Journal of Alzheimer's Disease - Volume 78, issue 1

Authors: Wang, Wei | Wei, Cuibai | Quan, Meina | Li, Tingting | Jia, Jianping

Article Type: Research Article

Abstract: Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, …was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, depression, neuroinflammation, oxidative stress, sulforaphane

DOI: 10.3233/JAD-200397

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 127-137, 2020

Authors: Mold, Matthew John | O’Farrell, Adam | Morris, Benjamin | Exley, Christopher

Article Type: Research Article

Abstract: Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high …level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease. Show more

Keywords: α-synuclein, aluminum in human brain tissue, amyloid-β , epilepsy, familial Alzheimer’s disease, Parkinson’s disease, tau

DOI: 10.3233/JAD-200838

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 139-149, 2020

Authors: Liu, Yi-Hsuan | Gao, Xiang | Na, Muzi | Kris-Etherton, Penny M. | Mitchell, Diane C. | Jensen, Gordon L.

Article Type: Research Article

Abstract: Background: Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia. Objective: In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori , and risk of dementia. Methods: We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in …English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results: Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratio = 0.82; 95% CI: 0.70, 0.95; n  = 12) and Alzheimer’s disease (pooled risk ratio = 0.61; 95% CI: 0.47, 0.79; n  = 6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results. Conclusion: Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia. Show more

Keywords: Alzheimer’s disease, dementia, diet quality, dietary pattern

DOI: 10.3233/JAD-200499

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 151-168, 2020

Authors: Alipour, Abolfazl | Mozhdehfarahbakhsh, Azadeh | Nouri, Saba | Petramfar, Peyman | Tahamtan, Mahshid | Kamali, Ali-Mohammad | Rao, K. S. | Nami, Mohammad

Article Type: Research Article

Abstract: Background: A proper explanation for perceptual symptoms in neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease (PD) is still lacking. Objective: This study aimed at investigating the imbalance between ‘bottom-up’ and ‘top-down’ information flow (IF) and processing in PD in relation with visual hallucination symptoms. Methods: Here, we looked at bottom-up and top-down IF markers using resting state electroencephalographic (EEG) data from PD patients analyzed through three different IF measures (direct Directed Transfer Function (dDTF), full frequency Directed Transfer Function (ff-DTF), and renormalized Partial Directed Coherence (rPDC). Results: We observed an increased gamma band …IF and a reduced beta band IF in PD patients compared to healthy controls. Additionally, we noticed a reduced theta band IF in PD patients using dDTF as a measure of IF. By source localizing the EEG activity of the PD patients and healthy controls, we looked at the alterations of IF in the prefrontal cortex of PD patients as well. Conclusion: In line with previous studies, our results suggest that the delicate balance between bottom-up and top-down IF is disrupted in Parkinson’s disease potentially contributing to the cognitive symptoms of PD patients. Show more

Keywords: Alzheimer’s disease, direct directed transfer function, EEG, full frequency directed transfer function, information flow, Parkinson’s disease, renormalized partial directed coherence, visual hallucinations

DOI: 10.3233/JAD-200590

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 169-183, 2020

Authors: Watermeyer, Tam | Marroig, Alejandra | Ritchie, Craig W. | Ritchie, Karen | Blennow, Kaj | Muniz-Terrera, Graciela | on behalf of the EPAD Consortium

Article Type: Research Article

Abstract: Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ42 ), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a cohort of older …adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ42 , t-tau, and p-tau and amyloid positivity (Aβ42  < 1000 pg/ml). Relationships between sociodemographics, APOE ɛ 4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β= –0.007, SE = 0.002, p  = 0.001) and less educated (β= –0.009, SE = 0.003, p  = 0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognition, risk factors, tau

DOI: 10.3233/JAD-200514

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 185-194, 2020

Authors: Yun, Yejin | Lee, Sang-Yeon | Choi, Won Hoon | Park, Jong-Chan | Lee, Dong Han | Kim, Yun Kyung | Lee, Jung Hoon | Lee, Jun-Young | Lee, Min Jae | Kim, Young Ho

