Scholarly Articles On Alzheimer’s Disease

Genetic Overlap With Other Neurodegenerative Diseases

We tested the association of the lead variants within our new loci with the risk of developing other neurodegenerative diseases or AD-related disorders . We also performed more precise colocalization analyses for five loci known to be associated with Parkinsons disease , types of frontotemporal dementia and amyotrophic lateral sclerosis . The IDUA signal for Parkinsons disease was independent of the signal in ADD 3=99.9%), but we were not able to determine whether the CTSB signals colocalized. The TMEM106B and GRN signals in frontotemporal lobar degeneration with TAR DNA-binding protein inclusions probably share causal variants with ADD . Lastly, we were not able to determine whether the TNIP1 signals colocalized for ADD and amyotrophic lateral sclerosis.

Primary Care: Initial Assessment When A Patient Presents

Table 3 Example questions for a clinician conducting an initial assessment with a patient and caregiver

• Confirm medical and family history

• Review the patients medications for any that could cause cognitive impairment

• Perform blood tests to eliminate potential reversible causes of cognitive impairment

• Conduct a quick clinical assessment to confirm the presence of cognitive impairment

Quality Control And Imputation

A standard quality control was performed on variants and samples from all datasets individually. The samples were then imputed with the TOPMed reference panel,. The Haplotype Reference Consortium panel was also used for some datasets . For the UKBB, we used the provided imputed data generated from a combination of the 1000 Genomes, HRC and UK10K reference panels .

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The 2000s: Mild Cognitive Impairment

Although in the 1990s a few investigators had begun to systematically study individuals at risk for dementia to determine whether cognitive declines could be detected before diagnosis , following the turn of this century, the focus of the field heavily shifted to the study of prodromal stages of AD that precede the full-blown dementia syndrome. Characterization of such early phases was largely crystallized by Ron Petersen, Glenn Smith, and colleagues from the Mayo Clinic who introduced of the concept of mild cognitive impairment .

MCI was defined as a condition in which individuals experience memory loss to a greater extent than one would expect for age, yet do not meet criteria for dementia. The specific clinical criteria for MCI they originally put forth were: subjective memory complaint, objective memory impairment for age, relatively preserved general cognition, essentially intact activities of daily living, and not demented . This classification scheme was subsequently broadened to include amnestic MCI or non-amnestic MCI subtypes, and single domain or multiple domain conditions to indicate the number of cognitive domains affected . It was proposed that these MCI subtypes correspond to various etiologies, with amnestic MCI being most indicative of AD and non-amnestic MCI suggesting other neurodegenerative conditions such as FTLD or DLB .

Current Landscape In Treatment Research For Ad

No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials.22,28 As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned.10 Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action that target either disease modification or symptoms.4,10 Some of the recent failures of anti-amyloid agents in phase 3 clinical trials in patients with early-stage, mild, or mild-to-moderate stage AD were semagacestat,29 bapineuzumab,30 solanezumab31 and in similar trials of -secretase inhibitors lanabecestat,32 verubecestat,33 and atabecestat.34

The National Institute on Aging and the Alzheimers Association proposed a new framework for research,39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.

Tau positron emission tomography , neurofilament light, and neurogranin are the new biomarkers that are increasingly used by clinical trials.40

In this review, agents currently studied as potential DMTs will be discussed. Furthermore, an approach to a future precision medicine multifactorial therapeutic model based on biomarkers profile, genetic analysis, neuropsychologic evaluation, and neuroimaging accomplished with risk factors restriction will be attempted.2,3

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Practical Guide For An Early Diagnosis Of Alzheimers Disease In Clinical Practice

As already raised, recent recommendations for evolving AD care to a more patient-centric, transdisciplinary model include guidance on realizing an efficient diagnostic processone in which HCPs, payers, and specialists are encouraged to combine their efforts to ensure the early warning signs of AD are not overlooked . The recommendations include dividing the diagnosis of AD into the following steps: detect, assess/differentiate, diagnose, and treat . We present here a practical guide for the early diagnosis of AD, based on this outlined approach, including a case study to highlight each of these key steps.

