The Significance of Subjective Cognitive Decline in Primary Care and Memory Clinic Patients : Risk of Alzheimer’s Dementia and Biological Correlates

Subjective Cognitive Decline (SCD) is defined as an individual’s perception of worsening cognitive function compared to his/her earlier performance level. In the elderly, SCD may occur as a common phenomenon of regular cognitive ageing processes. However, previous studies have also shown that cognitively unimpaired individuals who experience SCD are at increased risk of future Alzheimer’s disease (AD) dementia and of having abnormal values in biomarkers indicative of AD pathology. This has led to the hypothesis that SCD may emerge as a first clinical symptom in the transient stage between a completely asymptomatic stage and a pre-dementia clinical stage of AD commonly referred to as Mild Cognitive Impairment (MCI). Importantly, individuals with pre-MCI SCD represent a particularly relevant target population for early prevention approaches as they are enriched for risk of AD but still in a disease stage where interventions might be most effective. On the other hand, the usefulness of SCD for prediction of AD has been questioned, mainly because there is little cross-sectional correlation with objective cognitive performance and, more importantly, because of potential confounding factors such as depressive symptomatology, reduced symptom awareness (in MCI), and, to a lesser degree of evidence, anxiety and personality factors. This thesis presents empirical studies which examined the significance of SCD as a predictor of incident AD dementia and of AD biomarkers in the pre-MCI and the MCI stage. Study 1 evaluated the AD dementia risk of individuals with memory related SCD in the German study on Ageing, Cognition and Dementia (AgeCoDe). Results showed that cognitively normal individuals who reported SCD in the memory domain and who had concerns related to their experienced memory decline were at a significantly elevated risk to develop AD dementia over time. Their risk was similar to that of very mildly impaired MCI patients. These results highlight the relevance of subjective memory decline to predict future dementia at the very early stage of AD. They further suggest that concerns regarding the self-experienced memory decline may be a particularly important qualitative feature of AD-related SCD. Study 2 and study 3 investigated the significance of SCD in a memory clinic sample of patients with MCI (Competence Network Dementia MCI cohort). In the MCI population, the diagnostic and prognostic relevance of SCD has been questioned as its validity may be limited due to the potential of reduced symptom awareness in patients with more advanced cognitive impairment. As a consequence, the assessment of SCD in MCI is much less elaborated compared to objective cognitive testing. However, studies 2 and 3 found quantitative and qualitative aspects (again in the form of concerns about memory decline) of SCD to be significant predictors of incident AD dementia and of abnormal AD biomarkers. Further, results suggested that the significance of SCD as a predictor of AD may indeed decrease with decreasing memory performance, thereby providing evidence of a dynamic interplay of SCD and objective cognitive impairment in AD dementia prediction. Both studies suggest that a refined and improved SCD assessment in the MCI stage could contribute to improved prediction of AD dementia and prove useful for enrichment of MCI samples for underlying AD pathology. The thesis starts with a general introduction followed by a detailed presentation of the three empirical studies. In the last section, a discussion of the studies’ contributions to the field of AD research will be outlined together with directions for future research

Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer’s Dementia in the Oldest Old

Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age

The characterisation of subjective cognitive decline

A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases

Memory Concerns, Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment

Background: Concerns about worsening memory ("memory concerns"; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI). Methods: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n=305) vs. absence (n=112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models. Results: Risk of incident AD was increased by MC (HR=2.55, 95% CI: 1.33-4.89), lower memory performance (HR=0.63, 95% CI: 0.56-0.71) and ApoE4-genotype (HR=1.89, 95% CI: 1.18-3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment. Conclusions: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum.METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid.RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.</p

Exploring the ATN classification system using brain morphology

BackgroundThe NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.MethodsWe used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-A beta 42/A beta 40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups.ResultsThe ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.ConclusionUsing the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy

Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study

BackgroundWhite matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and A beta positivity on WMH, and their impact on cognition.MethodsWe analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years;178 female;NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (Delta PACC5).ResultsSubjects with hypertension or A beta positivity presented the largest WMH volumes (p(FDR) < 0.05), with spatial overlap in the frontal (hypertension: 0.42 +/- 0.17;A beta: 0.46 +/- 0.18), occipital (hypertension: 0.50 +/- 0.16;A beta: 0.50 +/- 0.16), parietal lobes (hypertension: 0.57 +/- 0.18;A beta: 0.56 +/- 0.20), corona radiata (hypertension: 0.45 +/- 0.17;A beta: 0.40 +/- 0.13), optic radiation (hypertension: 0.39 +/- 0.18;A beta: 0.74 +/- 0.19), and splenium of the corpus callosum (hypertension: 0.36 +/- 0.12;A beta: 0.28 +/- 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (p(FDR) < 0.05). A beta positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 +/- 0.08, p(FDR) < 0.001;executive: - 0.21 +/- 0.08, p(FDR) < 0.001;PACC5: - 0.29 +/- 0.09, p(FDR) = 0.006;Delta PACC5: - 0.34 +/- 0.04, p(FDR) < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 +/- 0.02, p(FDR) = 0.029;executive: - 0.04 +/- 0.02, p(FDR) = 0.067;PACC5: - 0.05 +/- 0.02, p(FDR) = 0.030;Delta PACC5: - 0.09 +/- 0.03, p(FDR) = 0.043) and WMH in the optic radiation partially mediated that between A beta positivity and memory (indirect effect-memory: - 0.05 +/- 0.02, p(FDR) = 0.029).ConclusionsPosterior white matter is susceptible to hypertension and A beta accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

Background and ObjectivesTo determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI).MethodsThis study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-beta (A beta)42/A beta 40, phosphorylated tau (p-tau181), total tau and A beta 42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M +/- SD: 40.6 +/- 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD.ResultsIn our sample (N = 672, mean age: 70.7 +/- 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215;HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups.DiscussionOur results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD