The Alzheimer’s Disease Clinical Spectrum

In the paper

“AD is the sixth leading cause of death in the United States and the only top-10 cause still significantly increasing.4”

What the sources say

• Not checked yetcites [4] Alzheimer’s Association, 2018, 2018 Alzheimer's disease facts and figures, Alzheimers Dement source

In the paper

“Alzheimer's disease (AD) is the most common cause of cognitive impairment or dementia in individuals older than 65 years”

What the sources say

• Not checked yetcites [1][2][3][4][5]

In the paper

“with rising longevity, a worldwide pandemic of mild cognitive impairment (MCI), AD, and AD-related dementia (ADRD) is anticipated.[1][2][3][4][5]”

What the sources say

• Not checked yetcites [1][2][3][4][5]

In the paper

“Symptoms too often go undiagnosed, misattributed, or dismissed and ignored, which causes distressing, costly, and potentially harmful delays in receiving appropriate care.1,4,5”

What the sources say

• Not checked yetcites [1] Livingston, 2017, Dementia prevention, intervention, and care, Lancet source
• Not checked yetcites [4] Alzheimer’s Association, 2018, 2018 Alzheimer's disease facts and figures, Alzheimers Dement source
• Not checked yetcites [5] Prince, 2015

In the paper

“The new 2018 NIA-AA research framework dissociates AD symptoms or phenotypes from the pathologic process.”

What the sources say

• Not checked yetcites [2] Deschaintre, 2009, Treatment of vascular risk factors is associated with slower decline in Alzheimer's disease, Neurology source

In the paper

“It defines AD, for research purposes, purely in terms of a biopathologic construct with the AD biomarkers of amyloid, tau, and neurodegeneration (ATN) criteria, which aids in defining the disease stages. 2”

What the sources say

• Not checked yetcites [2] Deschaintre, 2009, Treatment of vascular risk factors is associated with slower decline in Alzheimer's disease, Neurology source

In the paper

“In the dementia stages of AD, many patients have cortical or cortico-subcortical microhemorrhages due to cerebral amyloid angiopathy-related vasculopathy and leakage 19 ; hemosiderin microdeposition from microhemorrhages are seen on gradient-echo or susceptibility-weighted MRI sequences in 15% to 20% of patients.20”

What the sources say

• Not checked yetcites [19] Attems, 2011, Review: sporadic cerebral amyloid angiopathy, Neuropathol Appl Neurobiol source
• Not checked yetcites [20] Atri, 2005, Prevalence and effects of lobar microhemorrhages in early-stage dementia, Neurodegener Dis source

In the paper

“Prevailing models posit a central role of accumulation of synaptic neurotoxic forms of Aß to induce inflammatory and microglial cascades, broad ionic and neurotransmitter abnormalities, mitochondrial dysfunction, oxidative stress, and hyperphosphorylation of the microtubule stabilizing protein tau and formation of tangles.[26][27][28][29][30][31]”

What the sources say

• Not checked yetcites [26][27][28][29][30][31]

In the paper

“APOE-ε4 alleles are associated with accelerated Aß-deposition and earlier onset and higher risk of developing AD symptoms.21,23”

What the sources say

• Not checked yetcites [21] Loy, 2014, Genetics of dementia, Lancet source
• Not checked yetcites [23] Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families, Science source

In the paper

“Patterns of change may overlap but are not part of normal cognitive aging, as manifested by differential aging and AD effects on cognitive networks.34”

What the sources say

• Not checked yetcites [34] Chhatwal, 2018, Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing, Brain source

In the paper

“The 3 major clinical criteria for the AD spectrum are the revised 2011 NIA-AA criteria, 32,39 the International Working Group (Dubois and colleagues 39,40 ) 2010 revised new lexicon criteria, and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria.41”

What the sources say

• Not checked yetcites [32] McKhann, 2011, The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease, Alzheimers Dement source
• Not checked yetcites [39] Dubois, 2010, Revising the definition of Alzheimer's disease: a new lexicon, Lancet Neurol source
• Not checked yetcites [40] Dubois, 2007, Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria, Lancet Neurol source

In the paper

“Performance on measures of fluid intelligence, such as speed of mental processing; working memory; recall and retention of verbal and visual information (learning and memory), in particular visuospatial memory; and reasoning begin to decline in many individuals from age 20 to 30 years.134,135”

What the sources say

• Not checked yetcites [134] Salthouse, 2009, When does age-related cognitive decline begin?, Neurobiol Aging source
• Not checked yetcites [135] Weintraub, 2013, Cognition assessment using the NIH Toolbox, Neurology

In the paper

“In the most common form of AD, sporadic late-onset AD, many genetic variations contribute to increase or lower risk; greater than 20 have been identified (AlzGene Database; www.alzgene.org).22”

What the sources say

• Not checked yetcites [22] Bertram, 2007, Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database, Nat Genet source

In the paper

“dementia-level impairment requires cognitive or behavioral symptoms”

What the sources say

• Not checked yetcites [32] McKhann, 2011, The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease, Alzheimers Dement source

In the paper

“AD is a dual proteinopathy disease defined by a widespread but regionally specific pattern of intraparenchymal diffuse and neuritic ß-amyloid (Aß) plaques and intracytoplasmic (initially), then extracellular, neurofibrillary tangles with synaptic and neuronal loss and gliosis.[14][15][16][17]”

What the sources say

• Not checked yetcites [14][15][16][17]

In the paper

“Familial autosomal dominant AD is rare (<1%), usually manifests in early-onset AD (onset age <65 years; <4% of AD), and is caused by mutations in presenilin 1, amyloid precursor protein, or presenilin 2. 21”

What the sources say

• Not checked yetcites [21] Loy, 2014, Genetics of dementia, Lancet source

In the paper

“MCI diagnosis is a matter of”

What the sources say

• Not checked yetcites [32] McKhann, 2011, The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease, Alzheimers Dement source

In the paper

“which are associated with more rapid decline, earlier institutionalization, higher distress, worse quality of life, and greater health care utilization and costs.53,54”

What the sources say

• Not checked yetcites [53] Okura, 2012, Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study, J Am Geriatr Soc source
• Not checked yetcites [54] Kales, 2005, Rates of clinical depression diagnosis, functional impairment, and nursing home placement in coexisting dementia and depression, Am J Geriatr Psychiatry source

In the paper

“The AD-8 screening instrument provides a practical symptoms questionnaire for changes in thinking and memory that can be a red flag for ADc syndromes.43”

What the sources say

• Not checked yetcites [43] Galvin, 2005, The AD8: a brief informant interview to detect dementia, Neurology source

In the paper

“Presence of pathologic AD does not exclude other pathologies causing or contributing to the patient's CBS; for example, 70% to 80% of individuals with DLB are also amyloid-positive on PET.46”

What the sources say

• Not checked yetcites [46] Gomperts, 2008, Imaging amyloid deposition in Lewy body diseases, Neurology source

In the paper

“Short-term and long-term antipsychotic use is associated with substantial risk of cognitive decline, morbidity (eg, parkinsonism, falls, pneumonia, or cardiovascular and cerebrovascular events), and mortality.”

What the sources say

• Not checked yetcites [55] Ballard, 2014, Prescription of antipsychotics in people with dementia, Br J Psychiatry source
• Not checked yetcites [56] Kales, 2015, Assessment and management of behavioral and psychological symptoms of dementia, BMJ source

In the paper

“A recent systematic review and meta-analysis by Tricco and colleagues 64 included 110 studies and 23,432 subjects supports efficacy, effectiveness, and safety.”

What the sources say

• Not checked yetcites [64] Tricco, 2018, Comparative effectiveness and safety of cognitive enhancers for treating alzheimer's disease: systematic review and network metaanalysis, J Am Geriatr Soc source

In the paper

“Co-existent AD and vascular-ischemic pathology (causing the clinical spectrum of VCI, which includes dementia), and AD with DLB pathology (causing AD-DLB The Alzheimer's Clinical Spectrum variants), are prevalent in older individuals.9,49,50”

What the sources say

• Not checked yetcites [9] Kapasi, 2017, Impact of multiple pathologies on the threshold for clinically overt dementia, Acta Neuropathol source
• Not checked yetcites [49] Jellinger, 2008, Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease, Acta Neuropathol source
• Not checked yetcites [50] Schneider, 2007, Mixed brain pathologies account for most dementia cases in community-dwelling older persons, Neurology source

In the paper

“ChEIs and memantine also have complementary mechanisms of action, potentially additive effects, and demonstrate acceptable tolerability and safety profiles.63”