Article Type: Research Article

Abstract: Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive …Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42 , and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p  = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis. Show more

Keywords: Amyloid-β , biomarker, mild cognitive impairment, plasma, proteasome, tinnitus

DOI: 10.3233/JAD-200728

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 195-205, 2020

Authors: Henkel, Rebecca | Brendel, Matthias | Paolini, Marco | Brendel, Eva | Beyer, Leonie | Gutzeit, Andreas | Pogarell, Oliver | Rominger, Axel | Blautzik, Janusch

Article Type: Research Article

Abstract: Background: Various reasons may lead to cognitive symptoms in elderly, including the development of cognitive decline and dementia. Often, mixed pathologies such as neurodegeneration and cerebrovascular disease co-exist in these patients. Diagnostic work-up commonly includes imaging modalities such as FDG PET, MRI, and CT, each delivering specific information. Objective: To study the informative value of neuroimaging-based data supposed to reflect neurodegeneration (FDG PET), cerebral small vessel disease (MRI), and cerebral large vessel atherosclerosis (CT) with regard to cognitive performance in patients presenting to our memory clinic. Methods: Non-parametric partial correlations and an ordinal logistic regression model …were run to determine relationships between scores for cortical hypometabolism, white matter hyperintensities, calcified plaque burden, and results from Mini-Mental State Examination (MMSE). The final study group consisted of 162 patients (female: 94; MMSE: 6–30). Results: Only FDG PET data was linked to and predicted cognitive performance (r(157) = –0.388, p  < 0.001). Overall, parameters linked to cerebral small and large vessel disease showed no significant association with cognition. Further findings demonstrated a relationship between white matter hyperintensities and FDG PET data (r(157) = 0.230, p  = 0.004). Conclusion: Only FDG PET imaging mirrors cognitive performance, presumably due to the examination’s ability to reflect neurodegeneration and vascular dysfunction, thus capturing a broader spectrum of pathologies. This makes the examination a useful imaging-based diagnostic tool in the work-up of patients presenting to a memory clinic. Parameters of vascular dysfunction alone as depicted by conventional MRI and CT are less adequate in such a situation, most likely because they reflect one pathology complex only. Show more

Keywords: Atherosclerosis, cognitive performance, computed tomography, FDG PET, magnetic resonance imaging, neurodegeneration, small vessel disease

DOI: 10.3233/JAD-200826

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 207-216, 2020

Authors: Huang, Liang-Yu | Hu, He-Ying | Wang, Zuo-Teng | Ma, Ya-Hui | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. Objective: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). Methods: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. Results: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, …and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI = 0.34–0.94, I² = 85.00%, p  < 0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI = 0.91–1.00, I² = 57.00%, p  < 0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI = 1.05–1.39 I² = 62.00%, p  < 0.05; 95% CI = 1.05–1.26 I² = 31.00%, p  = 0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI = 1.01–1.57, I² = 69.00%, p  < 0.01) for dementia. Conclusion: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI. Show more

Keywords: Dementia, job strain, meta-analysis, occupation, occupational exposure, work complexity

DOI: 10.3233/JAD-200605

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 217-227, 2020

Authors: Squarzoni, Paula | Faria, Daniele de Paula | Yassuda, Mônica Sanches | Porto, Fábio Henrique de Gobbi | Coutinho, Artur Martins | Costa, Naomi Antunes da | Nitrini, Ricardo | Forlenza, Orestes Vicente | Duran, Fabio Luiz de Souza | Brucki, Sonia Maria Dozzi | Buchpiguel, Carlos Alberto | Busatto, Geraldo F.

Article Type: Research Article

Abstract: Background: Studies of elderly subjects using biomarkers that are proxies for Alzheimer’s disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. Objective: To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration. Methods: Patients with mild dementia compatible with AD (n  = 38) or amnestic mild cognitive impairment (aMCI; n  = 43) and a cognitively unimpaired group (n  = 27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18 F]FDG-PET assessing neurodegeneration …((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. Results: The A+(N)+ subgroup (n  = 32) showed decreased (p  < 0.001) cognitive test scores compared to both A+(N)–(n  = 18) and A–(N)–(n  = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n  = 9), the A–(N)+ subgroup showed lower (p  < 0.043) verbal memory scores relative to A–(N)–subjects, and trend lower (p  = 0.096) scores relative to A+(N)–subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)–groups. Conclusion: These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)–and A–(N)–subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cognition, cognitively unimpaired, 18-fluorode oxyglucose positron emission tomographic, Pittsburgh compound-B

DOI: 10.3233/JAD-200758

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 229-244, 2020

Authors: Sandau, Ursula S. | Wiedrick, Jack T. | Smith, Sierra J. | McFarland, Trevor J. | Lusardi, Theresa A. | Lind, Babett | Harrington, Christina A. | Lapidus, Jodi A. | Galasko, Douglas R. | Quinn, Joseph F. | Saugstad, Julie A.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group …and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ 4 allele (APOE ɛ 4) genotype and amyloid-β42 to total tau ratio (Aβ42 :T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42 :T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p  = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42 :T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ42 :T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42 :T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, biomarkers, cerebrospinal fluid, microRNA, mild cognitive impairment, tau proteins

DOI: 10.3233/JAD-200396

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 245-263, 2020

Authors: Asken, Breton M. | Elahi, Fanny M. | La Joie, Renaud | Strom, Amelia | Staffaroni, Adam M. | Lindbergh, Cutter A. | Apple, Alexandra C. | You, Michelle | Weiner-Light, Sophia | Brathaban, Nivetha | Fernandes, Nicole | Karydas, Anna | Wang, Paul | Rojas, Julio C. | Boxer, Adam L. | Miller, Bruce L. | Rabinovici, Gil D. | Kramer, Joel H. | Casaletto, Kaitlin B.

Article Type: Research Article

Abstract: Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer’s disease (AD). Objective: To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum. Methods: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. …All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p  = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p  = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5–4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages. Show more

Keywords: Alzheimer’s disease, amyloid, astrocyte, biomarker, glial fibrillary acidic protein, plasma

DOI: 10.3233/JAD-200755

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 265-276, 2020

Authors: Li, Yan | Li, Sha | Xu, Shunjiang | Yu, Hong | Tang, Longmei | Liu, Xiaoyun | Wang, Xuemei | Zhang, Yuanyuan | Zhang, Kaixia | Mi, Shixiong | Chen, Meiqin | Cui, Huixian

Article Type: Research Article

Abstract: Background: Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ 4 (APOE ɛ 4) is a risk factor for Alzheimer’s disease (AD). Objective: This study aimed to investigate the interactive role of androgen decline and APOE ɛ 4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD. Methods: In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated …with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay. Results: The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p  < 0.05), and even lower in the AD group (p  < 0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were higher in AD group (p  < 0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOE ɛ 4 had a risk role in global cognitive impairment (p  < 0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745. Conclusion: These results indicated that the interaction of androgen decline and APOE ɛ 4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, androgen, APOE, gonadotropin, testosterone

DOI: 10.3233/JAD-200233

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 277-290, 2020

Authors: Del Percio, Claudio | Drinkenburg, Wilhelmus | Lopez, Susanna | Pascarelli, Maria Teresa | Lizio, Roberta | Noce, Giuseppe | Ferri, Raffaele | Bastlund, Jesper Frank | Laursen, Bettina | Christensen, Ditte Zerlang | Pedersen, Jan T. | Forloni, Gianluigi | Frasca, Angelisa | Noè, Francesco M. | Fabene, Paolo Francesco | Bertini, Giuseppe | Colavito, Valeria | Bentivoglio, Marina | Kelley, Jonathan | Dix, Sophie | Infarinato, Francesco | Soricelli, Andrea | Stocchi, Fabrizio | Richardson, Jill C. | Babiloni, Claudio | on behalf of PharmaCog Consortium

