Current and Future Treatments in Alzheimer Disease: An Update

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

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Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽

10.1212/wnl.0000000000011081 ◽

2020 ◽

Vol 96 (1) ◽

pp. e81-e92

Author(s):

Joseph Therriault ◽

Tharick A. Pascoal ◽

Melissa Savard ◽

Andrea L. Benedet ◽

Mira Chamoun ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Characteristic Curve ◽

Tertiary Care ◽

Amyloid Β ◽

Executive Dysfunction ◽

Anterior Cingulate ◽

Amyloid Pet ◽

Clinical Criteria ◽

Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

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Amyloid-Targeting Drugs for the Treatment of Alzheimer Disease

Journal of the Korean Neurological Association ◽

10.17340/jkna.2021.3.4 ◽

2021 ◽

Vol 39 (3) ◽

pp. 134-140

Author(s):

Ae Young Lee

Keyword(s):

Cognitive Impairment ◽

Alzheimer Disease ◽

Drug Administration ◽

Functional Ability ◽

Amyloid Β ◽

Symptomatic Improvement ◽

Aβ Peptide ◽

Common Cause ◽

Disease Modifying ◽

Disease Modifying Treatment

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by cognitive impairment, neurobehavioral changes, and loss of functional ability. Current therapeutic options for AD are limited to medications that contribute to modest symptomatic improvement. The amyloid β (Aβ) peptide is central to the pathogenesis, so that immunotherapy targeting Aβ has been focused as a putative disease-modifying treatment for AD. In this review, I review the ongoing Aβ -directed immunotherapies, including aducanumab, which is the new AD medication since 2003 as well as the first disease-modifying treatment on the market approved by the Food and Drug Administration.

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The MMP-2/TIMP-2 System in Alzheimer Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200812223007 ◽

2020 ◽

Vol 19 (6) ◽

pp. 402-416

Author(s):

Hongyue Wang ◽

Longjian Huang ◽

Lei Wu ◽

Jiaqi Lan ◽

Xinhong Feng ◽

...

Keyword(s):

Alzheimer Disease ◽

Amyloid Β ◽

Matrix Proteins ◽

Matrix Metalloproteinase 2 ◽

Amyloid Β Protein ◽

Synaptic Loss ◽

Tissue Inhibitors Of Metalloproteinase ◽

Β Protein ◽

Underlying Mechanisms ◽

Brain Parenchymal

Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental, on AD, including: (1) MMP-2 directly degrades Aβ resulting in the clearance of Aβ deposits. Conversely, Aβ-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP- 2/TIMP-2 as therapeutic targets for AD.

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Loss of Lysosomal Proteins Progranulin and Prosaposin Associated with Increased Neurofibrillary Tangle Development in Alzheimer Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab056 ◽

2021 ◽

Author(s):

Anarmaa Mendsaikhan ◽

Ikuo Tooyama ◽

Geidy E Serrano ◽

Thomas G Beach ◽

Douglas G Walker

Keyword(s):

Alzheimer Disease ◽

Human Brain ◽

Tau Protein ◽

Neurofibrillary Tangle ◽

Neuronal Loss ◽

Amyloid Plaques ◽

Human Brain Tissue ◽

Tissue Sections ◽

Disease Modifying ◽

Lysosomal Proteins

Abstract Alzheimer disease (AD) is a progressive neurodegenerative disease causing cognitive decline in the aging population. To develop disease-modifying treatments, understanding the mechanisms behind the pathology is important, which should include observations using human brain samples. We reported previously on the association of lysosomal proteins progranulin (PGRN) and prosaposin (PSAP) with amyloid plaques in non-demented aged control and AD brains. In this study, we investigated the possible involvement of PGRN and PSAP in tangle formation using human brain tissue sections of non-demented aged control subjects and AD cases and compared with cases of frontotemporal dementia with granulin (GRN) mutations. The study revealed that decreased amounts of PGRN and PSAP proteins were detected even in immature neurofibrillary tangles, while colocalization was still evident in adjacent neurons in all cases. Results suggest that neuronal loss of PGRN preceded loss of PSAP as tangles developed and matured. The GRN mutation cases exhibited almost complete absence of PGRN in most neurons, while PSAP signal was preserved. Although based on correlative data, we suggest that reduced levels of PGRN and PSAP and their interaction in neurons might predispose to accumulation of p-Tau protein.

