Neurodegenerative disease is highly prevalent among older adults and, if undetected, may obscure estimates of cognitive change among aging samples. Our aim in this study was to determine the nature ...and magnitude of cognitive change in the absence of common neuropathologic markers of neurodegenerative disease. Cognitively normal older adults (ages 65–89 years, N = 199) were classified as normal or abnormal using neuroimaging and cerebrospinal-fluid biomarkers of β-amyloid, tau, and neurodegeneration. When cognitive change was modeled without accounting for biomarker status, significant decline was evident for semantic memory, processing speed, and working memory. However, after adjusting for biomarker status, we found that the rate of change was attenuated and that the biomarker-normal group demonstrated no decline for any cognitive domain. These results indicate that estimates of cognitive change in otherwise healthy older adults will be biased toward decline when the presence of early neurodegenerative disease is not accounted for.
Altered blood flow in the human brain is characteristic of typical aging. However, numerous factors contribute to inter-individual variation in patterns of blood flow throughout the lifespan. To ...better understand the mechanisms behind such variation, we studied how sex and APOE genotype, a primary genetic risk factor for Alzheimer's disease (AD), influence associations between age and brain perfusion measures. We conducted a cross-sectional study of 562 participants from the Human Connectome Project - Aging (36 to >90 years of age). We found widespread associations between age and vascular parameters, where increasing age was associated with regional decreases in cerebral blood flow (CBF) and increases in arterial transit time (ATT). When grouped by sex and APOE genotype, interactions between group and age demonstrated that females had relatively greater CBF and lower ATT compared to males. Females carrying the APOEε4 allele showed the strongest association between CBF decline and ATT incline with age. This demonstrates that sex and genetic risk for AD modulate age-associated patterns of cerebral perfusion measures.
Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic ...and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.
The apolipoprotein E ε4 allele (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 may have effects on cognition and brain atrophy years before the onset of ...symptomatic AD. We analyzed the effects of APOE4 in a unique cohort of young adults who had undergone comprehensive assessments as part of the Dominantly Inherited Alzheimer Network (DIAN), an international longitudinal study of individuals from families with autosomal dominant AD. We analyzed the effect of an APOE4 allele on cognitive measures, volumetric MRI, amyloid deposition, glucose metabolism, and on cerebrospinal fluid levels of AD biomarkers in 162 participants that did not carry the mutant gene (noncarriers). APOE4+ and APOE4− mutation noncarriers had similar performance on cognitive measures. Amyloid deposition began at an earlier age in APOE4+ participants, whereas hippocampal volume was similar between the groups. These preliminary findings are consistent with growing evidence that the APOE4 allele may exert effects in midlife years before symptom onset, promoting amyloid deposition before altering cognitive performance or brain structure.
•A single APOE4 allele does not affect cognitive measures in people aged 19–69 years.•A single APOE4 allele does not affect structural or imaging measures in people aged 19–69 years.•An APOE4 allele does affect amyloid deposition with age in people aged 19–69 years.•An APOE4 allele may accelerate amyloid deposition, possibly beginning as early as the 30–40 years of age.
We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset ...Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.
Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very ...small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09 × 10⁻⁵; OR = 2.21; 95%CI = 1.49-3.28) or an unselected population of 12,481 samples (p = 6.82 × 10⁻⁵; OR = 2.19; 95%CI = 1.347-3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due ...to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.
Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression ...is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
Synopsis
Neuroinflammation and microgliosis are key pathological features of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) protein levels analysis in large AD patients' cohorts reveals that CSF levels of Progranulin (PGRN) together with soluble TREM2 may serve as a microglia activity marker in AD.
CSF PGRN increases in carriers of autosomal‐dominant AD from the Dominant Inherited Alzheimer's Disease Network (DIAN), causing dominant mutations 10 years before the expected symptom onset.
CSF PGRN increases in late‐onset AD patients from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort during the course of the disease and is associated with cognitive decline.
CSF PGRN and CSF soluble TREM2 (sTREM2), both of which have key regulatory functions in microglia, are associated specifically when there is underlying neurodegeneration.
CSF PGRN together with CSF sTREM2 may serve as microglial activity markers and could be used to prove target engagement in clinical trials aiming to modulate microglial activity.
Neuroinflammation and microgliosis are key pathological features of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) protein levels analysis in large AD patients' cohorts reveals that CSF levels of Progranulin (PGRN) together with soluble TREM2 may serve as a microglia activity marker in AD.
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