Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable.

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer's disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases.

Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer's disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD).

Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.

Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes.

Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD.

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment.

To 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).

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.

We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age.

We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a 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.

Neuroinflammation constitutes a pathological hallmark of Alzheimer's disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.