Article Type: Research Article

Abstract: Background: The European PharmaCog study (http://www.pharmacog.org ) has reported a reduction in delta (1–6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. Methods: Ongoing EEG rhythms were recorded from a …frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12–24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. Results: Compared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p  < 0.05). This effect was observed in 3 out of 4 EEG recording units. Conclusion: TASTPM mice were characterized by “poor reactivity” of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies. Show more

Keywords: Active and passive state in wakefulness, Alzheimer’s disease, electroencephalography, TASTPM mice, wild type mice

DOI: 10.3233/JAD-190351

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 291-308, 2020

Authors: Blujus, Jenna Katherine | Korthauer, Laura Elizabeth | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Research Article

Abstract: Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE , CLU , CR1 , PICALM , and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal network (FPN), and …executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p ’s < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (p ’s < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p  < 0.05). There were no APOE - or PICALM -related differences in any of the networks investigated (p ’s > 0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU , CR1 , and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD. Show more

Keywords: Aging, Alzheimer’s disease, middle aged, neuroimaging, single nucleotide polymorphism

DOI: 10.3233/JAD-200444

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 309-320, 2020

Authors: Xia, Ying | Yassi, Nawaf | Raniga, Parnesh | Bourgeat, Pierrick | Desmond, Patricia | Doecke, James | Ames, David | Laws, Simon M. | Fowler, Christopher | Rainey-Smith, Stephanie R. | Martins, Ralph | Maruff, Paul | Villemagne, Victor L. | Masters, Colin L. | Rowe, Christopher C. | Fripp, Jurgen | Salvado, Olivier | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography …and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ–V–, Aβ–V+, Aβ+V–, or Aβ+V+. Results: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ 4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrovascular disease, white matter hyperintensities

DOI: 10.3233/JAD-200419

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 321-334, 2020

Authors: Stuart, Kimberley E. | Padgett, Christine

Article Type: Research Article

Abstract: Background: It has been estimated that one third of dementia cases may be preventable through modifiable lifestyle interventions. Epidemiological evidence suggests a link between stressful life events and aging-related cognitive decline and dementia; however, inherent methodological limitations in examining subjective and biological measures of stress separately leads to interpretive constraints. Objective: The aim of the current study was to conduct a systematic review of the research literature investigating the effect of perceived and biological measures of stress on dementia risk. Methods: A systematic review was conducted of cohort, case-control, longitudinal prospective or retrospective studies examining the …association between stress and risk of developing dementia. Studies were identified from a systematic search across major electronic databases from inception to February 2020. Results: Overall, 22 studies were identified including a total of 496,556 participants, approximately 50% were females, with sample sizes ranging from 62–270,977. There was considerable heterogeneity in the definition and measurement of stress. Most of the identified studies reported a significant positive association between stress and dementia risk. Conclusion: Evidenced from the current review is that personality traits linked to increased perceived stress and elevated reported perceived stress, are associated with greater statistical risk for dementia. However, this review highlights that caution must be exhibited in interpreting these findings, as methodological issues with confounding adjustment may mediate these results. Future research should focus on the investigation of stress on dementia risk with a full range of confounding adjustment, and on biological measures of stress. Show more

Keywords: Alzheimer’s disease, cortisol, dementia, distress proneness, neuroticism, perceived stress, stress, vascular dementia

DOI: 10.3233/JAD-191096

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 335-352, 2020

Authors: Moreira, Natália Chermont dos Santos | Lima, Jéssica Ellen Barbosa de Freitas | Chierrito, Talita Perez Cantuaria | Carvalho, Ivone | Sakamoto-Hojo, Elza Tiemi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. Objective: The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods: The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and …pathways of cell survival in response to drug treatments. Results: The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion: Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis. Show more

Keywords: Acetylcholinesterase inhibitors, AKT pathway, Alzheimer’s disease, neuronal differentiation, oxidative stress, SH-SY5Y cells

DOI: 10.3233/JAD-200425

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 353-370, 2020

Authors: Graves, Lisa V. | Edmonds, Emily C. | Thomas, Kelsey R. | Weigand, Alexandra J. | Cooper, Shanna | Bondi, Mark W.

