Low Lp(a) levels not associated with Alzheimer's disease or vascular-related dementia

In an analysis of 3 large prospective cohorts including 575,630 individuals, low Lp(a) levels were not associated with the risk of Alzheimer’s disease or vascular-related dementia.

This summary is based on the publication of Thomas PE, Vedel-Krogh S, Nielsen SF, et al. - Lipoprotein(a) and risk of dementia: findings from three cohort studies. Eur Heart J. 2025. 2025 Aug 18:ehaf465. [Online ahead of print] doi: 10.1093/eurheartj/ehaf465.

Introduction and methods

Background

Dementia shares risk factors with ASCVD, and high Lp(a) is a causal risk factor for ASCVD. Previous studies have shown inconsistent findings on the association between Lp(a) and dementia [1-3]. With potent Lp(a)-lowering therapies now in phase 3 clinical trials, a better understanding of the association between Lp(a) and dementia is essential.

Aim of the study

The aim of the study was to evaluate the relationship of Lp(a) with Alzheimer’s disease, vascular-related dementia and all-cause dementia, the latter was defined as Alzheimer’s disease and/or vascular-related dementia.

Methods

Data were collected from 3 contemporary prospective cohort studies: the Copenhagen General Population Study (n=106,458), the Copenhagen City Heart Study (10,571), and the UK Biobank (n=458,601) (total n=575,630). Plasma Lp(a) levels were available in 539,478 participants. In the Copenhagen cohorts, 117,029 individuals had data on LPA kringle IV type 2 (KIV-2) number of repeats, a determinant of isoform size that is inversely correlated with plasma Lp(a) concentrations [4-5]. Multivariable-adjusted subdistribution HR’s were calculated using the Fine and Gray method, accounting for competing risks of death, emigration, or other dementia diagnosis.

Median follow-up was 10.1 years in the Copenhagen studies and 13.7 years in the UK Biobank, with a maximum follow-up of 30.2 years and 16.0 years, respectively. During follow-up, 6,404 Alzheimer’s disease and 7,866 vascular-related dementia cases were recorded.

Main results

Plasma Lp(a) levels

• When not accounting for competing risks, Lp(a) levels were not associated with the risk of Alzheimer’s disease, vascular-related dementia or all-cause dementia across continuous analyses in both cohorts.
• When competing risks were considered, a 50 mg/dL higher Lp(a) level was not associated with Alzheimer’s disease, vascular dementia, or all-cause dementia in either the Copenhagen cohorts or UK Biobank (subdistribution HRs: ~0.98–1.00; all P>0.05), whereas the same increase was strongly associated with ASCVD risk (HR: 1.23; 95%CI: 1.19–1.27; P<0.001 in the Copenhagen studies; HR: 1.29; 95%CI: 1.27–1.30; P<0.001 in the UK Biobank).
• In absolute risk analyses accounting for competing risks, individuals from the UK Biobank with Lp(a) in the >95^th percentile had a slightly higher absolute risk of vascular dementia at age 80 compared with those in the ≤50^th percentile (3.6% vs. 3.3%; P=0.01), but not of Alzheimer’s disease (2.9% vs. 2.5%; P=0.10). No significant associations were observed in the Copenhagen cohorts.

LPA genotypes

• Genetic analyses in the Copenhagen population showed that carriers with LPA KIV-2 repeats in the lowest 5^th percentile (indicating smaller isoforms and lifelong elevated Lp(a)) had a higher risk of Alzheimer’s disease (subdistribution HR: 1.25; 95%CI: 1.06–1.46) compared with those individuals in the >50^th percentile.
• Compared with individuals in the >50^th KIV-2 percentile, individuals with KIV-2 repeats in the lowest 5^th percentile were at similar risk for vascular-related dementia (subdistribution HR: 0.93; 95%CI: 0.77–1.12) or all-cause dementia (subdistribution HR: 1.08; 95%CI: 0.94–1.23).

Conclusion

In this large analysis of 3 prospective cohorts, low Lp(a) levels were not associated with the risk of Alzheimer’s disease, vascular dementia, or all-cause dementia. However, a role for high Lp(a) concentrations or small isoform size in dementia risk cannot be fully excluded. According to the authors, their findings indirectly support that pharmacological lowering of Lp(a) is unlikely to lead to an increased risk of dementia.

Find this article online at Eur Heart J.

References

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