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Background: Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

Background: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. Objective: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer’s disease (ADN). Methods: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-β)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. Results: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. Conclusion: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.

Background: The olfactory system is affected early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. Objective: The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. Methods: A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. Results: After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. Conclusion: Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.

Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n = 236 healthy controls without FHAD from the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression.

It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer's disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation. Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2-/- mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2-/- mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice. Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.

We have previously reported that the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) regulates the transcription of β-secretase (BACE1), a key enzyme involved in amyloid-β (Aβ) generation. Here, we aimed to investigate the role of PPARγ coactivator-1α (PGC-1α), which controls major metabolic functions through the co-activation of PPARγ and other transcription factors. Western blotting experiments with nuclear extracts from brain cortex of AD cases and controls showed a reduction in the levels of PGC-1α in AD patients. PGC-1α overexpression in N2a neuroblastoma cells induced a decrease in the levels of secreted Aβ and an increase in the levels of non-amyloidogenic soluble AβPPα. The decrease in Aβ after exogenous expression of PGC-1α was a consequence of reduced BACE1 expression and transcription, together with a decrease in BACE1 promoter activity. In addition, we detected a significant reduction in β-secretase activity by measuring the levels of β-carboxy terminus fragment (β-CTFs) and by using a commercial assay for β-secretase. In contrast, down-regulation of PGC-1α levels by transfection with PGC-1α siRNA increased BACE1 expression. These effects appeared to be dependent on PPARγ, because PGC-1α did not affect Aβ and BACE1 levels in N2a cells transfected with PPARγ siRNA or in PPARγ knockout fibroblasts. In conclusion, since PGC-1α appears to decrease Aβ generation, therapeutic modulation of PGC-1α could have real potential as a treatment for AD.

Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.

Diffusion tensor imaging (DTI) detects microstructural changes of the cerebral white matter in Alzheimer's disease (AD). The use of DTI for the diagnosis of AD in a multicenter setting has not yet been investigated. We used voxel-based analysis of fractional anisotropy, mean diffusivity, and grey matter volumes from multimodal magnetic resonance imaging data of 137 AD patients and 143 healthy elderly controls collected across 9 different scanners. We compared different univariate analysis approaches to model the effect of scanner, including a linear model across all scans with a scanner covariate, a random effects model with scanner as a random variable as well as a voxel-based meta-analysis. We found significant reduction of fractional anisotropy and significant increase of mean diffusivity in core areas of AD pathology including corpus callosum, medial and lateral temporal lobes, as well as fornix, cingulate gyrus, precuneus, and prefrontal lobe white matter. Grey matter atrophy was most pronounced in medial and lateral temporal lobe as well as parietal and prefrontal association cortex. The effects of group were spatially more restricted with random effects modeling of scanner effects compared to simple pooled analysis. All three analysis approaches yielded similar accuracy of group separation in block-wise cross-validated logistic regression. Our results suggest similar effects of center on group separation based on different analysis approaches and confirm a typical pattern of cortical and subcortical microstructural changes in AD using a large multimodal multicenter data set.

Background Smoking has been found associated with decreased cerebral volumes in healthy adults and in various neuropsychiatric disorders. Objective We aimed to determine whether chronic nicotine exposure through smoking is associated with reduced volume of cortically projecting cholinergic basal forebrain nuclei in healthy aging, mild cognitive impairment (MCI), and dementia stages of Alzheimer's disease (AD). Methods We retrieved cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database including 179 cognitively normal elderly subjects, 270 subjects with early stage MCI, 136 subjects in later, more advanced, stage of MCI, and 86 subjects in dementia stages of AD. We determined the association between past or current smoking versus lifetime non-smoker status on the volumes of the basal forebrain determined from volumetric MRI scans. Hippocampus volume was used as a control region. Significant effects were controlled for mediating or moderating effects of respiratory and cardiovascular morbidity. Results In cognitively healthy individuals and early MCI, past or current smoking was significantly associated with smaller basal forebrain volume. This effect was independent from age, sex, or cardiovascular or respiratory morbidity. Hippocampus volume was not associated with smoking. In late MCI and AD dementia, smoking was not associated with basal forebrain or hippocampus volumes. Conclusions Our findings suggest that chronic nicotine exposure through smoking may lead to atrophy of cholinergic input areas of the basal forebrain. This effect may account for an increased risk of AD dementia onset with smoking by exhausting the cholinergic system reserve capacity.

Voxel-based morphometry (VBM) and cortical thickness measurement are common techniques to identify regional atrophy in neurodegenerative diseases such as Alzheimer's disease (AD). Because studies employing these methods draw conclusions regarding patterns of regional cortical degeneration, it is important to be aware of their possible limitations. To evaluate the effect of different VBM versions, we performed voxel-based analyses through successive versions-from SPM99 to SPM8-as well as FSL-VBM on n = 20 AD patients and n = 20 controls. Reproducibility was assessed in an independent sample, again of n = 20 per group, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Further, we tested the hypothesis that VBM can sensitively detect hippocampal atrophy, but is relatively insensitive to changes in the cortical ribbon, by contrasting VBM with FreeSurfer cortical thickness measurements. The results with both datasets confirmed that VBM preferentially identifies grey matter lesions in the mesial temporal lobe but is largely insensitive to isocortical atrophy. In contrast, FreeSurfer identified thinning of cortical ribbon association cortex more significant in post- rather than pre-Rolandic areas and with relative preservation of primary sensory-motor regions-in other words precisely as would be expected in AD. The results highlight a bias that VBM has toward detecting mesial temporal lobe atrophy. This finding has important implications for interpretation of clinical and cognitive studies in AD.

Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination (MMSE) score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score ≤ 4 after one year; n = 28) (fast versus slow cognitive decline: mean ± SD: 1051.1 ± 178.7 versus 1237.9 ± 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis.

The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N = 24) or mild AD (N = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD.

In vivo imaging of amyloid-β (Aβ) load as a biomarker of Alzheimer's disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AβPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AβPP/PS1 mice present with rapid-onset cerebral β-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aβ-deposition in brain. Data were analyzed with a novel automated voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AβPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aβ plaques and activated microglia. Grey matter density did not differ between wild-type mice and AβPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies.