The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans ( = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults. Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

IMPORTANCE Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease.OBJECTIVE To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured athome sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (β = 0.41, p = 0.007) and lower MD (β =-0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

The small EDRK-rich factor 2 (SERF2) is a highly conserved protein that modifies amyloid fibre assembly in vitro and promotes protein misfolding. However, the role of SERF2 in regulating age-related proteotoxicity remains largely unexplored due to a lack of in vivo models. Here, we report the generation of Serf2 knockout mice using an ES cell targeting approach, with Serf2 knockout alleles being bred onto different defined genetic backgrounds. We highlight phenotyping data from heterozygous Serf2+/− mice, including unexpected male-specific phenotypes in startle response and pre-pulse inhibition. We report embryonic lethality in Serf2−/− null animals when bred onto a C57BL/6 N background. However, homozygous null animals were viable on a mixed genetic background and, remarkably, developed without obvious abnormalities. The Serf2 knockout mice provide a powerful tool to further investigate the role of SERF2 protein in previously unexplored pathophysiological pathways in the context of a whole organism.

Objective: To investigate associations between peripheral innate immune activation and frontotemporal lobar degeneration (FTLD) in progranulin gene (GRN) haploinsufficiency.Methods: In this cross-sectional study, ELISA was used to measure six markers of innate immunity (sCD163, CCL18, LBP, sCD14, IL-18, and CRP) in plasma from 30 GRN mutation carriers (17 asymptomatic, 13 symptomatic) and 29 controls. Voxel based morphometry was used to model associations between marker levels and brain atrophy in mutation carriers relative to controls. Linear regression was used to model relationships between plasma marker levels with mean frontal white matter integrity [fractional anisotropy (FA)] and the FTLD modified Clinical Dementia Rating Scale sum of boxes score (FTLD-CDR SB).Results: Plasma sCD163 was higher in symptomatic GRN carriers [mean 321 ng/ml (SD 125)] compared to controls [mean 248 ng/ml (SD 58); p < 0.05]. Plasma CCL18 was higher in symptomatic GRN carriers [mean 56.9 pg/ml (SD 19)] compared to controls [mean 40.5 pg/ml (SD 14); p < 0.05]. Elevation of plasma LBP was associated with white matter atrophy in the right frontal pole and left inferior frontal gyrus (p FWE corrected <0.05) in all mutation carriers relative to controls. Plasma LBP levels inversely correlated with bilateral frontal white matter FA (R2 = 0.59, p = 0.009) in mutation carriers. Elevation in plasma was positively correlated with CDR-FTLD SB (b = 2.27 CDR units/μg LBP/ml plasma, R2 = 0.76, p = 0.003) in symptomatic carriers.Conclusion: FTLD-GRN is associated with elevations in peripheral biomarkers of macrophage-mediated innate immunity, including sCD163 and CCL18. Clinical disease severity and white matter integrity are correlated with blood LBP, suggesting a role for peripheral immune activation in FTLD-GRN.

Objective: White matter (WM) microstructure changes are increasingly recognized as a mechanism of age-related cognitive differences. This study examined the associations between patterns of WM microstructure and cognitive performance on the University of California, San Francisco (UCSF) Brain Health Assessment (BHA) subtests of memory (Favorites), executive functions and speed (Match), and visuospatial skills (Line Orientation) within a sample of older adults. Method: Fractional anisotropy (FA) in WM tracts and BHA performance were examined in 84 older adults diagnosed as neurologically healthy (47), with mild cognitive impairment (19), or with dementia (18). The relationships between FA and subtest performances were evaluated using regression analyses. We then explored whether regional WM predicted performance after accounting for variance explained by global FA. Results: Memory performance was associated with FA of the fornix and the superior cerebellar peduncle, and executive functions and speed with the body of the corpus callosum. The fornix – memory association, and the corpus callosum – executive association, remained significant after accounting for global FA. Neither tract-based nor global FA was associated with visuospatial performance. Conclusions: Memory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age-and-disease-related cognitive decline.

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer's disease in these individuals. Here we use a combination of nextgeneration mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp( 17)3Yey) and a knockin mouse model of amyloid-β accumulation (App NL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS, compared to those who have familial AD caused by triplication of APP.