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BackgroundAlzheimer's disease (AD) is a heterogeneous disorder.ObjectiveTo investigate whether cognitive AD subtypes are associated with different rates of disease progression.MethodsWe included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses.ResultsPatients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p

IntroductionPatients with Alzheimer's disease (AD) show heterogeneity in profile of cognitive impairment. We aimed to identify cognitive subtypes in four large AD cohorts using a data-driven clustering approach.MethodsWe included probable AD dementia patients from the Amsterdam Dementia Cohort (n = 496), Alzheimer's Disease Neuroimaging Initiative (n = 376), German Dementia Competence Network (n = 521), and University of California, San Francisco (n = 589). Neuropsychological data were clustered using nonnegative matrix factorization. We explored clinical and neurobiological characteristics of identified clusters.ResultsIn each cohort, a two-clusters solution best fitted the data (cophenetic correlation >0.9): one cluster was memory-impaired and the other relatively memory spared. Pooled analyses showed that the memory-spared clusters (29%-52% of patients) were younger, more often apolipoprotein E (APOE) ɛ4 negative, and had more severe posterior atrophy compared with the memory-impaired clusters (all P

A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum.

Background: Alzheimer's disease (AD) is a heterogeneous disorder.Objective: To investigate whether cognitive AD subtypes are associated with different rates of disease progression.Methods: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses.Results: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05).Conclusions: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment. [ABSTRACT FROM AUTHOR]