Lp(a) and dementia in 539,478 people: no association with Alzheimer's or vascular dementia on continuous scales (Thomas et al., EHJ 2025)

Background And Aims: Dementia is a leading cause of death and disability that shares risk factors with atherosclerotic cardiovascular disease (ASCVD). High lipoprotein(a) is a causal risk factor for ASCVD while results for dementia are conflicting. With lipoprotein(a) lowering drugs in clinical trials, it was tested whether lipoprotein(a) levels are associated with the risk of Alzheimer's disease and/or vascular-related dementia.

Methods: Lipoprotein(a) measurements were available in 539 478 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the UK Biobank. Individuals were followed for up to 30.2 years, during which 6404 developed Alzheimer's disease and 7866 vascular-related dementia. LPA kringle IV type 2 (KIV-2) number of repeats, which determines lipoprotein(a) isoform size and correlates inversely with lipoprotein(a) levels, were available in 117 029 individuals from the Copenhagen studies. Statistical analyses accounted for competing risk of death, important for studies of dementia occurring late in life.

Results: On continuous scales, lipoprotein(a) levels were not associated with the risk of Alzheimer's disease or vascular-related dementia. When accounting for competing risk of death, absolute risks of vascular-related dementia increased with higher lipoprotein(a) levels in the UK Biobank (n = 452 989; events = 5132; P = .01), but not in the Copenhagen studies (n = 80 313; events = 2734; P = .42). In the Copenhagen studies, LPA KIV-2 number of repeats ≤5th vs > 50th percentiles associated with a subdistribution hazard ratio for Alzheimer's disease of 1.25 (95% confidence interval, 1.06-1.46).

Conclusions: Low lipoprotein(a) levels were not associated with the risk of Alzheimer's disease or vascular-related dementia. It cannot be excluded that very high lipoprotein(a) or small isoform size increases the risk of dementia.