Alzheimer’s disease (AD) is traditionally thought of as a neurodegenerative disease. Recent evidence shows that beta amyloid-independent vascular changes and beta amyloid-dependent neuronal dysfunction both equally influence the disease, leading to loss of structural and functional connectivity. White matter changes (WMCs) in the brain are commonly observed in dementia patients. The effect of vascular factors on WMCs and the relationship between WMCs and severity of AD in patients remain to be clarified. We recruited 501 clinically diagnosed probable AD patients with a series of comprehensive neuropsychological tests and brain imaging. The WMCs in cerebral CT or MRI were rated using both the modified Fazekas scale and the combined CT-MRI age related WMC (ARWMC) rating scale. Periventricular WMCs were observed in 79.4% of the patients and deep WMCs were also seen in 48.7% of the patients. WMC scores were significantly higher in the advanced dementia stage in periventricular WMCs (p = 0.001) and total ARWMCs (p < 0.001). Age and disease severity were both independently associated with WMCs score, particularly in the total, frontal and parieto-occipital areas. Vascular factors including hypertension, diabetes mellitus, and gender were not significantly associated with WMCs. In conclusion, both age and severity of dementia were significantly associated with WMCs in AD patients. These associations highlight future research targets.

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase–containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase–containing neurons but not pyramidal neurons of the hippocampus.

Obstructive sleep apnea (OSA) has been associated with cognitive decline via several mechanisms, including intermittent hypoxemia, sleep fragmentation, and neuroinflammation. The neurological consequences of OSA have evolved into a major biopsychosocial concern in the elderly, especially memory impairment. We aimed to identify the polysomnographic (PSG) parameters capable of predicting memory impairment among OSA patients at or over age 50 with OSA. We reviewed the 10-year electronic medical records of OSA patients and compared the initial PSG parameters between those presenting and not presenting self-reported memory impairment. We conducted subgroup analyses based on OSA severity and performed multivariate analysis to correlate PSG parameters with memory impairment. The result showed that 25 out of the 156 (16%) investigated patients experienced self-reported memory impairment during follow-up. As compared to OSA patients without self-reported memory impairment, those reported with self-reported memory impairment had a higher oxygen desaturation index (ODI) (23.9 ± 17.8 versus 18.2 ± 12.0, p = 0.048). Regarding the associations between apnea-hypopnea index (AHI) as well as ODI and self-reported memory impairment among OSA subgroups classified by severity, the associations were only evident in the severe OSA subgroup in both univariate (p < 0.001; p = 0.005) and multivariate analyses (p = 0.014; p = 0.018). We concluded that AHI and ODI are the most relevant PSG parameters in predicting memory impairment in severe OSA patients.

Electronegative low-density lipoprotein (L5-LDL) drives vascular injury in metabolic syndrome (MetS), yet its hepatic origin remains undefined. Here, we identify a lysophosphatidylcholine (LPC)-hypoxia-inducible factor-1α (HIF-1α) axis that governs apolipoprotein E (apoE) glycosylation and lipoprotein electronegativity. LPC activates HIF-1α in hepatocytes, inducing polypeptide N-acetylgalactosaminyltransferase (GALNT2) and ST3 β-galactodise α-2,3-sialyltransferase 1 (ST3GAL1) to promote apoE O-glycosylation and sialylation. This remodeling redirects lipoprotein uptake from the LDL receptor (LDLR) to lectin-like oxidized LDL receptor-1 (LOX-1), facilitating the formation of electronegative very low-density lipoprotein (V5-VLDL) and L5-LDL. Consistently, V5-VLDL from MetS subjects exhibits hyperglycosylated apoE mirroring L5-LDL. Disruption of this pathway attenuates apoE modification and LOX-1 engagement. These findings establish a mechanistic link between hepatic lipid remodeling and vascular inflammation and suggest a therapeutic strategy for targeting residual cardiovascular risk.

The genetic architecture of Parkinson's disease (PD) and progression to PD dementia (PDD) remains incompletely characterized in Asians. Here, we investigated genetic risk factors for PD and PDD in Taiwanese individuals from the Taiwan Precision Medicine Initiative (TPMI), the largest non-European cohort integrating genetic and electronic medical record data. We conducted a two-stage population-based case–control genome-wide association study (GWAS) with a 1:10 case-to-control ratio. Results were meta-analyzed with an independent Asian GWAS. We further constructed a polygenic risk score (PRS) to distinguish PD cases from controls. PDD risk was assessed using logistic regression and Cox models, with replication in an independent cohort that underwent whole-genome sequencing (WGS). Among 463,447 TPMI participants, 4381 PD patients and 43,810 controls were analysed. We confirmed established PD loci at SNCA and LRRK2, and identified additional risk variants near HLA, AOAH–ELMO1, WFDC11–WFDC10B, TECPR1, BORCS7, and HIP1R. PRS models discriminated PD from controls with 70% accuracy. Among PD patients, 333 developed PDD. Genome-wide survival analysis identified PRDM15 rs141772267 as a novel PDD risk variant (HR = 4.20; 95% CI 2.67–6.60; P = 5.41 × 10⁻¹⁰), together with two loci near CNOT6L–MRPL1 and NPY2R–MAP9. Carriers of two or more minor risk alleles showed a markedly increased risk of progression to PDD (P = 2 × 10⁻¹⁶), which was replicated in an independent WGS cohort. Our findings highlight both shared and ethnicity-specific PD risk loci and identify PRDM15 as a potential novel contributor to PDD. Further multi-ethnic and functional studies are warranted. 10.13039/501100001869 Academia Sinica and National Development Fund.