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. 2023 Jul 29;18(1):50.
doi: 10.1186/s13024-023-00631-6.

Optimizing detection of Alzheimer's disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO

Zahinoor Ismail  1   2   3   4   5   6 , Rebeca Leon  7 , Byron Creese  8 , Clive Ballard  8 , Philippe Robert  9 , Eric E Smith  7   10   11
Affiliations

Optimizing detection of Alzheimer's disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO

Zahinoor Ismail et al. Mol Neurodegener. .

Abstract

Background: Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally.

Methods: Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003-2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions).

Results: Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96-15.70%]; p = 0.001), t-tau (7.71% [2.70-12.97%]; p = 0.002), p-tau/Aβ42 (p < 0.001), and t-tau/Aβ42 (p = 0.001). NPSnotMBI was associated only with lower Aβ42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99-6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49-1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aβ40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia.

Conclusions: These findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.

Keywords: ATN; Alzheimer’s disease; Amyloid; Biomarkers; Cerebrospinal fluid; Mild behavioral impairment; Mild cognitive impairment; Neurodegeneration; Neuropsychiatric symptoms; Prodromal disease; Tau.

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Conflict of interest statement

HC, RL, SN, PR report no conflicts. ES has received consulting fees from Eli Lilly. ZI has received consulting fees from Otsuka/Lundbeck, outside the submitted work. His institution has received funds from Biogen and Roche, also outside the submitted work.

Figures

Fig. 1
Fig. 1
Flowchart showing how the sample populations were obtained from the ADNI and MEMENTO datasets
Fig. 2
Fig. 2
Kaplan-Meir curve and Cox proportional hazards ratios for incident dementia
See this image and copyright information in PMC

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