OBJECTIVE: Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited. METHODS: We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers. RESULTS: There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]per 1-SD = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HRper 1-SD = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HRper 1-SD = 1.08, 95% CI = 1.04-1.13, Pinteraction = 0.003). Higher creatinine was inversely associated with FTD risk (HRper 1-SD = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (IVW), per 1-SD = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (Pnon-linearity = 0.006). INTERPRETATION: LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2025.