Figure 2

A stepwise infographic to highlight key stages within the diagnostic process, along with the recommended tests to support each step

What Are The Signs Of Alzheimer’s Disease

Scientists continue to unravel the complex brain changes involved in the onset and progression of Alzheimers disease. It seems likely that damage to the brain starts a decade or more before memory and other cognitive problems appear. During this preclinical stage of Alzheimers disease, people seem to be symptom-free, but toxic changes are taking place in the brain.

Damage occurring in the brain of someone with Alzheimers disease begins to show itself in very early clinical signs and symptoms. For most people with Alzheimersthose who have the late-onset varietysymptoms first appear in their mid-60s. Signs of early-onset Alzheimers begin between a persons 30s and mid-60s.

The first symptoms of Alzheimers vary from person to person. Memory problems are typically one of the first signs of cognitive impairment related to Alzheimers disease. Decline in non-memory aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment, may also signal the very early stages of Alzheimers disease. And some people may be diagnosed with mild cognitive impairment. As the disease progresses, people experience greater memory loss and other cognitive difficulties.

Alzheimers disease progresses in several stages: preclinical, mild , moderate, and severe .

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Symptoms Of Mild Cognitive Impairment

Some people have a condition called mild cognitive impairment, or MCI. It can be an early sign of Alzheimers. But, not everyone with MCI will develop Alzheimers disease. People with MCI can still take care of themselves and do their normal activities. MCI memory problems may include:

• Losing things often
• Forgetting to go to events or appointments
• Having more trouble coming up with words than other people the same age

Learn more about Alzheimer’s disease from MedlinePlus.

Currently Studied Dmts For Ad

Amyloid-related mechanismsDMTs

The crucial step in AD pathogenesis is the production of amyloid , which forms SPs . The A derives from a protein overexpressed in AD, APP through sequential proteolysis by -secretase in the extracellular domain and -secretase in the transmembrane region. Full-length APP is first cleaved by -secretase or -secretase. The APP cleavage by -secretase leads to nonamyloidogenic pathway, whereas APP cleavage by -secretase leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and -secretase in the transmembrane area results in the A production. Major sites of -secretase cleavage usually occur in positions 40 and 42 of A, thus A40 and A42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance.5

Consequently, anti-amyloid DMTs have focused on 3 major MOAs: reduction of A42 production , reduction of A-plaque burden , and promotion of A clearance .10

Reduction of A42 production

-secretase inhibitors

BACE inhibitors

Two BACE inhibitors are still elaborated: elenbecestat in phase 2 and umibecestat in phase 3.4 The later agent is studied in asymptomatic individuals at risk of developing AD .45

-secretase modulators

Reduction of A-plaque burden

Aggregation inhibitors

Promotion of A clearance

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The 2010s: The Era Of Biomarkers

Over the past 20 years great progress was made in identifying in vivo biological markers of AD. Several investigators refined the ability to detect and measure cerebrospinal fluid levels of A and tau protein that were indicative of AD pathology in the brain. Klunk and colleagues developed Pittsburgh compound-B , an agent that binds to A, for use with PET imaging to reveal deposition of amyloid in the brain. Tau-binding agents that can be used with PET imaging have also been recently developed .

Neuroimaging measures of hippocampal, cortical, and general brain atrophy were developed and applied to detect early neurodegenerative changes associated with AD . Other advanced structural and functional neuroimaging methodologies, including resting-state functional MRI and diffusion tensor imaging, have been used to detect pathological changes associated with AD and to create algorithms for classifying AD and MCI . All of these biomarkers have greatly increased the accuracy with which AD pathology in the brain can be detected before the onset of cognitive symptoms, and improved the ability to differentiate AD from other pathologies that lead to dementia.

Nelson et al.s contrasting depictions of the epidemiology of dementia. Panel is the schematic representation of the prevailing view of Alzheimer neuropathology by age, whereas panel depicts distinct brain diseases other than AD that may contribute to cognitive impairment in late life .

