Prognostic value of Alzheimer's disease plasma biomarkers in the oldest-old: a prospective primary care-based study

Abstract

Background: Blood-based biomarkers offer a promising, less invasive, and more cost-effective alternative for Alzheimer's disease screening compared to cerebrospinal fluid or imaging biomarkers. However, they have been extensively studied only in memory clinic-based cohorts. We aimed to validate them in a more heterogeneous, older patient population from primary care.

Methods: We measured plasma Aβ42/Aβ40, P-tau181, NfL, and GFAP in 1007 individuals without dementia, aged 79-94 years, from the longitudinal, primary care-based German AgeCoDe study. We assessed the association with cognitive decline, disease progression, and the capacity to predict future dementia of the Alzheimer's type (DAT). We also evaluated biomarker dynamics in 305 individuals with a follow-up sample (∼8 years later).

Findings: Higher levels of P-tau181 (HR = 1.32 [95% CI: 1.17-1.51]), NfL (HR = 1.19 [95% CI: 1.03-1.36]), and GFAP (HR = 1.36 [95% CI: 1.22-1.52]), and a lower Aβ42/Aβ40 ratio (HR = 0.80 [95% CI: 0.68-0.95]) were associated with an increased risk of progressing to clinically-diagnosed DAT. Additionally, higher levels of P-tau181 (β = -0.49 [95% CI: -0.71 to 0.26]), NfL (β = -0.29 [95% CI: -0.52 to 0.06]), and GFAP (β = -0.60 [95% CI: -0.83 to 0.38]) were linked to faster cognitive decline. A two-step DAT prediction strategy combining initial MMSE with biomarkers improved the identification of individuals in the prodromal stage for potential treatment eligibility. Biomarker levels changed over time, with increases in P-tau181 (β = 0.19 [95% CI: 0.14-0.25]), NfL (β = 2.88 [95% CI: 2.18-3.59]), and GFAP (β = 8.23 [95% CI: 6.71-9.75]). NfL (β = 2.47 [95% CI: 1.04-3.89]) and GFAP (β = 4.45 [95% CI: 1.38-7.51]) exhibited a faster increase in individuals progressing to DAT.

Interpretation: Evaluating plasma biomarkers, alongside brief cognitive assessments, might enhance the precision of risk assessment for DAT progression in primary care.

Funding: Alzheimer Forschung Initiative, Bundesministerium für Bildung und Forschung.

Keywords: Alzheimer's disease; Cognitive impairment; Disease prognosis; Oldest-old population; Plasma biomarkers; Primary care.

Fig. 1

Flowchart of the selection process of the study participants. The flowchart indicates the inclusion/exclusion criteria for AgeCoDe recruitment process in 2003–2004 and the selection of participants with plasma samples available for the study analyses. DAT, clinically-diagnosed dementia of the Alzheimer's type.

Fig. 2

Association between baseline plasma biomarker ratio or levels and cognitive decline in participants without dementia. Spaghetti plots show the association between plasma biomarker ratio/levels and cognitive decline for each participant without dementia. Normalised MMSE score was used as a proxy of cognitive performance. Biomarkers were split into quantiles with low (green, below 25%), medium (orange, 25–75%), and high (purple, over 75%) ratio/levels and regression lines were fitted for each group only for visualisation purposes. Each circle represents a MMSE score measurement. (a) Aβ42/Aβ40, N = 827; (b) P-tau181, N = 915; (c) NfL, N = 924; (d) GFAP, N = 925.

Fig. 3

Dynamics of plasma biomarkers in relation to clinical diagnosis. Spaghetti plots show the change in biomarker ratio/level from baseline until follow-up in participants that progressed to clinically-diagnosed dementia of the Alzheimer's type (yellow, DAT progression) or remained without dementia or progressed to other types of dementia (pink, no DAT progression). Each circle represents a biomarker measurement. Regression lines were fitted for each group only for visualisation purposes. (a) Aβ42/Aβ40, N = 283; (b) P-tau181, N = 284; (c) NfL, N = 287; (d) GFAP, N = 287. DAT, clinically-diagnosed dementia of the Alzheimer's type.