Detecting Alzheimer’s disease biomarkers: Timing matters

02 May 2024 bởiSarah Cheung
Detecting Alzheimer’s disease biomarkers: Timing matters

A 20-year nested case–control study in China has shown sequential and temporal changes in biomarkers 6–18 years before diagnosis of Alzheimer’s disease (AD). Accelerated changes in cerebrospinal fluid (CSF) biomarkers were found after the onset of cognitive impairment, followed by plateaus at AD diagnosis.

The study involved 1,789 Han Chinese individuals aged 45–65 years enrolled in the China Cognition and Aging Study (COAST) between January and June 2000. These participants had normal cognitive function at enrolment and underwent CSF biomarker testing (amyloid-beta [Aβ]42, Aβ40, p-tau181, total tau, neurofilament light chain [NfL]), cognitive assessments (Mini-Mental State Examination [MMSE], Clinical Dementia Rating–Sum of Boxes [CDR-SB], Logical Memory Test [LMT]) and brain MRI evaluation every 2–3 years. The median follow-up was 19.9 years. [N Engl J Med 2024;390:712-722]

In the study, 695 participants were diagnosed with AD at the last follow-up. After propensity score matching, 648 AD patients (mean age, 61.2 years; male, 50.5 percent) and 648 participants with normal cognitive function (control; mean age, 61.3 years; male, 50.6 percent) were included for analysis. At baseline, both groups of participants had similar levels of CSF biomarkers (mean: Aβ42/Aβ40 ratio, 0.1 for the AD group and 0.1 for the control group; p-tau181, 48.4 and 48.8 pg/mL; total tau, 214.6 and 219.2 pg/mL; NfL, 645.4 and 633.9 pg/mL), cognitive scores (mean: MMSE, 29.4 and 29.5; CDR-SB, 0 and 0; LMT, 16.8 and 16.8) and hippocampal volumes (mean: 7683.0 and 7708.3 mm3).

At an estimated 18 years before diagnosis, the AD group showed a lower mean Aβ42 level vs the control group (difference, -59.13 pg/mL). Mean Aβ42/Aβ40 ratio was lower in the AD vs control group at an estimated 14 years before diagnosis (difference, -0.01). In addition, the AD group was found to have higher mean CSF p-tau181 level at 11 years (difference, 7.10 pg/mL), higher mean total tau level at 10 years (difference, 87.10 pg/mL), and higher mean NfL level at 9 years (difference, 228.29 pg/mL) before diagnosis vs the control group.

Approximately 8 years before AD diagnosis, hippocampal volume was 358.94 mm3 smaller in the AD vs control group. In cognitive assessment at 6 years before diagnosis, a 0.33 increase in CDR-SB mean score was observed in the AD vs control group.

As cognitive impairment progressed, AD patients had accelerated changes in Aβ42 level and Aβ42/Aβ40 ratio, peaking at an MMSE score of approximately 25 and an LMT score of approximately 11. Changes in p-tau181 and total tau levels continued to increase until MMSE and LMT scores reached about 27 and 13, respectively. These changes subsequently slowed until AD diagnosis.

“This study provides starting points for [AD] prevention and treatment strategies,” wrote Dr Richard Mayeux of Columbia University, US, in an accompanying editorial. [N Engl J Med 2024;390:761-763]