Memory decline accompanies subthreshold amyloid accumulation

Landau, Susan; Horng, Andy; Jagust, William J.

doi:10.1212/wnl.0000000000005354

Cited by 130 publications

(131 citation statements)

References 32 publications

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“…This has no impact on the conclusion of the article, especially as our results remained unchanged when excluding the "intermediate" cases (who did not differ anymore from the controls in terms of florbetapir binding when compared voxelwise; see Supplementary Material). Yet, this further supports the relevance of subthreshold amyloid accumulation [47][48][49][50][51]. Differences in the samples (sample size or degree of cognitive impairment) could also explain the discordances between studies.…”

Section: Discussionsupporting

confidence: 64%

Neuropsychology and neuroimaging profiles of amyloid‐positive versus amyloid‐negative amnestic mild cognitive impairment patients

Tomadesso

Sayette

Flores

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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Introduction Patients with amnestic mild cognitive impairment (aMCI) are heterogeneous as regard to their amyloid status. The present study aimed at highlighting the neuropsychological, brain atrophy, and hypometabolism profiles of amyloid-positive (Aβpos) versus amyloid-negative (Aβneg) aMCI patients. Methods Forty-four aMCI patients and 24 Aβneg healthy controls underwent neuropsychological, structural magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans. Data were compared between groups in specific regions of interest and voxelwise with statistical parametric mapping. Results When directly comparing Aβpos to Aβneg aMCI, the former had lower performances in episodic memory tests ( P = .02 to P < .001) while the latter had worse scores in working memory ( P = .01) and language ( P < .005). Compared to Aβneg healthy controls, both aMCI subgroups showed similar profiles of atrophy and hypometabolism, with no difference between both aMCI subgroups. Conclusion In a sample of aMCI patients recruited and scanned in the same center, the main difference at baseline between Aβpos and Aβneg aMCI concerned the neuropsychological profile, but not the structural magnetic resonance imaging or 18F-fluorodeoxyglucose positron emission tomography profiles of brain alterations.

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Section: Discussionsupporting

confidence: 64%

Neuropsychology and neuroimaging profiles of amyloid‐positive versus amyloid‐negative amnestic mild cognitive impairment patients

Tomadesso

Sayette

Flores

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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“…Although there are established positron emission tomography and cerebrospinal fluid (CSF) beta-amyloid (Aß) and tau biomarkers, both are costly and invasive. Moreover, several studies have found cognitive function to be an earlier predictor of disease progression than currently defined biomarkers [4][5][6][7][8][9] . Development of additional, non-invasive markers of risk that might tap some aspect of the disease process even earlier might aid in prediction.…”

Section: Introductionmentioning

confidence: 99%

Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

Kremen

Panizzon²,

Elman³

et al. 2019

Preprint

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Pathological changes in Alzheimer's disease (AD) begin decades before dementia onset.Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to one's compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h 2 =.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohen's d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response-and by inference, locus coeruleus dysfunction-as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.

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“…More specifically, this effect was not associated with Aβ burden and was already observed in mutation carriers who did not reach Aβ-positivity, suggesting that accelerated functional brain aging occurs before Aβ accumulation can be detected using PET imaging. While we cannot exclude the fact that some Aβ negative individuals would in fact be Aβ accumulators [49][50][51] or present other forms of Aβ that cannot be detected through PET, this could also suggest that mutated genes have life-long effects on the brain that are not fully dependent on Aβ accumulation. Consistently, a previous study in PSEN1 mutation carriers from the Columbian cohort showed early changes in brain function before evidence of cerebral Aβ plaque accumulation.…”

Section: Discussionmentioning

confidence: 95%

Functional brain age prediction suggests accelerated aging in preclinical familial Alzheimer’s disease, irrespective of fibrillar amyloid-beta pathology

Gonneaud

Baria

Binette

et al. 2020

Preprint

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We aimed at developing a model able to predict brain aging from resting state functional connectivity (rs-fMRI) and assessing whether genetic risk/determinants of Alzheimer's disease (AD) and amyloid (Aβ) pathology contributes to accelerated brain aging. Using data collected in 1340 cognitively unimpaired participants from 18 to 94 years old selected across multi-site cohorts, we showed that chronological age can be predicted across the whole lifespan from topological properties of graphs constructed from rs-fMRI. We subsequently used the difference between the model-predicted age and the chronological age in pre-symptomatic autosomal dominant AD (ADAD) mutation carriers and asymptomatic individuals at risk of sporadic AD and assessed the influence of genetics and Aβ pathology on brain age. Applying our predictive model in the context of preclinical AD revealed that the presymptomatic phase of ADAD is characterized by accelerated functional brain aging. This phenomenon is independent from, and might precede, detectable fibrillar Aβ deposition.

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Memory decline accompanies subthreshold amyloid accumulation

Abstract: Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.

Cited by 130 publications

References 32 publications

Neuropsychology and neuroimaging profiles of amyloid‐positive versus amyloid‐negative amnestic mild cognitive impairment patients

Neuropsychology and neuroimaging profiles of amyloid‐positive versus amyloid‐negative amnestic mild cognitive impairment patients

Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

Functional brain age prediction suggests accelerated aging in preclinical familial Alzheimer’s disease, irrespective of fibrillar amyloid-beta pathology

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