Journal of Alzheimer's Disease - Volume 41, issue 4

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Scientists working in the fields of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review “Cognitive enhancers (nootropics): drugs interacting with receptors” was accepted for publication in July 2012. Since then, new targets for the potential treatment of Alzheimer's disease were identified. This update describes drugs interacting with 42 receptors versus 32 receptors in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through March 2014.

Keywords: Alzheimer's disease, cognitive enhancers, memantine, memory, nootropics, receptors

DOI: 10.3233/JAD-140228

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 961-1019, 2014

Authors: Ethell, Douglas W.

Article Type: Research Article

Abstract: Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal …submucosa. Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas—among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis—all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid, neurodegenerative disorder, olfactory bulb

DOI: 10.3233/JAD-130659

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1021-1030, 2014

Authors: Miyashita, Akinori | Wen, Yanan | Kitamura, Nobutaka | Matsubara, Etsuro | Kawarabayashi, Takeshi | Shoji, Mikio | Tomita, Naoki | Furukawa, Katsutoshi | Arai, Hiroyuki | Asada, Takashi | Harigaya, Yasuo | Ikeda, Masaki | Amari, Masakuni | Hanyu, Haruo | Higuchi, Susumu | Nishizawa, Masatoyo | Suga, Masaichi | Kawase, Yasuhiro | Akatsu, Hiroyasu | Imagawa, Masaki | Hamaguchi, Tsuyoshi | Yamada, Masahito | Morihara, Takashi | Takeda, Masatoshi | Takao, Takeo | Nakata, Kenji | Sasaki, Ken | Watanabe, Ken | Nakashima, Kenji | Urakami, Katsuya | Ooya, Terumi | Takahashi, Mitsuo | Yuzuriha, Takefumi | Serikawa, Kayoko | Yoshimoto, Seishi | Nakagawa, Ryuji | Saito, Yuko | Hatsuta, Hiroyuki | Murayama, Shigeo | Kakita, Akiyoshi | Takahashi, Hitoshi | Yamaguchi, Haruyasu | Akazawa, Kohei | Kanazawa, Ichiro | Ihara, Yasuo | Ikeuchi, Takeshi | Kuwano, Ryozo

Article Type: Short Communication

Abstract: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002–0.0059); however, no significant association with LOAD was observed in these variants. Considering …low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese. Show more

Keywords: Alzheimer's disease, Japanese, rare variants, SNP, TREM2

DOI: 10.3233/JAD-140225

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1031-1038, 2014

Authors: Sun, Jiya | Song, Fuhai | Wang, Jiajia | Han, Guangchun | Bai, Zhouxian | Xie, Bin | Feng, Xuemei | Jia, Jianping | Duan, Yong | Lei, Hongxing

Article Type: Research Article

Abstract: Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency …of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD. Show more

Keywords: Alzheimer's disease, generalized multifactor dimensionality reduction, genetic risk, high-order, intragenic epistasis

DOI: 10.3233/JAD-140054

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1039-1056, 2014

Authors: Brandner, Sebastian | Thaler, Christian | Lelental, Natalia | Buchfelder, Michael | Kleindienst, Andrea | Maler, Juan Manuel | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Background: Little information is available on the rostro-caudal concentration gradient of Alzheimer’s disease (AD) biomarkers. Objective: We studied the concentrations of amyloid-β (Aβ) peptides 1-42 and 1-40 as well as the Tau and pTau proteins in simultaneously collected ventricular and lumbar cerebrospinal fluid (CSF) samples. Methods: The samples were simultaneously collected from the ventricle and the lumbar spinal canal in two groups of patients: 10 subjects being treated for normal pressure hydrocephalus (NPH) by the placement of a ventriculo-peritoneal shunt and 5 patients treated simultaneously with an external ventricular drain and a lumbar CSF drain due …to posttraumatic hydrocephalus (PTH). Results: The ventricular-lumbar (V/L) concentration ratio for Aβ1-40 was 0.81 in NPH patients and 0.71 in PTH patients. The V/L-ratio for Aβ1-42 was 0.84 in NPH, reflecting significantly higher concentrations in lumbar CSF than in ventricular CSF, and 1.02 in PTH patients. The V/L-ratios for Tau and pTau differed significantly depending on the diagnostic group: the median V/L-ratio for Tau was 6.83 in NPH patients but only 0.97 in PTH patients. The median V/L-ratio for pTau was 2.36 in NPH patients and 0.91 in PTH patients. Conclusions: We conclude that the rostro-caudal concentration gradient for brain-derived proteins (Tau and pTau in this study) depends on the diagnosis and clinical status of the patient, which were largely neglected in the previously postulated models. Show more