Search Strategy And Selection Criteria

We followed the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2009 guidelines. PubMed, EMBASE and CENTRAL were searched using the terms Alzheimers, Alzheimer, dementia, and risk for OPS and Alzheimer, cognitive, cognition, prevent, and prevention for RCT up to 1 March 2019. Bibliographies of relevant literature and records in Clinicaltrials.gov and AlzRisk database were hand-searched in case of omission. The inclusion criteria were as follows: an OPS exploring the association between potentially modifiable exposures at baseline and incident AD independently diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association criteria, or a RCT targeting the impact of addressing modifiable risk factors on the incidence of AD or AD-related clinical endpoints , and a publication written in English to permit easy access to the source information of all included articles. The detailed exclusion criteria are shown in . Bibliographies of relevant original studies and systematic reviews were hand-searched. Literature selection was performed by three pairs of experienced investigators and any disagreements on inclusion were resolved by consensus and arbitration by a panel of investigators within the review team .

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Pathophysiology Of Alzheimers Disease

The presence of extracellular plaques of insoluble -amyloid peptide and neurofibrillary tangles of P-tau in neuronal cytoplasm is the hallmark of AD . Although the mechanisms by which these changes lead to cognitive decline are still debated, these deposits are believed to lead to atrophy and death of neurons resulting from excitotoxicity processes , collapse in calcium homeostasis, inflammation and depletion of energy and neuronal factors. As a result of this process, damage to neurons and synapses involved in memory processes, learning and other cognitive functions lead to the aforementioned cognitive decline .

According to amyloid cascade theory , the cerebral accumulation of A peptide, resulting from the imbalance between production and clearance of this protein, is the main event causing the disease, being other events observed resulting from this process .

The A peptide, which has 36 to 43 aminoacids, is derived from amyloid precursor protein enzymatic proteolysis, a physiologically produced protein that plays important roles in brain homeostasis . The APP gene is located on chromosome 21, which explains the higher incidence of early-onset AD in individuals with 21 trisomy and in individuals with APP gene locus duplication . It is believed that overexpression of APP results in an increase of cerebral A peptide, and consequently, in its deposition .

The 1990s: Neuropsychological Characterization Of Alzheimers Disease And Related Disorders

The new criteria for dementia and AD adopted in the 1980s improved the reliability of the clinical diagnosis and allowed group studies of mildly demented patients to be carried out with a reasonable degree of accuracy. Many of these studies applied the theories and methods of cognitive psychology to study the cognitive consequences of AD. By using this approach, these studies characterized the component cognitive processes underlying the neuropsychological deficits observed in AD, and showed that cognitive changes attributable to AD and other dementing disorders could have important implications for existing theories of brainbehavior relationships underlying normal cognition.

Several studies at this time showed that episodic memory impairment is usually the earliest and most salient aspect of the AD dementia syndrome. These findings were consistent with neuropathologic studies that showed extensive AD pathology occurs earliest in medial temporal lobe structures important for episodic memory . The memory deficit was shown to reflect an inability to effectively encode and store new information since patients with very early AD were particularly impaired on measures of delayed recall , exhibited an abnormal serial position effect with attenuation of the primacy effect , and remained impaired even if retrieval demands were reduced by the use of recognition testing .

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Keywords Country And Institution Map Analyses

Figure 4. Keyword maps globally and in China. Global keyword maps. Keyword maps in China. In this visualized network, each keyword is represented by a node. Node size reflects the number of publications in the node, and the distance between two nodes indicates the connectivity of the nodes as determined by co-occurrences. The larger the number of publications for which two nodes are both found, the stronger the relationship between the nodes. VOSviewer has its own clustering technique based on citation relations between clusters. Colors represent groups of nodes that are relatively strongly related to each other.

Figure 5 shows the bibliographic network of countries and regions in AD research in 1988, 1997, 2007, and 2017. As seen in this visualization, the United States, England, Canada, Japan, Italy, France, Australia, Germany, and Switzerland each developed more AD research over time and also increased research collaborations among countries. Globally, most institutions contributing to AD research are located in the European Union and the United States . By 2017, the number of AD publications from China had increased significantly, and Chinese research institutes with a focus on AD research had been established .

