Background Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. Methods We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. Results Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years , confirmation of cognitive decline by an informant , and decline-related worries . Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. Conclusions Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology. Electronic supplementary material The online version of this article (10.1186/s13195-019-0515-y) contains supplementary material, which is available to authorized users.

Objective:To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD).Method:We analyzed data from n=449 cognitively normal participants (n=209 healthy controls, n=240 SCD patients) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, five cognitive domain factor structure comprising learning & memory, executive functions, language abilities, working memory and visuospatial functions. We compared groups regarding global and domain-specific performance and correlated performance with different CSF markers of AD pathology.Results:We observed worse performance (Cohen’s d≈0.25-0.5, adjusted for age-, sex differences with ANCOVA) in global performance, memory, executive functions and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r≈0.3) associated with lower CSF-Aβ42/40 and CSF-Aβ42/ptau181 in the whole sample and specifically in the SCD subgroup.Conclusions:Within the spectrum of clinically unimpaired (i.e., “pre- mild cognitive impairment”) cognitive performance, SCD is associated with minor deficits in memory, executive function and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.

The feature binding task detects subtle cognitive impairments in participants with SCD, who are unimpaired in traditional neuropsychological testing. This corroborates the use of feature binding tests in preclinical AD studies and suggests that specific cognitive deficits can be found in SCD. Future studies incorporating AD biomarkers and longitudinal follow-up are needed to further establish the clinical utility of feature binding.

High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a "pre-MCI" at risk stage of AD.

Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes.

Background Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer’s disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. Methods We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. Results The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996–1.000, p < .05). Conclusion These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline. Trial registration German Clinical Trials Register DRKS00007966. Registered 4 May 2015.

Highlights Composite scores provide reliable metrics of domain function in multicenter cohort. Visuo-spatial domain composite scores relate to anatomic changes in AD spectrum. Domain scores relate to network-specific resting-state connectivity in AD spectrum.

Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.