Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline

Objective:To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline.Methods:Amyloid-positive participants with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models.Results:When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy.Conclusions:AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.

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Modeling the β secretase cleavage site and humanizing Amyloid-Beta Precursor Protein in rat and mouse to study Alzheimer Disease.

10.21203/rs.3.rs-32032/v1 ◽

2020 ◽

Author(s):

Lutgarde Serneels ◽

Dries T'Syen ◽

Laura Perez-Benito ◽

Tom Theys ◽

Bart De Strooper

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amino Acid ◽

Alzheimer Disease ◽

Early Onset ◽

Computational Modelling ◽

Original Strain ◽

Rodent Models ◽

App Processing

Abstract Background Three amino acid differences between rodent and human APP affect medically important features including β-secretase cleavage of APP and aggregation of the Aβ peptide(1–3). Most rodent models for Alzheimer’s disease (AD) are therefore based on the human APP sequence expressed from artificial mini-genes randomly inserted in the rodent genome. While these models mimic rather well biochemical aspects of the disease such as Aβ-aggregation, they are also prone to overexpression artifacts and to complex phenotypical alterations due to genes affected in or close to the insertion sites of the mini-genes(4,5). Knock-in strategies introducing clinical mutants in a humanized endogenous rodent APP sequence(6) represent useful improvements, but need to be compared with appropriate humanized wild type (WT) mice.Methods Computational modelling of the human β-CTF bound to BACE1 was used to study the differential processing of rodent and human APP. We humanized the three pivotal residues G676R, F681Y and R684H (labeled according to the human APP770 isoform) in the mouse as well as in the rat by a CRISPR-Cas9 approach. These new models, termed mouse and rat App hu/hu , express APP from the endogenous promotor. We also introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene.Results We show that the three amino acid substitutions in the rodent sequence lower the affinity of APP substrate for BACE1 cleavage. The effect on β-secretase processing was confirmed as both humanized rodent models produce three times more (human) Aβ compared to their WT rodent original strain. These models represent suitable controls or starting points for studying the effect of transgenes or knock-in mutations on APP processing(6). We introduced the early-onset familial Alzheimer disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene and provide an initial characterization of Aβ processing in this novel rat AD model.Conclusion The different humanized APP models (rat and mouse) expressing human Aβ and PSEN1 M139T are valuable controls to study APP processing in vivo and allow to implement the use of human Aβ Elisa which is more sensitive than their rodent counterpart. These animals will be made available to the research community.

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Psychometric Properties of the Clinical Dementia Rating – Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer’s Disease Population

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2020.73 ◽

2020 ◽

pp. 1-10

Author(s):

F. McDougall ◽

C. Edgar ◽

M. Mertes ◽

P. Delmar ◽

P. Fontoura ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Psychometric Properties ◽

Disease Assessment ◽

Clinical Dementia Rating ◽

Prodromal Ad ◽

Ceiling Effects ◽

Prodromal Alzheimer’S Disease ◽

Selective Reminding Test

BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

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Emerging biology of the cholinergic system across the spectrum of Alzheimer's disease

International Psychogeriatrics ◽

10.1017/s1041610206003991 ◽

2006 ◽

Vol 18 (s1) ◽

pp. S3-S16 ◽

Cited By ~ 7

Author(s):

Agneta Nordberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nicotinic Acetylcholine Receptors ◽

Cholinergic System ◽

Imaging Techniques ◽

Positron Emission Tomography Imaging ◽

Amyloid Plaques ◽

Hippocampal Volume ◽

Brain Morphology

The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that β-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.

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Cognitive reserve and clinical progression in Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000007821 ◽

2019 ◽

Vol 93 (4) ◽

pp. e334-e346 ◽

Cited By ~ 22

Author(s):

Anna Catharina van Loenhoud ◽

Wiesje Maria van der Flier ◽

Alle Meije Wink ◽

Ellen Dicks ◽

Colin Groot ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alzheimer Disease ◽

