Objective:We assessed whether novelty-related fMRI activity in medial temporal lobe (MTL) regions and precuneus follows an inverted U-shape pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy.Methods:We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus and precuneus, as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, gender, study site, and education.Results:In the precuneus, we observed an inverted U-shape pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared to HC, but not in AD patients who showed relatively lower activity than MCI. This non-linear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to precuneus, hippocampal activity was reduced in AD dementia compared to all other groups and related to AD biomarkers.Conclusion:Novelty-related activity in the precuneus follows a non-linear pattern across the clinical spectrum of increased AD risk. While the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the non-linearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity.

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<b><i>Introduction:</i></b> Several recent research studies show high performance of blood biomarkers to identify Alzheimer’s disease also in the pre-dementia mild cognitive impairment (MCI) stage, but data from the routine clinical care memory clinic setting are needed. <b><i>Methods:</i></b> We examined plasma samples of 144 memory clinic patients, including dementia of Alzheimer type (DAT, <i>n</i> = 54), MCI (<i>n</i> = 57), and subjective cognitive decline (SCD, <i>n</i> = 33), who either presented as self-referrals or were referred by general practitioners or neurologists or psychiatrists. The plasma biomarkers, amyloid-beta42 (Aß42), amyloid-beta40 (Aß40), phospho-Tau181 (pTau181), total-tau (tTau), and neurofilament light (NFL), as well as different ratios, were measured using the ultrasensitive single molecule array (Simoa) immunoassay technology. Statistical analysis including Kruskal-Wallis test, linear regression, and receiver operating characteristics analyses was performed. <b><i>Results:</i></b> Of the single markers, we observed statistically significant group effects of pTau181 (H(2) = 34.43, <i>p</i> &#x3c; 0.001) and NFL (H(2) = 27.66, <i>p</i> &#x3c; 0.001). All individual group comparisons of pTau181 were significant, while the contrast of SCD versus MCI for NFL was not significant. In addition, the ratios of Aß42/Aß40 (H(2) = 7.50, <i>p</i> = 0.02) and pTau181/Aß42 (H(2) = 25.26, <i>p</i> &#x3c; 0.001) showed significant group effects with significant difference between all groups for pTau181/Aß42 and an SCD versus MCI difference for Aß42/Aß40. PTau181 showed the highest area under the curve of 0.85 for the discrimination of SCD and DAT with a sensitivity of 80% and a specificity of 79% at a cut-off of 12.2 pg/mL. Age influenced Aß42, Aß40, and NFL concentrations. <b><i>Conclusion:</i></b> Plasma pTau181 and NFL, as well as the ratios Aß42/Aß40 and pTau181/Aß42, are biomarkers, which can differentiate diagnostic groups in a memory clinic setting outside of research studies.

Background: Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer’s disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied. Objective: The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI. Methods: In the empirical study, 100 MCI-patients and their close others will be recruited from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes. Results: The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed. Conclusion: The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation.