Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub

Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub

The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology

Longitudinal trajectories of cognitive reserve in hypometabolic subtypes of Alzheimer's disease

Previous studies have demonstrated resilience to AD-related neuropathology in a form of cognitive reserve (CR). In this study we investigated a relationship between CR and hypometabolic subtypes of AD, specifically the typical and the limbic-predominant subtypes. We analyzed data from 59 A beta-positive cognitively normal (CN), 221 prodromal Alzheimer's disease (AD) and 174 AD dementia participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) from ADNI and ADNIGO/2 phases. For replication, we analyzed data from 5 A beta positive CN, 89 prodromal AD and 43 AD dementia participants from ADNI3. CR was estimated as standardized residuals in a model predicting cognition from temporoparietal grey matter volumes and covariates. Higher CR estimates predicted slower cognitive decline. Typical and limbic-predominant hypometabolic subtypes demonstrated similar baseline CR, but the results suggested a faster decline of CR in the typical subtype. These findings support the relationship between subtypes and CR, specifically longitudinal trajectories of CR. Results also underline the importance of longitudinal analyses in research on CR

Left frontal cortex connectivity underlies cognitive reserve in prodromal Alzheimer disease

Objective: To test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory. Methods: Forty-four amyloid-PET-positive patients with amnestic mild cognitive impairment (MCI-A beta 1) and 24 amyloid-PET-negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Ab1, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity 3 FDG-PET hypometabolism on episodic memory were tested. Results: FDG-PET metabolism in the precuneus was reduced in MCI-A beta 1 compared to HC (p = 0.028), with stronger reductions observed in MCI-A beta 1 with more years of education (p = 0.006). In MCI-A beta 1, higher gLFC connectivity was associated with more years of education (p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated (p = 0.027). Conclusions: Higher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in earlystage AD

Cognitive Reserve Moderates the Association between Functional Network Anti-Correlations and Memory in MCI

Cognitive reserve (CR) shows protective effects on cognitive function in older adults. Here, we focused on the effects of CR at the functional network level. We assessed in patients with amnestic mild cognitive impairment (aMCI) whether higher CR moderates the association between low internetwork cross-talk on memory performance. In 2 independent aMCI samples (n = 76 and 93) and healthy controls (HC, n = 36), CR was assessed via years of education and intelligence (IQ). We focused on the anti-correlation between the dorsal attention network (DAN) and an anterior and posterior default mode network (DMN), assessed via sliding time window analysis of resting-state functional magnetic resonance imaging (fMRI). The DMN-DAN anti-correlation was numerically but not significantly lower in aMCI compared to HC. However, in aMCI, lower anterior DMN-DAN anti-correlation was associated with lower memory performance. This association was moderated by CR proxies, where the association between the internetwork anti-correlation and memory performance was alleviated at higher levels of education or IQ. In conclusion, lower DAN-DMN cross-talk is associated with lower memory in aMCI, where such effects are buffered by higher CR

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer\u27s disease

Patients with Alzheimer\u27s 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\u27s 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\u27s 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\u27s 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\u27s disease, 55 controls from the Dominantly Inherited Alzheimer\u27s 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\u27s 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\u27s disease and cerebrospinal fluid tau levels in sporadic Alzheimer\u27s disease cases. In both autosomal dominant and sporadic Alzheimer\u27s disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer\u27s 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\u27s 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\u27s disease is at least partially attributable to higher left frontal cortex-hub connectivity

Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

BACKGROUND To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. METHODS In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and \~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(-) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI-IV+/BraakI-VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. RESULTS Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen's d \~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. CONCLUSION Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings

KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia

sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta‐amyloid (CSF Aβ1‐42) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau181, and FDG‐PET. To determine disease stage, we stratified participants into early Aβ‐accumulators (Aβ CSF+/PET−; n = 70) or late Aβ‐accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ‐accumulators, higher centiloid was associated with cross‐sectional/longitudinal sTREM2 and p‐tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau181 increases and higher sTREM2 was associated with FDG‐PET hypermetabolism. In late Aβ‐accumulators, we found no association between centiloid and sTREM2 but a cross‐sectional association between higher sTREM2, higher p‐tau181 and glucose hypometabolism. Our findings suggest that a TREM2‐related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p‐tau181 increases in earliest AD