Translocase of outer mitochondrial membrane 40 (TOMM40) is located in the outer membrane of mitochondria. TOMM40 is essential for protein import into mitochondria. TOMM40 genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the TOMM40 gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three TOMM40 exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines.

Critical stroke causes high morbidity and mortality. We examined if variables in the early stage of critical stroke could predict in-hospital mortality. We recruited 611 ischemic and 805 hemorrhagic stroke patients who were admitted within 24 h after the symptom onset. Data were analyzed with independent t test and Chi square test, and then with multivariate logistic regression analysis. In ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score (OR 1.08; 95 % CI 1.06–1.11; P < 0.01), white blood cell count (OR 1.11; 95 % CI 1.05–1.18; P < 0.01), systolic blood pressure (BP) (OR 0.49; 95 % CI 0.26–0.90; P = 0.02) and age (OR 1.03; 95 % CI 1.00–1.05; P = 0.03) were associated with in-hospital mortality. In hemorrhagic stroke, NIHSS score (OR 1.12; 95 % CI 1.09–1.14; P < 0.01), systolic BP (OR 0.25; 95 % CI 0.15–0.41; P < 0.01), heart disease (OR 1.94; 95 % CI 1.11–3.39; P = 0.02) and creatinine (OR 1.16; 95 % CI 1.01–1.34; P = 0.04) were related to in-hospital mortality. Nomograms using these significant predictors were constructed for easy and quick evaluation of in-hospital mortality. Variables in acute stroke can predict in-hospital mortality and help decision-making in clinical practice using nomogram.

Cardiovascular diseases (CVDs) and dementia are the leading causes of disability and mortality. Genetic connections between cardiovascular risk factors and dementia have not been elucidated. We conducted a scoping review and pathway analysis to reveal the genetic associations underlying both CVDs and dementia. In the PubMed database, literature was searched using keywords associated with diabetes mellitus, hypertension, dyslipidemia, white matter hyperintensities, cerebral microbleeds, and covert infarctions. Gene lists were extracted from these publications to identify shared genes and pathways for each group. This included high penetrance genes and single nucleotide polymorphisms (SNPs) identified through genome wide association studies. Most risk SNPs to both diabetes and dementia participate in the phospholipase C enzyme system and the downstream nositol 1,4,5-trisphosphate and diacylglycerol activities. Interestingly, AP-2 (TFAP2) transcription factor family and metabolism of vitamins and cofactors were associated with genetic variants that were shared by white matter hyperintensities and dementia, and by microbleeds and dementia. Variants shared by covert infarctions and dementia were related to VEGF ligand–receptor interactions and anti-inflammatory cytokine pathways. Our review sheds light on future investigations into the causative relationships behind CVDs and dementia, and can be a paradigm of the identification of dementia treatments.

Memory complaint is one of the earliest symptoms of dementia. The causes and prognosis of memory complaint in the middle-aged population remain largely unknown. We reviewed the register-based data of 2129 patients with memory complaints. Among them, 404 participants were between 40 and 65 years old. The participants were separated into three groups: subjective cognitive decline (SCD), neurodegenerative diseases (ND), and non-neurodegenerative diseases (NND). One-year decline was defined as a decrease of ≥1 on the mini-mental state examination (MMSE). At baseline, 131 participants (32%) were diagnosed with SCD, 141 (35%) with ND, and 132 (33%) with NND. The 1-year cognitive decline rate was higher among patients with ND (36.8%) than in the SCD (7.3%, p = 1.3 × 10⁻⁸) and NND groups (7.6%, p = 1.1 × 10⁻⁷). One-year decline did not differ between the SCD and NND groups. Lower baseline MMSE score predicted increased risk of 1-year cognitive decline (odds ratio (OR) = 1.126, 95% confidence interval (CI) = 1.076–1.178, p = 2.52 × 10⁻⁷). Memory complaint in middle age carried a risk of 1-year cognitive decline, and baseline MMSE is an independent predictor of decline. An initial diagnosis of SCD held the same risk effect for decline as NND. These findings highlighted the necessity for neuropsychological tests in those with memory complaints presenting to the clinic.