Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET

Schindler, Suzanne E.; Li, Yan; Buckles, Virginia; Gordon, Brian A.; Benzinger, Tammie L.S.; Wang, Guoqiao; Coble, Dean W.; Klunk, William E.; Fagan, Anne M.; Holtzman, David M.; Bateman, Randall J.; Morris, John C.; Xiong, Chengjie

doi:10.1212/wnl.0000000000012775

Cited by 51 publications

(71 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this reason and because direct comparisons of factors that affect PET detection limits and variability were not available across cohorts, we used previously validated methods and A+ thresholds from each cohort that minimize PET binding estimate variance and used a study design focused on replicating findings across cohorts and methods rather than attempting pooled analyses across cohorts. As in our previous work 13 and a recently published similar work 14 estimating individualized EAOA in people who are A+ enables estimation of A+ disease duration from a single amyloid PET scan. This ability to define disease time from amyloid PET provides new insights into how known and unknown factors affect dementia risk and timing in Alzheimer's disease, which has clinical trial implications.…”

Section: Discussionmentioning

confidence: 68%

“…Similar findings regarding age, but not APOE or sex were recently reported using a similar approach. 14 EAOA shortening the preclinical timeframe may be explained by age-associated increases in comorbidity with other age-related diseases such as vascular disease and other neurodegenerative proteinopathies that co-occur in Alzheimer's disease. 52 APOE-e4 carriage shortening the preclinical timeframe could represent a pleiotropic susceptibility effect of APOE on brain health since APOE is also implicated in cerebrovascular health.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Betthauser

Bilgel

Koscik

et al. 2022

Brain

View full text Add to dashboard Cite

Alzheimer’s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

show abstract

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Betthauser

Bilgel

Koscik

et al. 2022

Brain

View full text Add to dashboard Cite

show abstract

“…Animal models will be helpful to elucidate the cellular and sub-cellular locations of changes in glycolysis in the context of AD pathology. The concept that youthful patterns of brain AG might reflect greater metabolic resilience to amyloid pathology might also help to explain why, at equivalent burdens of brain amyloid pathology, both chronological and brain age have been associated with an increased risk of cognitive impairment [39][40][41] . On the other hand, in young adults prior results have shown that brain amyloid preferentially deposits at sites of higher AG 22,23 ; thus, the relationship between amyloid deposition and AG could well be bidirectional.…”

Section: Discussionmentioning

confidence: 99%

Brain aerobic glycolysis and resilience in Alzheimer disease

Goyal

Blazey

Metcalf

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta deposition in individuals with dementia of the Alzheimer type (DAT) and asymptomatic individuals with brain amyloid deposition. Brain AG decreases with age but the functional significance of this decrease with regard to the development of DAT symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption and glucose utilization, from which we derive AG, we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in typical, cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results implicate preserved AG as a factor in brain resilience to amyloid pathology and suggest that white matter disease may be a cause and/or consequence of this impaired resilience.

show abstract

“… 4 and Lim and Mormino; 39 see also Schindler et al. 40 ), or no difference in amyloid accumulation by APOE ε4 genotype. 4 , 41 , 42 Our findings suggest that observed differences in Aβ 42 /Aβ 40 trajectories between APOE ε4 carriers and non‐carriers reflect higher rates and earlier ages of amyloid positivity among APOE ε4 carriers (resulting in a more advanced preclinical disease stage).…”

Section: Discussionmentioning

confidence: 91%

Longitudinal CSF Alzheimer's disease biomarker changes from middle age to late adulthood

Pettigrew

Soldan

Wang

et al. 2022

Alz & Dem Diag Ass & Dis Mo

View full text Add to dashboard Cite

Introduction We examined longitudinal cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker changes among cognitively normal individuals with 10.7 years follow‐up, on average. Methods Analyses included 278 participants ( M age = 57.5 years); 94 have progressed from normal cognition to mild cognitive impairment (MCI). Amyloid beta (Aβ) 42 /Aβ 40 , phosphorylated tau 181 (p‐tau 181 ), and total tau (t‐tau) were measured using automated electrochemiluminescence assays. Results Apolipoprotein E ( APOE ) ε4 carriers had lower baseline Aβ 42 /Aβ 40 , but longitudinal Aβ 42 /Aβ 40 decreases did not differ by APOE ε4 after accounting for Aβ 42 /Aβ 40 positivity. Lower baseline Aβ 42 /Aβ 40 was associated with greater increases in tau (more strongly in males), and APOE ε4 genotype was associated with greater tau increases after reaching Aβ 42 /Aβ 40 positivity. Participants who progressed to MCI had more abnormal biomarker levels and greater tau increases prior to MCI symptom onset. Biomarkers were more abnormal among older adults, but unrelated to sex or education. Discussion Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations.

show abstract

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET

Cited by 51 publications

References 50 publications

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Brain aerobic glycolysis and resilience in Alzheimer disease

Longitudinal CSF Alzheimer's disease biomarker changes from middle age to late adulthood

Contact Info

Product

Resources

About