Article Type: Research Article

Abstract: Background: Research suggests that actuarial neuropsychological criteria improve the accuracy of mild cognitive impairment (MCI) diagnoses relative to conventional diagnostic methods. Objective: We sought to examine the utility of actuarial criteria relative to consensus diagnostic methods used in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), and more broadly across the continuum of normal aging, MCI, and dementia. Methods: We compared rates of cognitively normal (CN), MCI, and dementia diagnoses at baseline using actuarial versus consensus diagnostic methods in 1524 individuals from the NACC UDS. Results: Approximately one-third (33.59%) of individuals diagnosed …as CN and more than one-fifth (22.03%) diagnosed with dementia based on consensus methods, met actuarial criteria for MCI. Many participants diagnosed with MCI via consensus methods also appeared to represent possible diagnostic errors. Notably, the CNa /CNc group (i.e., participants diagnosed as CN based on both actuarial [a ] and consensus [c ] criteria) had a lower proportion of apolipoprotein E ɛ 4 carriers than the MCIa /MCIc group, which in turn had a lower proportion of ɛ 4 carriers than the dementia (Dem)a /Demc group. Proportions of ɛ 4 carriers were comparable between the CNa /CNc and CNa /MCIc , MCIa /MCIc and MCIa /CNc , MCIa /MCIc and MCIa /Demc , and Dema /Demc and Dema /MCIc groups. These results were largely consistent with diagnostic agreement/discrepancy group comparisons on neuropsychological performance. Conclusion: The present results extend previous findings and suggest that actuarial neuropsychological criteria may enhance diagnostic accuracy relative to consensus methods, and across the wider continuum of normal aging, MCI, and dementia. Findings have implications for both clinical practice and research. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic errors, mild cognitive impairment, misdiagnosis, neuropsychology

DOI: 10.3233/JAD-200778

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 371-386, 2020

Authors: Coppola, Cinzia | Saracino, Dario | Oliva, Mariano | Puoti, Gianfranco | Lus, Giacomo | Le Ber, Isabelle | Pariente, Jérémie | Tessitore, Alessandro | Benussi, Luisa | Ghidoni, Roberta | Carrara, Matteo | Ricci, Martina | Redaelli, Veronica | Tiraboschi, Pietro | Caroppo, Paola | Giaccone, Giorgio | Bonavita, Simona | Rossi, Giacomina

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration (FTLD) designates a group of neurodegenerative diseases with remarkable clinical, pathological, and genetic heterogeneity. Mutations in progranulin gene (GRN ) are among the most common causes of familial FTLD. The GRN C157KfsX97 mutation is the most frequent mutation occurring in Southern Italy and has been already described in a previous work. Objective: In this study, we reported on additional cases carrying the same mutation and performed a genetic study on the whole cohort, aiming at demonstrating the existence of a founder effect and estimating the age of this mutation. Methods/Results: Based …on the haplotype sharing analysis, a founder effect was highly probable, while the age of the mutation, estimated by means of DMLE+ software, resulted in a range between 52 and 82 generations, with the highest frequency at about 62 generations, 1,550 years ago. Conclusion: This is the first study that reports the age estimation of the most recent common ancestor for the GRN C157KfsX97 mutation recurring in Southern Italy. Mutation dating in a geographically restricted population may be useful in order to plan genetic counseling and screening programs in the field of public health. Show more

Keywords: Common founder, frontotemporal lobar degeneration, GRN , haplotype, mutation, mutation dating

DOI: 10.3233/JAD-200924

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 387-394, 2020

Authors: Zhang, Rui-Qi | Chen, Shi-Dong | Shen, Xue-Ning | Yang, Yu-Xiang | Lu, Jia-Ying | Cui, Mei | Zuo, Chuan-Tao | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory …and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects. Show more

