Journal of Alzheimer's Disease - Volume 57, issue 2

Authors: Robinson, Morgan | Lee, Brenda Y. | Hane, Francis T.

Article Type: Review Article

Abstract: This is the second part of a three-part review series reviewing the most important advances in Alzheimer’s disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis.

Keywords: Alzheimer’s disease, amyloid precursor protein, APOE, epidemiology, factors, genetics

DOI: 10.3233/JAD-161149

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 317-330, 2017

Authors: Toepper, Max

Article Type: Review Article

Abstract: Both normal aging and Alzheimer’s disease (AD) are associated with changes in cognition, grey and white matter volume, white matter integrity, neural activation, functional connectivity, and neurotransmission. Obviously, all of these changes are more pronounced in AD and proceed faster providing the basis for an AD diagnosis. Since these differences are quantitative, however, it was hypothesized that AD might simply reflect an accelerated aging process. The present article highlights the different neurocognitive changes associated with normal aging and AD and shows that, next to quantitative differences, there are multiple qualitative differences as well. These differences comprise different neurocognitive dissociations as …different cognitive deficit profiles, different weights of grey and white matter atrophy, and different gradients of structural decline. These qualitative differences clearly indicate that AD cannot be simply described as accelerated aging process but on the contrary represents a solid entity. Show more

Keywords: Activation, aging, Alzheimer’s disease, atrophy, cognition, connectivity, fractional anisotropy, mean diffusivity, structural integrity, volume

DOI: 10.3233/JAD-161099

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 331-352, 2017

Authors: de la Torre, Jack c.

Article Type: Research Article

Abstract: There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer’s disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in …the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia. Show more

Keywords: Alzheimer’s disease, autophagy, brain hypoperfusion, cerebral blood flow, cognitive decline, Creutzfeldt-Jakob disease, dementia with Lewy bodies, frontotemporal dementia, inclusion bodies, prion, protein misfolding, unfolded protein response

DOI: 10.3233/JAD-161266

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 353-371, 2017

Authors: Alghamdi, Amani | Vallortigara, Julie | Howlett, David R. | Broadstock, Martin | Hortobágyi, Tibor | Ballard, Clive | Thomas, Alan J. | O’Brien, John T. | Aarsland, Dag | Attems, Johannes | Francis, Paul T. | Whitfield, David R.

Article Type: Research Article

Abstract: Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have …also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n  = 31), dementia with Lewy bodies (DLB, n  = 44), Alzheimer’s disease (AD, n  = 16), and control (n  = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p  < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p  = 0.001, p  = 0.001, and p  = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cognitive impairment, dementia with Lewy bodies, Parkinson’s disease with dementia, RPT6, tau, ubiquitin proteasome system

DOI: 10.3233/JAD-160946

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 373-386, 2017

Authors: Bloniecki, Victor | Aarsland, Dag | Blennow, Kaj | Cummings, Jeffrey | Falahati, Farshad | Winblad, Bengt | Freund-Levi, Yvonne

Article Type: Research Article

Abstract: Background: Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF). Objective: This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42 , and Aβ42/40 -ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers …are associated with the clinical course of NPS. Methods: 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n  = 44) or risperidone (n  = 39) treatment. CSF samples were collected at baseline and after 12 weeks. Results: Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1  - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42 , Aβ42/40 , and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p  = 0.03). Conclusions: Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued. Show more

Keywords: Biomarkers, dementia, galantamine, neuropsychiatric symptoms, risperidone

DOI: 10.3233/JAD-160758

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 387-393, 2017

Authors: Li, Yin | Li, Ze-Xu | Jin, Tan | Wang, Zhan-You | Zhao, Pu

Article Type: Research Article

Abstract: Hyaluronic acid (HA) is the backbone of the extracellular matrix (ECM) and provides biochemical and physical support to aggrecan-based perineuronal nets (PNNs), which are associated with the selective vulnerability of neurons in Alzheimer’s disease (AD). Here, we showed that HA synthases (HASs), including Has1, Has2, and Has3, were widely expressed in murine central nervous system. All types of HASs were localized to cell bodies of neurons; only Has1 existed in the membranes of neural axons. By using TauP301S transgenic (Tg) mouse model, we found that the axonal-localization of Has1 was abolished in TauP301S overexpressed mouse brain, and the …redistribution of Has1 was also observed in human AD brains, suggesting that the localization of Has1 is dependent on intact microtubules which are regulated partially by the phosphorylation and dephosphorylation cycles of tau proteins. Furthermore, Has1 was reduced and Has3 was increased in TauP301S Tg mouse brain, resulting in the upregulation of shorter-chain HA in the ECM. These findings suggest that by abolishing the axonal-localization of Has1 and promoting the expression of Has3 and the synthesis of shorter-chain HA, the tau pathology breaks the balance of ECM components, promotes the reorganization of the ECM, and inhibits the formation of PNNs in the hippocampus, and then regulates neuronal plasticity during the progression of AD. Show more