Gray Matter ◽

Cognitive Reserve ◽

Disease Stage ◽

Disease Assessment ◽

White Matter Hyperintensity ◽

Cerebral Damage ◽

Clinical Progression

ObjectiveTo investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum.MethodsWe selected 839 β-amyloid (Aβ)–positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale–cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF).ResultsThe median follow-up period was 24 months (interquartile range 6–42). Corrected for age, sex, APOE4 status, and baseline cerebral damage, higher gray matter volume-based W scores (i.e., greater CR) were associated with a lower diagnostic conversion risk (hazard ratio [HR] 0.22, p < 0.001) and slower decline in memory (β = 0.48, p < 0.001) and executive function (β = 0.67, p < 0.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR 0.30, p = 0.038; ADNI-MEM: β = 0.52, p = 0.028; ADNI-EF: β = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: β = 0.43, p = 0.003; ADNI-EF: β = 0.59, p < 0.001), but opposite findings (i.e., more rapid decline) for AD dementia (ADNI-MEM: β = −0.91, p = 0.002; ADNI-EF: β = −0.77, p = 0.081).ConclusionsAmong Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.

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Rationale for combination therapy with galantamine and memantine in alzheimer’s disease: the efficacy of treatment of addition

European Psychiatry ◽

10.1016/s0924-9338(11)72214-3 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 507-507

Author(s):

J. Zarra

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Events ◽

Well Being ◽

Disease Assessment ◽

Clinical Aspects ◽

Neurocognitive Disorder ◽

Clinical Dementia Rating ◽

Open Label ◽

Behavioural Symptoms

ObjectiveThe efficacy, safety, and tolerability of nootropic cholinergic agent: GALANTAMINE (with a dual mechanism of action on the cholinergic a system) and moderate affinity NMDA- receptor antagonist: MEMANTINE, were assessed taking into account the profile of patients with neurocognitive disorder: Alzheimer's disease, from the clinical aspects and the different classifications.MethodsThe experience included 428 patients who were enrolled in a prospective, observational, multicenter, and open-label study to receive 16 mg/day of galantamine and 30 mg/day of memantine for 12 months of treatment of addition.ResultsThe therapeutic response was measured using the Mini Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Alzheimer's Disease Assessment Scale (ADAS-GOG), Functional Activities Questionnaire(FAQ) the Clinical Global Impression Scale (CGI) and the UKU scale of adverse effectstaking into account the efficacy, safety and adverse events of the treatment.The final results of the study showed that galantamine with addition memantine improves cognition, behavioural symptoms, and the general well-being of patients with cognitive impairment: Alzheimer's disease. The incidence of adverse events was not significant and a very good profile of tolerability and safety was observed.ConclusionAt the conclusion of this session, the participant should be able to demonstrate with use the association memantine - galatamine in neurocognitive disorder: Alzheimer's disease, improve cognition, behavioural symptoms, and the general state recognized as neurocognitive disorder.

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Association of Carotid and Intracranial Stenosis with Alzheimer’s Disease Biomarkers

10.21203/rs.3.rs-19023/v1 ◽

2020 ◽

Author(s):

Koung Mi Kang ◽

Min Soo Byun ◽

Jun Ho Lee ◽

Dahyun Yi ◽

Hye Jeong Choi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hippocampal Volume ◽

Artery Stenosis ◽

Intracranial Artery ◽

Positron Emission ◽

Intracranial Artery Stenosis ◽

Intracranial Arteries ◽

Demographic Covariates

Abstract Background To clarify whether atherosclerosis of the carotid and intracranial arteries is related to Alzheimer’s disease (AD) pathology in vivo, we investigated the associations of carotid and intracranial artery stenosis with cerebral beta-amyloid (Aβ) deposition and neurodegeneration in middle- and old-aged individuals. Given the differential progression of Aβ deposition and neurodegeneration across clinical stages of AD, we focused separately on cognitively normal (CN) and cognitively impaired (CI) groups.Methods A total of 281 CN and 199 CI (mild cognitive impairment and AD dementia) subjects underwent comprehensive clinical assessment, [11C] Pittsburgh Compound B positron emission tomography, and magnetic resonance (MR) imaging including MR angiography. We evaluated extracranial carotid and intracranial arteries for the overall presence, severity (i.e. number and degree of narrowing) and location of stenosis.Results We found no associations between carotid and intracranial artery stenosis and cerebral Aβ burden in either CN or CI group. In terms of AD-related neurodegeneration, exploratory univariate analyses showed associations between the presence and severity of stenosis and neurodegeneration biomarkers of AD (i.e. reduced hippocampal volume [HV] and cortical thickness in the AD-signature regions) in both CN and CI groups. In confirmatory multivariate analyses controlling for demographic covariates and diagnosis, the association between number of stenotic intracranial arteries ≥ 2 and reduced HV in the CI group remained significant.Conclusions Neither carotid nor intracranial artery stenosis appears to be associated with brain Aβ burden, while intracranial artery stenosis is related to amyloid-independent neurodegeneration, particularly hippocampal atrophy. These observations support the importance of proper management of intracranial artery stenosis for delaying the progression of AD neurodegeneration and related cognitive decline.