Specialist Role In Assessment

Following the initial assessment in primary care, further cognitive, behavioral, functional, and imaging assessments can be carried out in a specialist setting. With their additional AD experience, access to other specialties, and possibly fewer time constraints than the PCP, the specialist is able to conduct a more comprehensive testing battery, using additional clinical assessments and biomarkers to determine causes of impairment and confirm diagnosis .

Cognitive assessments

Because the cognitive impacts of early-stage AD may vary from patient to patient, it is important to consider which cognitive domains are affected in these early stages when considering which assessments to use. Specialists are able to conduct a full neuropsychological test battery that covers the major cognitive domains preferably, a battery should contain more than one test per domain to ensure adequate sensitivity in capturing cognitive impairment . This step can help with obtaining an in-depth understanding of the subtle changes in cognition seen in the early stages of AD and enables the clinician to monitor subsequent changes over time.

Functional assessments

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Definition Of Associated Loci

A region of ±500kb was defined around each variant with a stage I P value below 1×105. These regions were then merged to define nonoverlapping regions. The region corresponding to the APOE locus was excluded. We then used the PLINK clumping procedure to define independent hits in each region. An iterative clumping procedure was applied to all variants with a stage I P value below 1×105, starting with the variant with the lowest P value . Variants with a stage I P value below 1×105, located within 500kb of this index variant and in LD with the index variant were assigned to the index variants clump. The clumping procedure was then applied until all the variants had been clumped. LD in the EADB-TOPMed dataset was computed using high-quality imputed genotypes.

Study Category And Article Type Analyses

Globally, AD articles were categorized into 144 study types. As shown in Figure 3A, the most frequently observed categories were neuroscience/neurology with 84,864 articles , followed by biochemistry/molecular biology with 25,769 articles , geriatrics/gerontology with 22,620 articles , psychiatry with 18,389 articles , and pharmacology/pharmacy with 18,154 articles . As shown in Figure 3B, the first several research categories of Chinese AD literature do not differ from the top several categories globally. The top five research categories in China were neuroscience/neurology with 5,550 articles , biochemistry/molecular biology with 2,219 articles , pharmacology/pharmacy with 1,961 articles , chemistry with 1,671 articles , and cell biology with 1,066 articles .

Figure 3. Research categories and article types globally and in China. Research categories and fractions in global AD research. Research categories and fractions in Chinese AD research. Randomized controlled trials, clinical trials, case reports, and basic research worldwide from 1988 to 2017. Article type analysis from the top 10 countries by publication volume from 1988 to 2017.

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Alzheimers Disease Risk Factors

5.2.1. Aging

The most important risk factor in AD is aging. Younger individuals rarely have this disease, and most AD cases have a late onset that starts after 65 years of age . Aging is a complex and irreversible process that occurs through multiple organs and cell systems with a reduction in the brain volume and weight, a loss of synapses, and ventricles enlargement in specific areas accompanied by SP deposition and NFT. Moreover, several conditions might emerge during aging such as glucose hypometabolism, cholesterol dyshomeostasis, mitochondria dysfunction, depression, and cognitive decline. These changes also appear in normal aging, which makes it difficult to distinguish the cases in early AD . AD can be divided based on age of onset into early-onset AD , the rare form with around 16% of cases, in which most of them are familial AD characterized by having more than one member in more than one generation with AD, and ranges from 3060 or 65 years. The second type is the late-onset AD , which is more common with age of onset above 65 years. Both types may occur in people who have a family with a positive history of AD and families with a late-onset disease .

5.2.2. Genetics

Herein, we discuss the strong genetic risk factors in AD.

• Amyloid Precursor Protein

• Presenilin-1 and Presenilin-2

• Apolipoprotein E

• ATP Binding Cassette Transporter A1

• Clusterin Gene and Bridging Integrator 1

• Evolutionarily Conserved Signaling Intermediate in Toll pathway

• Estrogen Receptor Gene