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316 - Lewy Body Study: An Australian longitudinal biomarker study of dementia with Lewy bodies

International Psychogeriatrics ◽

10.1017/s1041610220002161 ◽

2020 ◽

Vol 32 (S1) ◽

pp. 74-74

Author(s):

Kai Sin Chin ◽

Nawaf Yassi ◽

Zina Hijazi ◽

Victor Villemagne ◽

Christopher Rowe ◽

...

Keyword(s):

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Treatment Strategies ◽

Lewy Bodies ◽

Amyloid Β ◽

Tissue Donation ◽

Cognitive Assessments ◽

People With Dementia ◽

Longitudinal Biomarker ◽

The Impact

Background:Cerebral multi-morbidity is common in older people with dementia, including people with dementia with Lewy bodies (DLB). We describe the first Australian-based, longitudinal observational biomarker study of DLB.Aims:To investigate the frequency and influence of Alzheimer’s disease (AD) pathology (amyloid-β and tau) and cerebrovascular disease on clinical symptoms and disease outcome in DLB.Methods:The study will recruit 100 people with mild to moderate probable DLB, who will undergo comprehensive clinical and cognitive assessments. Scales targeting DLB-specific clinical features (such as cognitive fluctuations and rapid eye movement sleep behaviour disorder) are administered. Biomarker protocols incorporate blood sampling (including ApoE genotyping and systemic inflammatory markers), molecular imaging (amyloid-β [18F-NAV 4694], tau [18F-MK6240], VMAT2 [18F-AV133] PET scans), 3-tesla magnetic resonance imaging and optional lumbar puncture. Clinical assessments are completed 6 - monthly and imaging 18-monthly. Participants are also invited to register for post-mortem brain tissue donation.Results:Thirty participants with probable DLB have been enrolled to date (mean age 75.4 years, range 64-82; 87% male). All participants have mild to moderate cognitive impairment (mean MMSE 25, range 17-30). Approximately 64% of the participants were amyloid-β positive. Study procedure tolerability has been excellent with no adverse events reported.Conclusions:There is significant overlap of AD-related proteinopathies in people with DLB. Understanding the impact of multi-morbidity is essential in the development of effective treatment strategies. This study supports the feasibility of intensive, longitudinal biomarker studies in DLB in the Australian setting.

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Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

Biomedicines ◽

10.3390/biomedicines8100421 ◽

2020 ◽

Vol 8 (10) ◽

pp. 421 ◽

Cited By ~ 1

Author(s):

Adrian Florian Bălașa ◽

Cristina Chircov ◽

Alexandru Mihai Grumezescu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Amyloid Plaques ◽

Protein Levels ◽

Chronic Neuroinflammation ◽

Complex Process ◽

Novel Biomarkers ◽

Underlying Mechanisms

Neurodegeneration is a highly complex process which is associated with a variety of molecular mechanisms related to ageing. Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common, affecting more than 45 million individuals. The underlying mechanisms involve amyloid plaques and neurofibrillary tangles (NFTs) deposition, which will subsequently lead to oxidative stress, chronic neuroinflammation, neuron dysfunction, and neurodegeneration. The current diagnosis methods are still limited in regard to the possibility of the accurate and early detection of the diseases. Therefore, research has shifted towards the identification of novel biomarkers and matrices as biomarker sources, beyond amyloid-β and tau protein levels within the cerebrospinal fluid (CSF), that could improve AD diagnosis. In this context, the aim of this paper is to provide an overview of both conventional and novel biomarkers for AD found within body fluids, including CSF, blood, saliva, urine, tears, and olfactory fluids.

