Catarina Tristão-Pereira

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. Despite global efforts to promote resilience, delay cognitive decline, and slow aging, APOE ε2, one of the most robust resilience-associated variants, remains relatively underexplored in translational research. Exceptional longevity offers a window into cognitive trajectories. We present clinical, cognitive and neuroimaging data from five APOE ε2/ε3 siblings aged 94–105. Cognition ranged from normal to mild dementia. MRI showed less atrophy than expected for advanced age, and FDG-PET revealed preserved metabolism. Findings demonstrate APOE ε2-associated resilience in the oldest-old and offer insight into mechanisms of exceptional cognitive aging with potential translational relevance.

Cerebral glucose metabolism is distinctly disrupted in Alzheimer's disease (AD), though its role in downstream cognitive decline remains unclear. Ueda et al. leverage Mendelian Randomization by integrating genetics, imaging and cognitive data to demonstrate that cerebral glucose metabolism is causally linked to cognitive performance. This approach lays the groundwork for novel therapeutic strategies by suggesting that metabolism-focused interventions may mitigate cognitive impairment in AD. Future studies should further integrate single-cell and multi-omics strategies to elucidate cellular and molecular pathways related to causal effects and explore the influence of co-pathologies and epigenetics on metabolic and cognitive performance.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE -genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE -ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE -ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47–0.81]; P =0.00043; femorals: 0.60 [0.47–0.78]; P =9.96×10 ⁻⁵ ; coronaries: 0.53 [0.39–0.74]; P =0.00013; and increased PESA score: 0.58 [0.48–0.71]; P =3.16×10 ⁻⁸ ). This APOE -ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50–54 years: 0.49 [95% CI, 0.32–0.73]; P =0.00045), and normal (P =4.70×10 ⁻⁹ versus 0.90 [0.57–1.43]; P =0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2’s atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov : NCT01410318.

Objectives Neurodevelopmental impairment has become the most important comorbidity in infants with congenital heart disease (CHD). We aimed to (1) investigate the burden of brain lesions in infants with CHD prior to surgery and (2) explore clinical factors associated with injury. Study design Prospective observational study. Setting Single centre UK tertiary neonatal intensive care unit. Patients 70 newborn infants with critical or serious CHD underwent brain MRI prior to surgery. Main outcome measures Prevalence of cerebral injury including arterial ischaemic strokes (AIS), white matter injury (WMI) and intracranial haemorrhage. Results Brain lesions were observed in 39% of subjects (95% CI 28% to 50%). WMI was identified in 33% (95% CI 23% to 45%), subdural haemorrhage without mass effect in 33% (95% CI 23% to 45%), cerebellar haemorrhage in 9% (95% CI 4% to 18%) and AIS in 4% (95% CI 1.5% to 12%). WMI was distributed widely throughout the brain, particularly involving the frontal white matter, optic radiations and corona radiata. WMI exhibited restricted diffusion in 48% of cases. AIS was only observed in infants with transposition of the great arteries (TGA) who had previously undergone balloon atrial septostomy (BAS). AIS was identified in 23% (95% CI 8% to 50%) of infants with TGA who underwent BAS, compared with 0% (95% CI 0% to 20%) who did not. Conclusions Cerebral injury in newborns with CHD prior to surgery is common.