Keywords: Amyloid-β, biomarker, cerebrospinal fluid, rostro-caudal gradient, tau

DOI: 10.3233/JAD-132708

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1057-1062, 2014

Authors: Szigeti, Kinga | Kellermayer, Blanka | Lentini, Jenna M. | Trummer, Brian | Lal, Deepika | Doody, Rachelle S. | Yan, Li | Liu, Song | Ma, Changxing | The Texas Alzheimer Research and Care Consortium

Article Type: Research Article

Abstract: Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor …that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets. Show more

Keywords: Age at onset, Alzheimer's disease, copy number variation

DOI: 10.3233/JAD-132693

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1063-1071, 2014

Authors: Hernández-Rodríguez, Maricarmen | Correa-Basurto, José | Martínez-Ramos, Federico | Padilla-Martínez, Itzia Irene | Benítez-Cardoza, Claudia G. | Mera-Jiménez, Elvia | Rosales-Hernández, Martha Cecilia

Article Type: Research Article

Abstract: Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were …designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, amyloid-β, β-site AβPP cleaving enzyme 1, inhibitor

DOI: 10.3233/JAD-140471

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1073-1085, 2014

Authors: Blanc, Frederic | Philippi, Nathalie | Cretin, Benjamin | Kleitz, Catherine | Berly, Laetitia | Jung, Barbara | Kremer, Stephane | Namer, Izzie Jacques | Sellal, François | Jaulhac, Benoit | de Seze, Jerome

Article Type: Research Article

Abstract: Introduction: Descriptions of Lyme disease and dementia are rare. Objective: To describe patients with dementia and a positive “intrathecal anti-Borrelia antibody index” (AI), specific for neuroborreliosis. Methods: Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 ± 2.9 years. Results: We found two groups of patients with dementia, the first (n = …7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer’s disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Aβ42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second. Conclusion: Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal lobe dementia, hippocampal sclerosis, intrathecal anti-Borrelia antibody index, Lewy body dementia, Lewy body disease, Lyme disease, Lyme neuroborreliosis, vascular dementia

DOI: 10.3233/JAD-130446

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1087-1093, 2014

Authors: Mowszowski, Loren | Hermens, Daniel F. | Diamond, Keri | Norrie, Louisa | Cockayne, Nicole | Ward, Philip B. | Hickie, Ian B. | Lewis, Simon J.G. | Batchelor, Jennifer | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: With predicted increases in dementia incidence, interventions targeting neuroplasticity and neuroprotection are required. Cognitive Training (CT) is an intervention which has been shown to improve aspects of cognition, but the pathophysiological mechanisms contributing to its efficacy are unknown. Objective: We aimed to explore the neurobiological correlates of CT using Mismatch Negativity (MMN), a neurophysiological marker of pre-attentive information processing, which in turn, is postulated to underpin higher-order cognitive processes. Methods: As part of a larger randomized controlled trial, forty ‘at risk’ (i.e., mild cognitive impairment or late-life depression) participants aged 51–79 years underwent neurophysiological, neuropsychological, …and psychiatric assessments before and after a multi-faceted seven-week CT program or a ‘treatment-as-usual’ seven-week waitlist period. Results: The treatment group demonstrated significantly increased fronto-central MMN responses (p < 0.05), as well as improved phonemic verbal fluency (p < 0.05) and decreased self-rated memory difficulties (p < 0.05) following CT, in comparison to the waitlist control group. However, there were no significant correlations between enhanced MMN and cognitive/psychosocial outcomes. Conclusions: Results from this preliminary investigation indicate that CT is associated with enhanced neurophysiological mechanisms suggestive of improved pre-attentive processing, which may reflect alterations in underlying neurobiology. Further research is warranted to confirm these findings, to explicate whether CT is associated with restorative or compensatory neuroplastic processes and to determine whether MMN is a useful biomarker for treatment response. Show more

Keywords: Cognitive training, late-life depression, mild cognitive impairment, Mismatch Negativity, neurophysiological, neuropsychological

DOI: 10.3233/JAD-131985

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1095-1108, 2014

Authors: Xie, Jing | Gabelle, Audrey | Dorey, Aline | Garnier-Crussard, Antoine | Perret-Liaudet, Armand | Delphin-Combe, Floriane | Bathsavanis, Anthony | Dauphinot, Virginie | Lehmann, Sylvain | Mercier, Bernadette | Desestret, Virginie | Roullet-Solignac, Isabelle | Vighetto, Alain | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown. Objective: The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD. Methods: Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a …Mini-Mental State Examination (MMSE) score ≥20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT. Results: The median age was 72 year-old [interquartiles: 65–76]. The median MMSE score was 23 [interquartiles: 21–25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups. Conclusion: In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, memory

DOI: 10.3233/JAD-131916

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1109-1116, 2014