Alzheimer’s disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

Sex differences in the human olfactory function reportedly exist for olfactory sensitivity, odorant identification and memory, and tasks in which odors are rated based on psychological features such as familiarity, intensity, pleasantness, and others. Which might be the neural bases for these behavioral differences? The number of cells in olfactory regions, and especially the number of neurons, may represent a more accurate indicator of the neural machinery than volume or weight, but besides gross volume measures of the human olfactory bulb, no systematic study of sex differences in the absolute number of cells has yet been undertaken. In this work, we investigate a possible sexual dimorphism in the olfactory bulb, by quantifying postmortem material from 7 men and 11 women (ages 55–94 years) with the isotropic fractionator, an unbiased and accurate method to estimate absolute cell numbers in brain regions. Female bulbs weighed 0.132 g in average, while male bulbs weighed 0.137 g, a non-significant difference; however, the total number of cells was 16.2 million in females, and 9.2 million in males, a significant difference of 43.2%. The number of neurons in females reached 6.9 million, being no more than 3.5 million in males, a difference of 49.3%. The number of non-neuronal cells also proved higher in women than in men: 9.3 million and 5.7 million, respectively, a significant difference of 38.7%. The same differences remained when corrected for mass. Results demonstrate a sex-related difference in the absolute number of total, neuronal and non-neuronal cells, favoring women by 40–50%. It is conceivable that these differences in quantitative cellularity may have functional impact, albeit difficult to infer how exactly this would be, without knowing the specific circuits cells make. However, the reported advantage of women as compared to men may stimulate future work on sex dimorphism of synaptic microcircuitry in the olfactory bulb.

Objective: Higher late life body mass index (BMI) is unrelated to or even predicts lower risk of dementia in late life, a phenomenon that may be explained by reverse causation due to weight loss during preclinical phases of dementia. We aim to investigate the association of baseline BMI and changes in BMI with dementia in a large prospective cohort, and to examine whether weight loss predicts cognitive function. Methods: Using a national cohort of adults average age 58 years at baseline in 1994 (n=7029), we investigated the associations between baseline BMI in 1994 and memory scores from 2000 to 2010. We also examined the association of BMI change from 1994 to 1998 with memory scores from 2000 to 2010. Last, to investigate reverse causation, we examined whether memory scores in 1996 predicted BMI trajectories from 2000 to 2010. Results: Baseline overweight predicted better memory scores 6 to 16 years later (β=0.012, 95% confidence interval (CI)=0.001; 0.023). Decline in BMI predicted lower memory scores over the subsequent 12 years (β=−0.026, 95% CI= −0.041; −0.011). Lower memory scores at mean age 60 years in 1996 predicted faster annual rate of BMI decline during follow-up (β=−0.158 kg m⁻² per year, 95% CI= −0.223; −0.094). Conclusion: Consistent with reverse causation, greater decline in BMI over the first 4 years of the study was associated with lower memory scores over the next decade and lower memory scores was associated with a decline in BMI. These findings suggest that preclinical dementia predicts weight loss for people as early as their late 50s.

Hypertension, particularly in middle age, has been associated with worse cognitive function, but evidence is inconclusive. This study investigated whether hypertension, prehypertension, age, and duration of diagnosis, as well as blood pressure control, are associated with a decline in cognitive performance in ELSA-Brasil participants. This longitudinal study included 7063 participants, mean age 58.9 years at baseline (2008–2010), who attended visit 2 (2012–2014). Cognitive performance was measured in both visits and evaluated by the standardized scores of the memory, verbal fluency, trail B tests, and global cognitive score. The associations were investigated using linear mixed models. Hypertension and prehypertension at baseline were associated with decline in global cognitive score; being hypertension associated with reduction in memory test; and prehypertension with reduction in fluency test. Hypertension diagnose ≥55 years was associated with lower global cognitive and memory test scores, and hypertension diagnose <55 years with lower memory test scores. Duration of hypertension diagnoses was not associated with any marker of cognitive function decline. Among treated individuals, blood pressure control at baseline was inversely associated with the decline in both global cognitive and memory test scores. In this relatively young cohort, hypertension, prehypertension, and blood pressure control were independent predictors of cognitive decline in distinct abilities. Our findings suggest that both lower and older age of hypertension, but not duration of diagnosis, were associated with cognitive decline in different abilities. In addition to hypertension, prehypertension and pressure control might be critical for the preservation of cognitive function.

Argyrophilic grain disease (AGD) is a frequent late-onset, 4-repeat tauopathy reported in Caucasians with high educational attainment. Little is known about AGD in non-Caucasians or in those with low educational attainment. We describe AGD demographics, clinical, and neuropathological features in a multiethnic cohort of 983 subjects ≥50 years of age from São Paulo, Brazil. Clinical data were collected through semistructured interviews with an informant and included in the Informant Questionnaire on Cognitive Decline in the Elderly, the Clinical Dementia Rating, and the Neuropsychiatric Inventory. Neuropathologic assessment relied on internationally accepted criteria. AGD was frequent (15.2%) and was the only neuropathological diagnosis in 8.9% of all cases (mean, 78.9 ± 9.4 years); it rarely occurred as an isolated neuropathological finding. AGD was associated with older age, lower socioeconomic status (SES), and appetite disorders. This is the first study of demographic, clinical, and neuropathological aspects of AGD in different ethnicities and subjects from all socioeconomic strata. The results suggest that prospective studies of AGD patients include levels of hormones related to appetite control as possible antemortem markers. Moreover, understanding the mechanisms behind higher susceptibility to AGD of low SES subjects may disclose novel environmental risk factors for AGD and other neurodegenerative diseases.