Biomarkers

Background: Alzheimer's disease (AD) is clinically heterogeneous, and can manifest as amnestic or non-amnestic dementia, or be pre-manifest in persons with normal cognition (NormCog). Utility of plasma biomarkers to diagnose AD and prognose cognitive decline must be evaluated in a clinically heterogeneous population representative of the AD spectrum. We investigate pathological and cognitive correlates of plasma phosphorylated tau 181 (p-tau₁₈₁), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across AD and AD-related dementias (ADRD). We test 1.) if combing biomarkers improves diagnostic accuracy for β-amyloid (Aβ) in NormCog and impaired cognition (ImpCog), 2.) if Aβ diagnostic accuracy in ImpCog differs by clinical syndrome (amnestic dementia vs. non-amnestic dementia vs. mild cognitive impairment [MCI]), and 3.) how biomarkers predict future cognitive decline in Aβ+ and Aβ-.

Methods: Participants were NormCog (n=132) and ImpCog (n=461; 130 MCI/impairment without MCI; 61 amnestic; 270 non-amnestic), with confirmed Aβ status (247 Aβ+; 346 Aβ-; cerebrospinal fluid/positron emission tomography/autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested discrimination of Aβ+ from Aβ-; K-folds cross-validation and exhaustive selection determined optimal biomarker combinations. Chi-square tests compared correct classifications to errors of the multivariable model and plasma p-tau₁₈₁ across phenotype. Survival analyses tested time to global clinical dementia rating (CDR) progression.

Results: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC=0.87) and were significantly better in Impaired (ROCAUC=0.87) compared to single analytes (all p<0.018) (Table 1; Figure 1). In ImpCog, multivariable model classification differed by phenotype (χ²=7, p=0.032), with highest accuracy in amnestic dementia (Accuracy: 92%), followed by MCI/impaired not MCI (81%), and non-amnestic dementia (76%). Likewise, plasma p-tau₁₈₁ performance significantly differed by phenotype (χ²=6.8, p=0.035) (Accuracy: amnestic=90%; MCI/impairment without MCI=80%; non-amnestic=74%). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (HR=2.94, p=8.1e-06) and Aβ- individuals (HR=3.11, p=2.6e-09) (Figure 2).

Conclusion: Combining plasma biomarkers can optimize detection of AD pathology across cognitively normal and clinically diverse neurodegenerative disease. Still, diagnostic accuracy may be lower for non-amnestic AD. Plasma NfL showed the most accurate prognosis across neurodegenerative spectrum.