What the sources say

• Not checked yetcites [63] Atri, 2013, Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy, Alzheimers Res Ther source

In the paper

“Cholinesterase inhibitors (ChEIs) (donepezil, galantamine, rivastigmine) and the N-methyl-D-aspartate (NMDA)-antagonist, memantine, are the only FDA-approved treatments for AD dementia and are recommended broadly in consensus guidelines and practice parameters.1,52,61,62”

What the sources say

• Not checked yetcites [1] Livingston, 2017, Dementia prevention, intervention, and care, Lancet source
• Not checked yetcites [52] National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers (NG97). NICE, UK, June 20, 2018.
• Not checked yetcites [61] Schmidt, 2015, EFNS-ENS/EAN guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease, Eur J Neurol source
• Not checked yetcites [62] Gauthier, 2012, Recommendations of the 4th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4), Can Geriatr J source

In the paper

“and to delay nursing home placement without prolongation of time to death.64,65”

What the sources say

• Not checked yetcites [64] Tricco, 2018, Comparative effectiveness and safety of cognitive enhancers for treating alzheimer's disease: systematic review and network metaanalysis, J Am Geriatr Soc source
• Not checked yetcites [65] Rountree, 2013, Effectiveness of antidementia drugs in delaying Alzheimer disease progression, Alzheimers Dement source

In the paper

“Sustained treatments provide a modest expectation of short-term stabilization or improvement, and longer-term slowing of clinical decline.”

In the paper

“In the long run, current treatments of AD dementia mitigate decline but do not prevent it.”

In the paper

“In more than 40 short-term randomized controlled trials (RCTs) using placebos over 24 to 52 weeks investigating efficacy, and in meta-analyses of RCTs, all 3 ChEIs have demonstrated small to medium effect size treatment benefits at the sibject-group level in terms of improving, stabilizing, or delaying decline in cognition, ADL, and global status, and in ameliorating BPSD and caregiver burden.35,”

What the sources say

• Not checked yetcites [35] Farlow, 2007, Effective pharmacologic management of Alzheimer's disease, Am J Med source
• Not checked yetcites [65] Rountree, 2013, Effectiveness of antidementia drugs in delaying Alzheimer disease progression, Alzheimers Dement source
• Not checked yetcites [70] Farlow, 2000, A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease, Eur Neurol source
• Not checked yetcites [71] Howard, 2012, Donepezil and memantine for moderate-to-severe Alzheimer's disease, N Engl J Med source

In the paper

“Level II or equivocal level I evidence suggest donepezil treatment may be beneficial in very mild stage AD or for subgroups with MCI due to AD (ie, carriers of APOE-ε4 allele, 96 those with depression or depressive symptoms 97 ).”

What the sources say

• Not checked yetcites [96] Petersen, 2005, Vitamin E and donepezil for the treatment of mild cognitive impairment, N Engl J Med source
• Not checked yetcites [97] Lu, 2009, Donepezil delays progression to AD in MCI subjects with depressive symptoms, Neurology source

In the paper

“Even temporary discontinuation is associated with irreversible declines and greater risk of nursing home placement.[67][68][69][70][71][72]”

What the sources say

• Not checked yetcites [67] Raskind, 2000, Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 study group, Neurology source
• Not checked yetcites [68] Courtney, 2004, Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial, Lancet source
• Not checked yetcites [69] Doody, 2001, Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease, Arch Neurol source

In the paper

“Treatment benefits include improvement, stabilization, or reduced decline in the domains of cognition, function (ADLs), and global status; and by amelioration of BPSD and caregiver burden.63,71,73,[98][99][100][101][102][103][104][105][106][107][108][109][110][111]”

What the sources say

• Not checked yetcites [63] Atri, 2013, Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy, Alzheimers Res Ther source
• Not checked yetcites [71] Howard, 2012, Donepezil and memantine for moderate-to-severe Alzheimer's disease, N Engl J Med source
• Not checked yetcites [73] Weycker, 2007, Cost-effectiveness of memantine in moderate-to-severe Alzheimer's disease patients receiving donepezil, Curr Med Res Opin source
• Not checked yetcites [98] McShane, 2006, Memantine for dementia, Cochrane database Syst Rev
• Not checked yetcites [99] Winblad, 1999, Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine), Int J Geriatr Psychiatry source
• Not checked yetcites [100] Reisberg, 2003, Memantine in moderate-to-severe Alzheimer's disease, N Engl J Med source
• Not checked yetcites [101] Bullock, 2006, Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date, Alzheimer Dis Assoc Disord source
• Not checked yetcites [102] Doody, 2004, Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer's disease, Demenr Geriatr Cogn Disord source
• Not checked yetcites [103] Grossberg, 2009, Memantine therapy of behavioral symptoms in community-dwelling patients with moderate to severe Alzheimer's disease, Dement Geriatr Cogn Disord source
• Not checked yetcites [104] Schmitt, 2006, Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis, Alzheimer Dis Assoc Disord source