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Neuropsychiatric symptoms and executive function impairments in Alzheimer’s disease and vascular dementia: The role of subcortical circuits

Dementia & Neuropsychologia ◽

10.1590/1980-57642018dn13-030005 ◽

2019 ◽

Vol 13 (3) ◽

pp. 293-298 ◽

Cited By ~ 2

Author(s):

Chan Tiel ◽

Felipe Kenji Sudo ◽

Ana Beatriz Calmon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Vascular Dementia ◽

Neuropsychiatric Symptoms ◽

Vascular Lesions ◽

Cognitive Test ◽

Pathophysiological Mechanism ◽

Clinical Dementia Rating

ABSTRACT Neuropsychiatric symptoms (NPS) in dementia are prevalent, under-recognized and little studied regarding their pathophysiological aspects. The pathophysiological mechanism, as well as the possible role of vascular lesions in the genesis of these symptoms, are still matters of debate. Objective: to describe and compare the prevalence and severity of NPS in subjects with Alzheimer's disease (AD) and vascular dementia (VaD). Methods: a cross-sectional study involving 82 outpatients, divided into two groups (AD × VaD), was conducted. Patients were submitted to the Cambridge Cognitive Test (CAMCOG), the Clock Drawing Test (CLOX 1 and 2), the Neuropsychiatric Inventory (NPI) and the Clinical Dementia Rating (CDR) scale. Neuroimaging was scored using the de Leon and Fazekas scales. Results: 90.8% of the patients had at least one neuropsychiatric symptom. There were statistical differences on the CLOX test and in the apathy symptoms between AD and VaD groups. Apathy and disinhibition proved more prevalent in patients with higher vascular load. Conclusion: apathy and impaired executive function may reflect vascular damage in subcortical circuits in dementia patients.

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Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Journal of Alzheimer s Disease ◽

10.3233/jad-200896 ◽

2020 ◽

Vol 78 (3) ◽

pp. 989-1010

Author(s):

Gary E. Gibson ◽

José A. Luchsinger ◽

Rosanna Cirio ◽

Huanlian Chen ◽

Jessica Franchino-Elder ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Placebo Group ◽

Cognitive Decline ◽

Controlled Trial ◽

Amyloid Β ◽

Cognitive Outcomes ◽

Disease Assessment ◽

Clinical Dementia Rating ◽

Positron Emission

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

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Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-200526 ◽

2020 ◽

Vol 78 (1) ◽

pp. 395-404 ◽

Cited By ~ 1

Author(s):

Rui-Qi Zhang ◽

Shi-Dong Chen ◽

Xue-Ning Shen ◽

Yu-Xiang Yang ◽

Jia-Ying Lu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Amyloid Β ◽

Amyloid Pet ◽

Elderly Persons ◽

Cross Sectional ◽

Memory Decline ◽

Tau Pet

Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.

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DETECTING TREATMENT GROUP DIFFERENCES IN ALZHEIMER’S DISEASE CLINICAL TRIALS: A COMPARISON OF ALZHEIMER’S DISEASE ASSESSMENT SCALE - COGNITIVE SUBSCALE (ADAS-COG) AND THE CLINICAL DEMENTIA RATING - SUM OF BOXES (CDR-SB)

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2018.2 ◽

2018 ◽

pp. 1-6

Author(s):

A.M. Wessels ◽

S.A. Dowsett ◽

J.R. Sims

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Treatment Group ◽

Assessment Tool ◽

Disease Assessment ◽

Group Differences ◽

Original Form ◽

Clinical Dementia Rating ◽

Cognitive Subscale

The Alzheimer’s Disease Assessment Scale’s cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer’s Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.

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