Keywords: Alzheimer’s disease, amyloid-PET, cognitive impairment, tau-PET

DOI: 10.3233/JAD-200526

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 395-404, 2020

Authors: Zygouris, Stelios | Iliadou, Paraskevi | Lazarou, Eftychia | Giakoumis, Dimitrios | Votis, Konstantinos | Alexiadis, Anastasios | Triantafyllidis, Andreas | Segkouli, Sofia | Tzovaras, Dimitrios | Tsiatsos, Thrasyvoulos | Papagianopoulos, Sotirios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia. Objective: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Methods: …Two groups, one of healthy older adults with SMC (N = 48) and one of MCI patients (N = 47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery. Results: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%. Conclusion: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC. Show more

Keywords: Aging, Alzheimer’s disease, computers, dementia, diagnosis, memory disorders, mild cognitive impairment, serious games, subjective cognitive decline, user-computer interface

DOI: 10.3233/JAD-200880

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 405-412, 2020

Authors: Geerts, Hugo | Spiros, Athan

Article Type: Research Article

Abstract: Background: Many Alzheimer’s disease patients in clinical practice are on polypharmacy for treatment of comorbidities. Objective: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. Methods: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer’s disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531 , and APOE genotypes and with benzodiazepines, antidepressants, …and antipsychotics, all together 9,585 combinations. Results: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. Conclusion: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials. Show more

Keywords: ADAS-Cog, clinical variability, pharmacodynamic interactions, polypharmacy, protocol amendments

DOI: 10.3233/JAD-200688

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 413-424, 2020

Authors: Yuan, Xiaodong | Wang, Lu | Tandon, Neha | Sun, Huili | Tian, Jing | Du, Heng | Pascual, Juan M. | Guo, Lan

Article Type: Research Article

Abstract: Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer’s disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment. Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon …in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production. Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function. Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice. Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent. Show more

Keywords: Alzheimer’s disease, amyloid-β, anaplerosis, mitochondrial function, triheptanoin

DOI: 10.3233/JAD-200594

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 425-437, 2020

Authors: Li, Dongxue | Liu, Yuancheng | Zeng, Xianchun | Xiong, Zhenliang | Yao, Yuanrong | Liang, Daiyi | Qu, Hao | Xiang, Hui | Yang, Zhenggui | Nie, Lisha | Wu, Pu-Yeh | Wang, Rongpin

Article Type: Research Article

Abstract: Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained …using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p  < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p  < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p  < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p  < 0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, Brainnetome Atlas, 3D-arterial spin labeling, quantitative susceptibility mapping

DOI: 10.3233/JAD-200843

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 439-452, 2020

Authors: Alafuzoff, Irina | Libard, Sylwia

Article Type: Research Article

Abstract: Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer’s disease neuropathologic change (ADNC). Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney. Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry. Results: Hyperphosphorylated τ …(HPτ ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α -synuclein (α S) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology. Conclusion: In most (66%) subjects with CI, the cause of impairment was “mixed pathology”, i.e., ADNC combined with TDP43, α S, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC. Show more

Keywords: Aging, α-synuclein, amyloid-β , cardiac pathology, cerebrovascular lesions, hyperphosphorylated-τ , nephrosclerosis, transactive DNA binding protein 43

DOI: 10.3233/JAD-200925

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 453-465, 2020

Authors: Mezlini, Aziz M. | Magdamo, Colin | Merrill, Emily | Chibnik, Lori B. | Blacker, Deborah L. | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ɛ 4 to AD risk could be population-specific, with ɛ 4 conferring a lower risk to Blacks or African Americans. Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods: We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes …from the Alzheimer’s Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ 3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ 4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ɛ 4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ 4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion: Our study finds similar effects of the ɛ 4-linked haplotypes defined by rs769449 on AD as compared to ɛ 3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations. Show more

Keywords: African Americans, APOE , clinicopathological features, Europeans, genotype

DOI: 10.3233/JAD-200228

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 467-477, 2020