In the paper

“Short-term (6 months or less) memantine treatment effect sizes are small to medium in size and clinically significant at the moderate to severe stages of AD. 109,110,112,113”

What the sources say

• Not checked yetcites [109] Winblad, 2007, Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials, Dement Geriatr Cogn Disord source
• Not checked yetcites [110] Livingston, 2004, The place of memantine in the treatment of Alzheimer's disease: a number needed to treat analysis, Int J Geriatr Psychiatry source
• Not checked yetcites [112] Abbott, 2009, All-sky LIGO search for periodic gravitational waves in the early fifth-science-run data, Phys Rev Lett source
• Not checked yetcites [113] Wilkinson, 2009, Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate Alzheimer's disease, Dement Geriatr Cogn Disord source

In the paper

“The benefits may also extend to reducing antipsychotic use.”

In the paper

“Persistence, higher dosage (in later dementia stages), and duration of treatment are associated with better outcomes, even in those with advanced dementia.92,95,114,115,130”

What the sources say

• Not checked yetcites [92] Wattmo, 2011, Long-term outcome and prediction models of activities of daily living in Alzheimer disease with cholinesterase inhibitor treatment, Alzheimer Dis Assoc Disord source
• Not checked yetcites [95] Wallin, 2011, Galantamine treatment in Alzheimer's disease: response and long-term outcome in a routine clinical setting, Neuropsychiatr Dis Treat source
• Not checked yetcites [114] Atri, 2008, Long-term course and effectiveness of combination therapy in Alzheimer disease, Alzheimer Dis Assoc Disord source
• Not checked yetcites [115] Rountree, 2009, Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease, Alzheimers Res Ther source
• Not checked yetcites [130] Wattmo, 2011, Predictors of long-term cognitive outcome in Alzheimer's disease, Alzheimers Res Ther source

In the paper

“The FDA-approved anti-AD pharmacotherapies; the ChEIs donepezil, galantamine, and rivastigmine; and the NMDA antagonist memantine can reduce progression of clinical symptoms and disability.”

In the paper

“Unfortunately, large RCTs have failed to support benefits from ginkgo biloba, high-dose vitamin B 12 or folic acid combinations, omega-3 fatty acid or fish oil components or preparations, nonsteroidal anti-inflammatory drugs, and statin medications at the dementia stage of AD. 76,81”

What the sources say

• Not checked yetcites [76] Tayeb, 2012, Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors, Pharmacol Ther source
• Not checked yetcites [81] Ballard, 2011, Alzheimer's disease, Lancet source

In the paper

“The rates of discontinuation due to adverse events for ChEIs and memantine combination treatment are low, between 5% to 10%, and not generally significantly different from placebo.100,120,121,125,126”

What the sources say

• Not checked yetcites [100] Reisberg, 2003, Memantine in moderate-to-severe Alzheimer's disease, N Engl J Med source
• Not checked yetcites [120] Tariot, 2004, Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial, JAMA source
• Not checked yetcites [121] Porsteinsson, 2008, Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial, Curr Alzheimer Res source
• Not checked yetcites [125] Choi, 2011, Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study, Curr Med Res Opin source
• Not checked yetcites [126] Grossberg, 2013, The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors, CNS Drugs source

In the paper

“there were no concerning safely signals or increased mortality with high-dose vitamin E. 127,128”

What the sources say

• Not checked yetcites [127] Sano, 1997, A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study, N Engl J Med source
• Not checked yetcites [128] Dysken, 2014, Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial, JAMA source

In the paper

“Anti-AD medications can be maintained in late-stages to support basic psychomotor processes, praxis, functional communication, the behavioral responses required to assist caregivers to deliver basic ADL care, and the elementary processes of movement and eating.”