Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts

Scheltens, Nienke M.E.; Tijms, Betty M.; Koene, Teddy; Barkhof, Frederik; Teunissen, Charlotte E.; Wolfsgruber, Steffen; Wagner, Michael; Kornhuber, Johannes; Peters, Oliver; Cohn‐Sheehy, Brendan I.; Rabinovici, Gil D.; Miller, Bruce L.; Kramer, Joel H.; Scheltens, Philip; Flier, Wiesje M. van der

doi:10.1016/j.jalz.2017.03.002

Cited by 67 publications

(92 citation statements)

References 46 publications

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“…Sixteen patients in this study developed clinically evident nonamnestic features (in addition to memory decline). A recent analysis of four large cohorts of AD dementia patients (that were not limited to incident cases) found that nonamnestic features were more likely in APOE e4 noncarriers . NonAD pathologies may partially account for our findings, although we found that APOE e4 carriers were heavily over‐represented in our atypical group.…”

Section: Discussioncontrasting

confidence: 41%

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Caselli

Langlais

Dueck

et al. 2020

Alzheimer's & Dementia

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Introduction Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? Methods Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). Results 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post‐inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. Discussion The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

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Section: Discussioncontrasting

confidence: 41%

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Caselli

Langlais

Dueck

et al. 2020

Alzheimer's & Dementia

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“…Except for the rare dominantly inherited Alzheimer's disease (AD), most AD patients are sporadic [1,2]. The apolipoprotein E (ApoE) gene encodes an 35-kDa extracellular lipid and cholesterol carrier glycoprotein, and its ε4 allele is a major genetic risk factor for sporadic AD [1,3]. The presence of this allele increases the risk of AD in a dose-dependent manner and lowers the age at onset [4,5].…”

Section: Introductionmentioning

confidence: 99%

Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer’s disease

Baek

Cho

Lee

et al. 2020

Preprint

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Background: To assess effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum.Methods: Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for partial-volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.Results: The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.Conclusions: Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on Aβ burden depending on the existing amyloidosis and enhances vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

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“…However, these models focus on only a small subset of the available biomarkers and rely on a dichotomous definition of abnormality. AD, however, is known to be heterogeneous in terms of clinical presentation [10] and pathophysiology [11], making such binary cutoffs difficult to determine [12].…”

Section: Introductionmentioning

confidence: 99%

Characterizing heterogeneity in the progression of Alzheimer's disease using longitudinal clinical and neuroimaging biomarkers

Goyal

Tjandra

Migrino

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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Introduction Models characterizing intermediate disease stages of Alzheimer's disease (AD) are needed to inform clinical care and prognosis. Current models, however, use only a small subset of available biomarkers, capturing only coarse changes along the complete spectrum of disease progression. We propose the use of machine learning techniques and clinical, biochemical, and neuroimaging biomarkers to characterize progression to AD. Methods We used a large multimodal longitudinal data set of biomarkers and demographic and genotype information from 1624 participants from the Alzheimer's Disease Neuroimaging Initiative. Using hidden Markov models, we characterized intermediate disease stages. We validated inferred disease trajectories by comparing time to first clinical AD diagnosis. We trained an L2-regularized logistic regression model to predict disease trajectory and evaluated its discriminative performance on a test set. Results We identified 12 distinct disease states. Progression to AD occurred most often through one of two possible paths through these states. Paths differed in terms of rate of disease progression (by 5.44 years on average), amyloid and total-tau (t-tau) burden (by 10% and 69%, respectively), and hippocampal neurodegeneration ( P < .001). On the test set, the predictive model achieved an area under the receiver operating characteristic curve of 0.85. Discussion Progression to AD, in terms of biomarker trajectories, can be predicted based on participant-specific factors. Such disease staging tools could help in targeting high-risk patients for therapeutic intervention trials. As longitudinal data with richer features are collected, such models will help increase our understanding of the factors that drive the different trajectories of AD.

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Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts

Cited by 67 publications

References 46 publications

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Neuropsychological decline up to 20 years before incident mild cognitive impairment

Effect of APOE ε4 genotype on amyloid-β and tau accumulation in Alzheimer’s disease

Characterizing heterogeneity in the progression of Alzheimer's disease using longitudinal clinical and neuroimaging biomarkers

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