Statin Therapy and Alzheimer’s Disease Risk: Implications for Precision Medicine

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a growing global impact. Currently, AD affects over 6 million Americans, and its incidence is projected to triple over the next three decades. This surge not only presents a major public health concern but also bears immense economic and social implications, with associated costs expected to approach $1 trillion. In response to this crisis, the National Alzheimer's Project Act (NAPA) set the goal to effectively prevent and treat AD and AD-related dementias (ADRD) by 2025. Achieving this goal within such a short timeframe is undoubtedly challenging, yet it remains an aspiration within reach. NAPA highlights targeting modifiable risk factors as a potentially effective strategy for dementia prevention. It is estimated that up to one-third of AD cases worldwide may be attributable to modifiable risk factors and addressing them could mitigate nearly 40% of dementia cases. Upon examining the landscape of modifiable risk factors for AD, the strongest evidence consistently points to cardiovascular health. Numerous studies emphasize the association between cardiovascular disease and an increased AD risk, highlighting the importance of shared risk factors. Among these, one stands out as a common link—dyslipidemia. Cholesterol dysregulation is increasingly recognized as an early risk mechanism in the pathogenesis of AD. Statin therapy, the first-line pharmacological therapy for the treatment of hypercholesterolemia and prevention of cardiovascular disease, are among the most widely used medications globally and have multiple pleiotropic effects that could influence AD risk. Studies examining the effects of statins on AD risk have found varying responses depending on the specific statin molecule, age, sex, and APOE genotype. Precision AD therapy, which considers factors such as APOE genotype and sex, is a growing area of interest. Therefore, individualized statin therapy holds potential for reducing AD risk, although further research is needed to refine these approaches. The central hypothesis guiding this program of doctoral research is that statin therapy can impact neurological health by targeting AD risk mechanisms that are specific to sex and/or APOE genotype. I propose that if statin therapy modulates risk mechanisms associated with female sex or APOE4 genotype, then sex and or genotype specific profiles of Alzheimer’s prevention or risk should emerge. Further sex and or APOE genotype specific mechanistic pathways should be evident. To test this hypothesis, a reverse translational program of research was conducted that integrated medical bioinformatic data analytics with mechanistic discovery research. First, medical informatic analyses determined the impact of statin use on AD risk. Outcomes of real-world data analytics indicated that statin therapy was associated with a highly significant 54% reduction in incidence of AD. Magnitude of AD risk reduction varied across different statins based on mechanistic target profile. Pathway analyses revealed that select statins activated multiple pathways beyond cholesterol synthesis that included immune modulation, epigenetic regulation, and metabolic processes. To determine impact of sex and APOE genotype, a responder analysis was conducted. Outcomes of these analyses revealed that statins mitigated the risk conferred by APOE4. Non-responder analyses indicated that female sex coupled with cardiovascular disease conferred greatest AD risk. Further, statin therapy administered during the prodromal stage of AD, could mitigate mechanisms of AD risk associated with APOE4 genotype, such as bioenergetic and synaptic deficits as well as neuroinflammation. Conversely, statin use after an AD diagnosis was associated with a cholesterol-dependent delay in cognitive decline. This benefit was more pronounced in non-APOE4 carriers, while APOE4 carriers experienced a decline similar to that of non-APOE4 carriers. Moreover, statin use in combination with risk factor-targeting therapeutics yielded greater delay in cognitive decline compared to monotherapy. Collectively, the body of new knowledge generated herein indicates that statin therapy for prevention, significantly reduced the risk of Alzheimer’s through activation of multiple mechanistic pathways beyond regulation of cholesterol synthesis. Further, reduction of AD risk was particularly effective in APOE4 carriers wherein statin therapy mitigated the adverse impact of the APOE4 genotype. Statin therapy benefit in Alzheimer’s patients was hypercholesterolemia-dependent and was effective in both APOE4 carriers and non- carriers with non-carriers exhibiting greater benefit. A combination therapy approach that included statins was effective in delaying cognitive decline in AD patients. Mechanistic pathways unique to specific statins coupled with chromosomal sex and APOE genotype enables a precision medicine approach to sustain neurological function and reduce risk of Alzheimer’s disease during aging.