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Applying fluid biomarkers to Alzheimer's disease

AJP Cell Physiology ◽

10.1152/ajpcell.00007.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. C3-C10 ◽

Cited By ~ 29

Author(s):

Henrik Zetterberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Clinical Symptoms ◽

Senile Plaque ◽

Neurofibrillary Tangle ◽

Amyloid Β ◽

Differential Diagnoses ◽

Blood Tests ◽

The Brain

Alzheimer’s disease (AD) is a common neurodegenerative disease that starts with a clinically silent phase of a decade or more during which brain pathologies accumulate predominantly in the medial temporal lobe but also elsewhere in the brain. Network dysfunction and clinical symptoms typically appear when senile plaque (amyloid-β) and neurofibrillary tangle (tau) pathologies meet in the brain parenchyma, producing synapse and neuronal loss. For plaque and tangle pathologies, reliable fluid biomarkers have been developed. These require sampling of cerebrospinal fluid. Reliable blood tests for plaque and tangle pathologies are currently lacking, but blood tests for general neurodegeneration have recently been developed. In AD, plaques and tangles often coexist with other pathologies, including Lewy bodies, and to what extent these contribute to symptoms is currently unknown. There are also important differential diagnoses that may be possible to distinguish from AD with the aid of biomarkers. The scope of this review is fluid biomarkers for AD and related pathologies. The purpose is to provide the reader with an updated account of currently available fluid biomarkers for AD and clinically relevant differential diagnoses.

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Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

Journal of Biological Chemistry ◽

10.1074/jbc.m112.445734 ◽

2013 ◽

Vol 288 (29) ◽

pp. 20868-20882 ◽

Cited By ~ 24

Author(s):

Min Suk Kang ◽

Seung-Hoon Baek ◽

Yoon Sun Chun ◽

A. Zenobia Moore ◽

Natalie Landman ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Amyloid Β ◽

Presenilin 1 ◽

Amyloid Β Peptide ◽

Lipid Kinase ◽

Rate Limiting Step ◽

Secretase Activity ◽

Phosphatidylinositol 4 ◽

Rate Limiting

Amyloid β-peptide (Aβ) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aβ levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis.

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Alu retrotransposons and COVID-19 susceptibility and morbidity

Human Genomics ◽

10.1186/s40246-020-00299-9 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Manci Li ◽

Luca Schifanella ◽

Peter A. Larsen

Keyword(s):

Clinical Outcomes ◽

Host Response ◽

Human Population ◽

Treatment Strategies ◽

Specific Treatment ◽

Patient Specific ◽

Regulate Gene Expression ◽

The World ◽

Novel Biomarkers ◽

Regulate Gene

AbstractSARS-CoV-2 has spread rapidly across the world and is negatively impacting the global human population. COVID-19 patients display a wide variety of symptoms and clinical outcomes, including those attributed to genetic ancestry. Alu retrotransposons have played an important role in human evolution, and their variants influence host response to viral infection. Intronic Alus regulate gene expression through several mechanisms, including both genetic and epigenetic pathways. With respect to SARS-CoV-2, an intronic Alu within the ACE gene is hypothesized to be associated with COVID-19 susceptibility and morbidity. Here, we review specific Alu polymorphisms that are of particular interest when considering host response to SARS-CoV-2 infection, especially polymorphic Alu insertions in genes associated with immune response and coagulation/fibrinolysis cascade. We posit that additional research focused on Alu-related pathways could yield novel biomarkers capable of predicting clinical outcomes as well as patient-specific treatment strategies for COVID-19 and related infectious diseases.

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Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

Youth STEM Matters ◽

10.51892/ysm.1.202201 ◽

2022 ◽

Vol 2 ◽

Author(s):

Ciara Downey ◽

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Focal Point ◽

Passive Immunization ◽

Amyloid Β ◽

Clinical Results ◽

Aβ Oligomers ◽

Current Therapies ◽

Differential Selectivity ◽

Amyloid Cascade

Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.

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