The occurrence of obesity, commonly estimated using body mass index (BMI), and the most common late-onset dementia, Alzheimer's disease (AD), are increasing globally. The year 2013 marked a decade of epidemiologic observational reports on the association between BMI and late-onset dementias. In this review, we highlight epidemiological studies that measured both mid- and late-life BMI in association with dementia. Studies investigating the association between midlife BMI and risk for dementia demonstrated generally an increased risk among overweight and obese adults. When measured in late-life, elevated BMI has been associated with lower risk. In addition, being underweight and/or having a decrease in BMI in late-life are associated with higher dementia risk compared to BMI in the normal range or stable BMI. In this review, a decade (2003-2013) of epidemiologic observational studies on associations between BMI and AD is highlighted. These observations provide a strong base for addressing biological mechanisms underlying this complex association.

Background/PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous case-reports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.Methods/ResultsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.Eight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (ALT/AST/aPTT) improved or normalized already using 1g/kg/day D-gal. Antithrombin-III levels and Transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal LLO-profile, and abnormal nucleotide-sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment.ConclusionD-gal increased both UDP-Glc and UDP-gal levels and improved LLO fractions in concert with improved glycosylation in PGM1-CDG. Oral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer duration trials are ongoing.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER-and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.

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It is well established that the cholesterol-transporter apolipoprotein (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of 4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock-out (KO) mice at 12 (adult) and 18 months of age.Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research.