Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia.

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection.

Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer's Disease Dementia: Evidence for Dependency on Alzheimer's Disease Neuropathological Changes.

Autopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cerebrovascular disease, including white matter rarefaction (WMR) and cerebral infarcts. Comorbidities may interfere with ADD therapeutic trials evaluation of ADD clinical trials as they may not respond to AD-specific molecular therapeutics. It is possible, however, that at least some comorbidities may be, to some degree, secondary consequences of AD pathology, and if this were true then effective AD-specific therapeutics might also reduce the extent or severity of comorbid pathology. Comorbidities in ADD caused by autosomal dominant mutations such as those in the presenilin-1 (PSEN1) gene may provide an advantageous perspective on their pathogenesis, and deserve attention because these subjects are increasingly being entered into clinical trials. As ADD associated with PSEN1 mutations has a presumed single-cause etiology, and the average age at death is under 60, any comorbidities in this setting may be considered as at least partially secondary to the causative AD mechanisms rather than aging, and thus indicate whether effective ADD therapeutics may also be effective for comorbidities. In this study, we sought to compare the rates and types of ADD comorbidities between subjects with early-onset sporadic ADD (EOSADD; subjects dying under age 60) versus ADD associated with different types of PSEN1 mutations, the most common cause of early-onset autosomal dominant ADD. In particular, we were able to ascertain, for the first time, the prevalences of a fairly complete set of ADD comorbidities in United States (US) PSEN1 cases as well as the Colombian E280A PSEN1 kindred. Data for EOSADD and US PSEN1 subjects (with multiple different mutation types) was obtained from the National Alzheimer Coordinating Center (NACC). Colombian cases all had the E280A mutation and had a set of neuropathological observations classified, like the US cases according to the NACC NP10 definitions. Confirmatory of earlier reports, NACC-defined Alzheimer Disease Neuropathological Changes (ADNC) were consistently very severe in early-onset cases, whether sporadic or in PSEN1 cases, but were slightly less severe in EOSADD. Amyloid angiopathy was the only AD-associated pathology type with widely-differing severity scores between the 3 groups, with median scores of 3, 2 and 1 in the PSEN1 Colombia, PSEN1 US and EOSADD cases, respectively. Apoliprotein E genotype did not show significant proportional group differences for the possession of an E-4 or E-2 allele. Of ADD comorbidities, LBD was most common, being present in more than half of all cases in all 3 groups. For TDP-43 co-pathology, the Colombian PSEN1 group was the most affected, at about 27%, vs 16% and 11% for the US PSEN1 and sporadic US cases, respectively. Notably, hippocampal sclerosis and non-AD tau pathological conditions were not present in any of the US or Colombian PSEN1 cases, and was seen in only 3% of the EOSADD cases. Significant large-vessel atherosclerosis was present in a much larger percentage of Colombian PSEN1 cases, at almost 20% as compared to 0% and 3% of the US PSEN1 and EOSADD cases, respectively. Small-vessel disease, or arteriolosclerosis, was much more common than large vessel disease, being present in all groups between 18% and 37%. Gross and microscopic infarcts, however, as well as gross or microscopic hemorrhages, were generally absent or present at very low percentages in all groups. White matter rarefaction (WMR) was remarkably common, at almost 60%, in the US PSEN1 group, as compared to about 18% in the EOSADD cases, a significant difference. White matter rarefaction was not assessed in the Colombian PSEN1 cases. The results presented here, as well as other evidence, indicates that LBD, TDP-43 pathology and WMR, as common comorbidities with autosomal dominant and early-onset sporadic ADD, should be considered when planning clinical trials with such subjects as they may increase variability in response rates. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease.

We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRß AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aß-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.

Reactive Astrocytes Contribute to Alzheimer's Disease-Related Neurotoxicity and Synaptotoxicity in a Neuron-Astrocyte Co-culture Assay.

Pathological hallmarks of Alzheimer's disease (AD) include deposition and accumulation of amyloid- ß (Aß), neurofibrillary tangle formation, and neuronal loss. Pathogenesis of presymptomatic disease stages remains elusive, although studies suggest that the early structural and functional alterations likely occur at neuronal dendritic spines. Presymptomatic alterations may also affect different CNS cell types. However, specific contributions of these cell types as cause or consequence of pathology are difficult to study in vivo. There is a shortage of relatively simple, well-defined, and validated in vitro models that allow a straightforward interpretation of results and recapitulate aspects of pathophysiology. For instance, dissecting the AD-related processes (e.g., neurotoxicity vs. synaptotoxicity) may be difficult with the common cell-based systems such as neuronal cell lines or primary neurons. To investigate and characterize the impact of reactive astrocytes on neuronal morphology in the context of AD-related cues, we modified an in vitro co-culture assay of primary mouse neurons and primary mouse astrocytes based on the so-called Banker "sandwich" co-culture assay. Here, we provide a simple and modular assay with fully differentiated primary mouse neurons to study the paracrine interactions between the neurons and the astrocytes in the co-culture setting. Readouts were obtained from both cell types in our assay. Astrocyte feeder cells were pre-exposed to neuroinflammatory conditions by means of Aß42, Aß40, or lipopolysaccharide (LPS). Non-cell autonomous toxic effects of reactive astrocytes on neurons were assessed using the Sholl analysis to evaluate the dendritic complexity, whereas synaptic puncta served as a readout of synaptotoxicity. Here, we show that astrocytes actively contribute to the phenotype of the primary neurons in an AD-specific context, emphasizing the role of different cell types in AD pathology. The cytokine expression pattern was significantly altered in the treated astrocytes. Of note, the impact of reactive astrocytes on neurons was highly dependent on the defined cell ratios. Our co-culture system is modular, of low cost, and allows us to probe aspects of neurodegeneration and neuroinflammation between the two major CNS cell types, neurons, and astrocytes, under well-defined experimental conditions. Our easy-to-follow protocol, including work-flow figures, may also provide a methodological outline to study the interactions of astrocytes and neurons in the context of other diseases in the future.