2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. Objective: …Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ -secretase activity as well as exaggerated inflammatory cytokine release, NFκ B activity, and Aβ internalization. In vivo , PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mouse brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production. Show more

Keywords: Alzheimer’s disease, cytokine, glia, inflammation, microglia, phagocytosis, presenilin

DOI: 10.3233/JAD-200492

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 675-688, 2020

Authors: Gallucci, Maurizio | Mazzarolo, Anna Paola | Focella, Lucia | Piovesan, Cinzia | Mazzetto, Manuela | Ramigni, Mauro | Marzetti, Emanuele

Article Type: Research Article

Abstract: Background: Frailty is a condition of increased vulnerability to exogenous and endogenous stressors, which is correlated with aging, functional decline, institutionalization, hospitalization, and mortality. Given the multifaceted nature of frailty, programs aimed at its prevention are recommended to act on multiple domains. Objective: The present intervention program aimed at assessing the effects of combined physical and cognitive training in older people with mild cognitive impairment (MCI) and at investigating how their frailty status changed over one year of follow-up. Methods: Two-hundred and seven participants were recruited among outpatients of the Cognitive Impairment Center who agreed to …receive a comprehensive assessment. Forty-six participants, who joined a structured program of physical activity and group readings for a period of one year, were defined as active. The remaining 161, who decided not to engage in those activities, were considered controls. In both groups, frailty status was assessed at baseline and over one year of follow-up. Results: Control participants showed twice the risk of becoming frail at 12 months compared with those in the active group. Participants in the active group had more than three times the probability of improving their frailty status compared with the control group from T0 to T12. Age and NPI scores were significantly associated with worsening frailty status. When analyses were restricted to participants who were robust at baseline, the frailty status varied significantly between groups over time. Conclusion: Findings of the present study confirm the beneficial effects of physical activity and reading to prevent frailty in older people with MCI. Show more

Keywords: Cognitive frailty, community, multi-domain intervention, neuroimaging, TREDEM registry

DOI: 10.3233/JAD-200542

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 689-699, 2020

Authors: Fu, Pengfei | Yung, Ken Kin Lam

Article Type: Research Article

Abstract: Background: Ambient air pollution has been associated with Alzheimer’s disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively. Objective: We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence. Methods: We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM10 ), PM2.5 , ozone (O3 ), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and carbon monoxide (CO). The subgroup analysis was conducted based on …the pollution levels. Results: Nine studies were included in the meta-analysis and review. The OR per 10μ g/m3 increase of PM2.5 was 1.95 (95% CI: 0.88–4.30). The corresponding values per 10μ g/m3 increment of other pollutants were 1.03 (95% CI: 0.68–1.57) for O3 , 1.00 (95% CI: 0.89–1.13) for NO2 , and 0.95 (95% CI: 0.91–0.99) for PM10 (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09–1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO2 or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO2 or CO exposure increased risks of dementia, implying that SO2 or CO might have a potential impact on AD. Conclusion: Air pollution exposure may exacerbate AD development. Show more

Keywords: Air pollution, Alzheimer’s disease, meta-analysis, systematic review

DOI: 10.3233/JAD-200483

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 701-714, 2020

Authors: Poptsi, Eleni | Moraitou, Despina | Tsardoulias, Emmanouil | Symeonidisd, Andreas L. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The early diagnosis of neurocognitive disorders before the symptoms’ onset is the ultimate goal of the scientific community. REMEDES for Alzheimer (R4Alz) is a battery, designed for assessing cognitive control abilities in people with minor and major neurocognitive disorders. Objective: To investigate whether the R4Alz battery’s tasks differentiate subjective cognitive decline (SCD) from cognitively healthy adults (CHA) and mild cognitive impairment (MCI). Methods: The R4Alz battery was administered to 175 Greek adults, categorized in five groups a) healthy young adults (HYA; n  = 42), b) healthy middle-aged adults (HMaA; n  = 33), c) healthy older adults (HOA; …n  = 14), d) community-dwelling older adults with SCD (n  = 34), and e) people with MCI (n  = 52). Results: Between the seven R4Alz subtasks, four showcased the best results for differentiating HOA from SCD: the working memory updating (WMCUT-S3), the inhibition and switching subtask (ICT/RST-S1&S2), the failure sets (FS) of the ICT/RST-S1&S2, and the cognitive flexibility subtask (ICT/RST-S3). The total score of the four R4Alz subtasks (R4AlzTot4) leads to an excellent discrimination among SCD and healthy adulthood, and to fare discrimination among SCD and MCI. Conclusion: The R4Alz battery is a novel approach regarding the neuropsychological assessment of people with SCD, since it can very well assist toward discriminating SCD from HOA. The R4Alz is able to measure decline of specific cognitive control abilities - namely of working memory updating, and complex executive functions - which seem to be the neuropsychological substrate of cognitive complaints in community dwelling adults of advancing age. Show more

Keywords: Cognitive control assessment battery, cognitively healthy adults, mild cognitive impairment, normative data, subjective cognitive decline

DOI: 10.3233/JAD-200562

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 715-732, 2020