Blood biomarkers in dynamic prediction of conversion to Alzheimer's disease: An application of joint modeling.

OBJECTIVES: To investigate the accuracy of longitudinal trajectories of blood biomarkers for predicting future onset of AD among MCI participants as well as to demonstrate dynamic prediction of the individual conversion risk applying joint modeling. METHODS: A total of 446 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative database were included. We introduced joint modeling to analyze the effects of the longitudinal blood biomarkers on the conversion risk to AD, and further to build individual-specific prediction risk model. RESULTS: During the follow-up, 345 participants remained with MCI and 101 progressed to AD, and were categorized as non-progression and progression group, respectively. Longitudinally, the positive association of the concentration dynamics of plasma p-tau181 and NfL with the conversion risk to AD from MCI was also demonstrated, with Hazard Ratio (HR) = 5.83 and HR = 4.18, respectively. When incorporating plasma p-tau181 and NfL together to predict AD progression, we observed improved performance (AUC = 0.701, Brier Score = 0.119). Two participants were chosen to exemplify the individual-specific risk prediction at different follow-up time for comparative analysis. CONCLUSIONS: Plasma p-tau181 and NfL could serve as biomarkers for the prediction of AD onset, and the individualized prediction opens up the possibility to provide clinical information at a personal level.

Trajectories of cognitive decline in different domains prior to AD onset in persons with mild cognitive impairment.

OBJECTIVES: To explore the trajectories and the change-points of global and five domain-specific cognitive functions before the onset of Alzheimer's disease (AD). METHODS: Data was retrieved from the Alzheimer's Disease Neuroimaging Initiative with follow-up from 2005 to 2022. Participants with mild cognitive impairment (MCI) at baseline and those who progressed to AD during follow-up were included. The time of AD onset was defined as the visit time when participant was first diagnosed as AD during follow-up. Global and five domain-specific cognitive functions (immediate memory, visuospatial ability, language, processing speed and executive function) were assessed by Mini-Mental State Examination, Immediate recalling trials of Rey Auditory Verbal Learning Test, Clock Drawing Test, Animal Fluency Test, Part A and B of Trail Making Test, respectively. Their trajectories and change-points before AD onset were explored by generalized additive mixed models and piecewise linear regression models, respectively. RESULTS: 349 participants were diagnosed as MCI at baseline and converted to AD during follow-up, who were included in this study. They had been visited on an average of 4.6 times (SD = 2.1, range = 2.0-13.0), with a total of 1593 visits. Their mean baseline age and AD onset age were 74.4 (SD = 6.4, range = 60.0-88.4) and 77.0 (SD = 6.8, range = 60.5-94.7) years, respectively. Baseline age and educational year were significantly associated with global cognitive, immediate memory, language and executive function. Men presented better global cognitive function (ß = 0.54, p < 0.05) but poorer immediate memory (ß = -1.72, p < 0.05) than women. Immediate memory and visuospatial ability showed the earliest change-points at 4 years before the onset of AD (Note as T-4years), followed by language (T-3.5years), executive function (T-2.5 years), processing speed (T-2.0 years), and finally the global cognitive function (T-1.5years). CONCLUSIONS: The trajectories of the six neuropsychological scores were non-linear and showed deterioration in functions over time. Immediate memory and visuospatial ability showed the earliest change-points prior to AD onset.

Longitudinal trajectory effects of different MCI subtypes on general cognitive and daily functions in a population-based cohort of older adults.

OBJECTIVES: To identify different mild cognitive impairment (MCI) phenotypes based on substantial relative impairment in specific cognitive domains and then characterize the complex process of general cognitive and daily functions over time in older adults with these MCI subtypes. METHODS: A total of 1020 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were recruited. MCI subtypes were obtained based on neuropsychological tests in five cognitive domains: memory (M), visuospatial function (V), language (L), processing speed (P), and executive function (E). General cognitive function and daily function were measured by the Mini-Mental State Examination (MMSE) and the Functional Assessment Questionnaire (FAQ), respectively. Linear mixed models were fitted to curve their trajectories across different MCI subtypes. RESULTS: Considering visuospatial function, subtypes were MO (memory impaired only), M&V (memory and visuospatial function impaired) and M&nV (memory impaired and visuospatial function non-impaired). Similar subtypes and naming rules were obtained based on language, executive function, and processing speed. Further, depending on the number of relative impaired cognitive domains M&S and M&M were obtained. Participants with MO had the highest prevalence in the sample (53.4 %), followed by M&nV (31.1 %). Participants with M&V had the highest mean age (74.69 years) at baseline and the greatest dementia conversion rate (53.2 %). The MMSE and FAQ score trajectories changed most slowly in participants with MO while fastest in those with M&V. Obvious different trajectories of both MMSE and FAQ scores were observed across different subtypes based on visuospatial function and executive function. CONCLUSION: Compared to MO, individuals with multi-dimensional cognitive impairment have worse general cognitive and daily functions, especially for those with M&V.