Keywords: Alzheimer’s disease, extracellular matrix, hyaluronan synthase, hyaluronic acid, tau pathology

DOI: 10.3233/JAD-160804

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 395-409, 2017

Authors: Hollands, Simone | Lim, Yen Ying | Laws, Simon M. | Villemagne, Victor L. | Pietrzak, Robert H. | Harrington, Karra | Porter, Tenielle | Snyder, Peter | Ames, David | Fowler, Christopher | Rainey-Smith, Stephanie R. | Martins, Ralph N. | Salvado, Olivier | Robertson, Joanne | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE ) ɛ 4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE ɛ 4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. Objective: To determine the extent and nature to which APOE ɛ 4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n  = 765) and Aβ-imaged (n  = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) …Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ 4 risk for clinical disease progression over a 72-month follow-up. Results: With Aβ status unknown and risk from demographic characteristics controlled, ɛ 4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ 4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ 4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of ɛ 4 for clinical disease progression occurs through the effect of ɛ 4 increasing Aβ levels. Show more

Keywords: Alzheimer’s disease, Alzheimer type dementia, amyloid-β, apolipoprotein E4, positron emission tomography

DOI: 10.3233/JAD-161019

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 411-422, 2017

Authors: Andrews, Shea J. | Das, Debjani | Anstey, Kaarin J. | Easteal, Simon

Article Type: Research Article

Abstract: Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimer’s disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance (ABCA7, MS4A4E, SORL1 ), …linear rate of change (APOE, ABCA7, INPP5D, ZCWPW1, CELF1 ), or quadratic rate of change (APOE, CLU, EPHA1, HLA-DRB5, INPP5D, FERMT2 ). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline. Show more

Keywords: Alzheimer’s disease, cognitive aging, genetic epidemiology, genetic risk scores, longitudinal studies, single nucleotide polymorphisms

DOI: 10.3233/JAD-160774

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 423-436, 2017

Authors: Gervaise-Henry, Christelle | Watfa, Gasshan | Albuisson, Eliane | Kolodziej, Allan | Dousset, Brigitte | Olivier, Jean-Luc | Jonveaux, Thérèse Rivasseau | Malaplate-Armand, Catherine

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for AD diagnosis. Unfortunately, their wider use in routine and interpretation require more standardization, particularly for the pre-analytical steps. In particular, amyloid-β (Aβ)42 peptide measurement is strongly influenced by the type of collection tube and by repeated freeze/thaw cycles. Objective : The objectives of this study were to compare, in clinical setting, the impact of collection tubes and the repetition of freeze/thaw cycles on Aβ42 and Aβ40 concentrations and consequently determine if the Aβ42 /Aβ40 ratio could resolve the …diagnosis difficulties related to these pre-analytical parameters. Methods : CSF from 35 patients was collected in different polypropylene (PP) and stored at – 80°C after sampling. For CSF collected in the reference tube, three successive freeze-thaw cycles were done. Aβ42 and Aβ40 concentrations were determined in each condition in order to calculate the Aβ42 /Aβ40 ratio. Results : Our results showed that CSF Aβ42 and Aβ40 values were significantly different according to the type of collection tube and the number of freeze/thaw cycles. Although the calculation of the Aβ42 /Aβ40 ratio eliminated the effect of PP tube-dependent variation, this was not the case for freeze-thaw cycle-associated variation. Conclusion : The use of Aβ42 /Aβ40 ratio rather than Aβ42 alone could contribute toward pre-analytical standardization, thus allowing the general use of CSF AD biomarkers in routine practice. Show more

Keywords: Alzheimer’s disease, Aβ40 peptide, Aβ42/Aβ40 ratio, Aβ42 peptide, cerebrospinal fluid, pre-analytical standardization, tube, freeze-thaw cycles

DOI: 10.3233/JAD-160865

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 437-445, 2017

Authors: Espinosa, Ana | Alegret, Montserrat | Pesini, Pedro | Valero, Sergi | Lafuente, Asunción | Buendía, Mar | San José, Itziar | Ibarria, Marta | Tejero, Miguel A. | Giménez, Joan | Ruiz, Susana | Hernández, Isabel | Pujadas, Francesc | Martínez-Lage, Pablo | Munuera, Josep | Arbizu, Javier | Tárraga, Lluis | Hendrix, Suzanne B. | Ruiz, Agustín | Becker, James T. | Landau, Susan M. | Sotolongo-Grau, Oscar | Sarasa, Manuel | Boada, Mercè | for the AB255 Study Group | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer’s disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. …The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n  = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p -value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the “MCI due to AD” with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= –0.61, p  = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p  = 0.01) and FDG-PET SUVR (β= 0.27, p  = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, amyloid, cognition, hippocampus, magnetic resonance imaging, memory, positron emission tomography

DOI: 10.3233/JAD-161223

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 447-459, 2017