Abstract
BackgroundIn vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10–20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories.MethodsWe included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer’s dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression.ResultsWe found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = − 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = − 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = − 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] − 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (β − 0.75[0.08] patients (Pinteraction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive.ConclusionsDiscordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by accumulation of amyloid-β (Aβ) plaques in the earliest phase of the disease [1, 2]
The proportion of patients with a discordant Cerebrospinal fluid (CSF)/Positron emission tomography (PET) profile varied between diagnostic groups, but was not significantly different (SCD 15%, Mild cognitive impairment (MCI) 13%, AD dementia 9%, and non-AD dementia 16%, P = 0.13) (Table 1)
We examined PET-CSF discordance using the CSF total tau/Aβ 1–42 (Aβ42) ratio, using a cut-off derived from predicting amyloid PET positivity
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by accumulation of amyloid-β (Aβ) plaques in the earliest phase of the disease [1, 2]. There are currently two established methods for detecting presence of Aβ pathology in vivo, i.e., reduced concentrations of Aβ 1–42 (Aβ42) in CSF and increased retention of Aβ PET tracers [3, 4] These biomarkers have been incorporated in research and diagnostic criteria [5,6,7,8]. A glimpse of this was provided by a previous study assessing longitudinal differences in cognition between participants without dementia with different CSF/PET profiles [15]. They found no memory decline in concordant-negative (CSF−/PET−) and discordant (CSF+/PET−) groups, while the concordant-positive (CSF+/PET+) group did deteriorate over time. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories
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