Statins are a class of widely prescribed drugs used to reduce low-density lipoprotein cholesterol (LDL-C) and important to prevent cardiovascular diseases (CVD). Most statin users are older adults with CVD, who are also at high risk of cognitive decline. It has been suggested that statins can alter cognitive performance, although their positive or negative effects are still debated. With more than 200 million people on statin therapy worldwide, it is crucial to understand the reasons behind discrepancies in the results of these studies. Here, we review the effects of statins on cognitive function and their association with different etiologies of dementia, and particularly, Alzheimer’s disease (AD). First, we summarized the main individual and statin-related factors that could modify the cognitive effects of statins. Second, we proposed the underlying mechanisms for the protective and adverse effects of statins on cognitive performance. Finally, we discussed potential causes of discrepancies between studies and suggested approaches to improve future studies assessing the impact of statins on dementia risk and cognitive function.

Statins are widely used for cardiovascular disease prevention but their effects on cognition remain unclear. Statins reduce cholesterol concentration and have been suggested to provide both beneficial and detrimental effects. Our aim was to investigate the cross-sectional and longitudinal association between statin use and cognitive performance, and whether blood low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, C-reactive protein, and vitamin D biomarkers mediated this association. We used participants from the UK biobank aged 40–69 without neurological and psychiatric disorders (n = 147 502 and n = 24 355, respectively). We performed linear regression to evaluate the association between statin use and cognitive performance and, mediation analysis to quantify the total, direct, indirect effects and the proportion meditated by blood biomarkers. Statin use was associated with lower cognitive performance at baseline (β = −0.40 [−0.53, −0.28], p = <.0001), and this association was mediated by low-density lipoprotein (proportion mediated = 51.4%, p = .002), C-reactive protein (proportion mediated = −11%, p = .006) and blood glucose (proportion mediated = 2.6%, p = .018) concentrations. However, statin use was not associated with cognitive performance, measured 8 years later (β = −0.003 [−0.11, 0.10], p = .96). Our findings suggest that statins are associated with lower short-term cognitive performance by lowering low-density lipoprotein and raising blood glucose concentrations, and better performance by lowering C-reactive protein concentrations. In contrast, statins have no effect on long-term cognition and remain beneficial in reducing cardiovascular risk factors.

Recent evidence suggests that a high glycemic load (GL) diet is a risk factor for dementia, especially among apolipoprotein E ε4 allele (APOE4) carriers, while its association with cognitive decline is poorly known. Here, we investigated the association of high-GL meals with cognitive decline in older adults during a 12-year follow-up, according to their APOE4 carrier status. We used random-effect models and data from 2539 elderly participants from the Three-City study who completed a food frequency questionnaire (FFQ) to longitudinally assess the association of GL with changes in different cognitive domains (verbal fluency, visual memory, attention, visual motor processing speed, episodic memory). In APOE4 carriers, afternoon snack with high GL was significantly associated with cognitive decline in visual memory, episodic memory, and global cognition compared with APOE4 non-carriers. This study suggests a detrimental association between a high-GL diet and cognitive decline. The promotion of a low GL diet as a target to prevent cognitive decline in high-risk populations deserves more research.

Insulin resistance is a major mechanism involved in the onset of physical frailty (PF). Although rich carbohydrate diets may promote insulin resistance, few studies have examined their association with PF risk. This study aimed to investigate the spectrum of carbohydrate exposure, including carbohydrate intake (simple, complex, and total), glycemic load (a measure of the diet-related insulin demand), and adherence to a low-carbohydrate diet with the incident risk of PF in community-dwelling older adults. Baseline carbohydrate exposure was assessed in nonfrail participants of the Three-City Bordeaux cohort using a 24-hour dietary recall. Over 15 years of follow-up, participants were screened for PF, defined by the FRAIL scale (≥3 criteria out of Fatigue, Resistance, Ambulation, Illnesses, and weight Loss). Associations were estimated using mixed-effects logistic models adjusted for sex, age, education, smoking status, alcohol consumption, depressive symptomatology, global cognitive performances, and protein and energy intakes. The sample included 1 210 participants (62% females, mean age 76 years). Over the follow-up, 295 (24%) incident cases of PF were documented (28% in females, 18% in males). Higher intake of simple carbohydrates was significantly associated with greater odds of incident PF (per 1-SD increased: OR = 1.29; 95% CI = 1.02–1.62), specifically among males (OR = 1.52; 95% CI = 1.04–2.22). No association was observed with complex or total carbohydrate intake, glycemic load, or low-carbohydrate diet. Among the whole carbohydrate exposure, only higher consumption of simple carbohydrates in older age was associated with a higher risk of developing PF. Further studies are required to explore underlying mechanisms.

Previous studies have highlighted links between a high-glycemic-load (GL) diet and Alzheimer’s disease in apolipoprotein E ε4 (APOE4) carriers. However, the impact of high-GL diet on plasma amyloid-β (Aβ), an Alzheimer’s disease hallmark that can be detected decades before clinical symptomatology, is unknown. This study examined the association between plasma Aβ peptides (Aβ₄₀, Aβ₄₂ concentration and Aβ₄₂/Aβ₄₀ ratio) and GL. The influence of the GL of four meal types (breakfast, lunch, afternoon snack, and dinner) was also determined. From the prospective Three-City study, 377 participants with plasma Aβ measurements, and who completed the Food Frequency Questionnaire, were selected. The association between plasma Aβ and GL was tested using an adjusted linear regression model. Lunch GL was associated with a lower plasma Aβ₄₂ concentration (β = −2.2 [CI = −4.27, −0.12], p = 0.038) and lower Aβ₄₂/Aβ₄₀ ratio (β = −0.009 [CI = −0.0172, −0.0007], p = 0.034) in the model adjusted for center, age, sex, education level, APOE4 status, energy intake, serum creatinine, total cholesterol, and Mediterranean-like diet. No significant association was found with the GL of the other meal types. These results suggest that dietary GL may independently modulate the plasma Aβ of the APOE4 status. The mechanism underlying diet, metabolic response, and Aβ peptide regulation must be elucidated.