Forskningsartikler

Abstract

Apolipoprotein E (APOE) genotype and cardiovascular risk are both associated with dementia, but their separate and joint contributions remain uncertain. We examined the independent and combined associations of APOE genotype and cardiovascular disease (CVD) risk with incident dementia in a Norwegian populationbased cohort. In this prospective cohort study, baseline data were obtained from the second Trøndelag Health Study (HUNT2, 1995–97), with follow-up through linkage to specialist health-care records and the Norwegian Cause of Death Registry through Dec 31, 2023. We included 22,108 participants aged 50 years or older who were free of CVD, diabetes, and dementia at baseline. APOE genetic risk and cardiovascular risk based on SCORE2 were each classified into three categories. Adjusted hazard ratios (HRs) for incident dementia were estimated using Cox models. During a median follow-up of 22.0 years, 3,714 incident dementia events occurred. Compared with low APOE genetic risk, adjusted HRs were 1.25(95% CI1.10–1.41) for intermediate risk and 3.09(2.73–3.49) for high risk. Compared with low-to-moderate CVD risk, adjusted HRs were 1.19(1.07–1.32) for high risk and 1.36(1.19–1.55) for very high risk. In joint analyses, the highest risk was observed in participants with high APOE genetic risk and very high cardiovascular risk (HR 3.78, 2.85–5.01). Higher cardiovascular risk was more clearly associated with dementia in participants without high APOE genetic risk, whereas dementia risk was consistently There was no clear evidence of multiplicative interaction (p=0.059). APOE genotype and cardiovascular risk were independently associated with incident dementia, with highest risk among individuals with both high genetic and cardiovascular risk.

Nora Grøtting, Brooke N. Wolford, Kirsti Kvaløy, Torbjørn Omland, Geir Selbæk & Linda Ernstsen

Abstract

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer’s disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

Jun-Ping Pan  (潘君平), Ping-Jie Wang  (王平洁), Jianying Zhang  (张剑英), Anne-Brita Knapskog, Leiv Otto Watne, He-Ling Wang  (王鹤龄), Maria Jose Lagartos-Donate, Sofie Lautrup, Li-Peng Mao  (茅立鹏), Qian Wang  (王倩), Zhi-Peng Ling  (凌志鹏), Shi-qi Zhang  (张诗琦), Tomás Schmauck-Medina, Ruixue Ai  (艾瑞雪), Trine Holt Edwin, Tianjiao Zhang  (张天娇), Ingvild Saltvedt, Rannveig Sakshaug Eldholm, Annabel Smith, Kateřina Veverová, Domenica Caponio, Asgeir Kobro-Flatmoen, Huanhuan Pang  (庞欢欢), Zijian Wang  (王子健), Haoyun Wang  (王昊云), Li-juan Gao  (高利娟), Nathalie Bodd Halaas, Garry Wong, Martin Vyhnalek, Oscar Junhong Luo  (罗钧洪), William A. McEwan, Jon Storm-Mathisen, Li Gan, Zeping Hu  (胡泽平), Henrik Zetterberg, Menno P. Witter, Dag Aarsland, Geir Selbæk, Guobing Chen  (陈国兵) & Evandro Fei Fang  (方飛)