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Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

INTRODUCTIONThe reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.METHODSWe assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use in 1870 participants in a multiethic study of aging and dementia.RESULTSReliability of self-reported for hypertension, diabetes, and heart disease was excellent. Agreement between self-reports and clinical measures was moderate for hypertension (kappa: 0.58), good for diabetes (kappa: 0.76-0.79), and moderate for heart disease (kappa: 0.45) differing slightly by age, sex, education, and race/ethnic group. Sensitivity and specificity for hypertension was 88.6%-78.1%, for diabetes was 87.7%-92.0% (HbA1c>6.5%) or 92.7%-92.8% (HbA1c>7%), and for heart disease was 85.8%-75.5%.DISCUSSIONSelf-reported history of hypertension, diabetes, and heart disease are reliable and valid compared to direct measurements or medication use.

ImportanceCerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.ObjectiveTo assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.Design, Setting, and ParticipantsIn this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023.Main Outcomes and MeasuresMain outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests.ExposuresExposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index.ResultsThis study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD.Conclusions and RelevanceIn this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort.GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.

In order to examine the effect of adrenergic influences on pancreatic polypeptide (PP) secretion, a series of insulin tolerance tests was carried out in five normal volunteers. Control ITT's, as well as ITT's following pretreatment with oral cyproheptadine (4 mg q 6 hr for 48 hr ITT-cyp), and intravenous phentolamine (5 mg stat, then 0.5 mg/min for 120 min, ITT-phe), and propranolol (3 mg stat, then 0.08 mg/min for 120 min, ITT-pro), were performed. Alpha blockade established during ITT-phe augmented the peak PP concentration after insulin from 1470 ± 472 to 2684 ± 840 pg/ml (p

Piperidine, a nicotinic cholinergic receptor stimulator, was used in paired design studies of sleep-related and insulin-induced GH and PRL secretion. For the sleep studies, 100 mg piperidine or an equal volume of saline were infused for 30 min starting at sleep onset in eight normal volunteers. The same dose of piperidine was infused for 30 min (beginning 15 min before insulin injection) in an additional eight volunteers undergoing insulin tolerance tests. After piperidine administration, there was a significant (P less than 0.01) enhancement of sleep-related GH secretion, abut no change in PRL. GH concentrations during the first 2 h of sleep were 7.2 +/- 1.2 ng/ml after saline and 15.2 +/-2.9 ng/ml after piperidine (P less than 0.01). No alteration in any measured sleep parameter was noted with the drug. Piperidine did not affect the daytime insulin-induced secretion of either GH or PRL, as assessed by an analysis of variance. However, paired analysis of increments and areas under the response curves indicated a statistically significant effect for GH but not PRL. The maximum GH increment with piperidine was 48.0 +/- 4.3 ng/ml, compared to 36.8 +/- 3.6 ng/ml with saline (P less than 0.01). Piperidine given alone did not influence daytime concentrations of GH. These data are consistent with the view proposed by us, on the bass of methoscopolamine inhibition of nocturnal GH secretion, that cholinergic pathways play a facilitatory role in sleep-related and insulin-induced GH secretion. Thus, cholinergic mechanisms stimulate GH secretion. Nicotinic as well as muscarinic pathways appear to be involved, although the quantitative nicotinic contribution seems to be smaller than the associated with muscarinic sites.

Previous studies have shown that the infusion of dopamine (DA; 4 µg/kg-min) both stimulates GH secretion and abolishes the GH response to hypoglycemia when insulin (0.1 U/kg) is given 30 min after the start of the infusion. Additional studies on the mechanism of this inhibitory effect are now reported. When insulin was given to seven normal male volunteers 15 min before the start of the DA infusion, the maximal GH increment (44.7 ± 5.7 ng/ml) was comparable to insulin alone (45.5 ± 5.3 ng/ml), and both were greater than the maximum increment when insulin was given 30 or 120 min into the DA infusion (17.3 ± 3.3 and 23.0 ± 7.4 ng/ml, respectively; P < 0.05). In contrast, DA potently inhibited PRL secretion regardless of the timing of DA and insulin; PRL fell during all DA plus insulin studies despite a maximal PRL increment after insulin alone of 24.4 ± 6.0 ng/ml. The GH response to 500 mg L-dopa given orally was inhibited by DA in a fashion similar to the insulin response. Thus, when L-dopa was given to si...

The influence of short term, high dose glucocorticoids on pancreatic polypeptide (PP), GH, and PRL responses to insulin-induced hypoglycemia was studied in normal young men. Subjects underwent insulin tolerance tests before (ITTb) and on the fifth day (ITT5) of treatment with prednisone (25 mg orally twice daily) and again 2 (ITT7) and 5 (ITT10) days after termination of prednisone therapy. Eleven subjects completed ITTh, ITT7) and ITT10. Five of these underwent ITT5. Despite the more pronounced hypoglycemia associated with the higher insulin dose used during prednisone treatment, PP responses were significantly diminished. Basal PP was reduced from 92.7 ± 13 to 38.6 ± 5.7 pg/ml (P < 0.05) at the time of ITT5 and returned to pretreatment values at the time of ITT7. The peak pretreatment PP concentration of 1328 ± 203 pg/ml was reduced to 584 ± 118 (P < 0.05) during ITT5, and after discontinuation of prednisone returned progressively to pretreatment values. A more marked suppression was evident from compar...