There has been intense interest in identifying modifiable AD risk factors, such as cardiovascular risk factors, with an eye toward prevention or at least delaying disease onset 4
. Yet little attention has been given to the influence of these factors on disease progression. Cerebrovascular lesions, common in AD patients, may accelerate the clinical manifestation of AD30
. Vascular risk factors may increase oxidative stress or activate a neuroinflammatory response, triggering amyloid production. Thus it has been suggested that Alzheimer pathology and cerebrovascular disease may work synergistically to cause cognitive decline 31
Consistent with previous research 32
, we found that higher total cholesterol and LDL were associated with faster cognitive decline among AD patients. An earlier study of the WHICAP cohort found higher total cholesterol was associated with lower
risk of incident AD 10
. The prodromal stage of AD is associated with decreased plasma cholesterol, possibly due to dietary insufficiency and weight loss. By limiting the current study to incident cases, we may have eliminated bias and/or confounding in cholesterol levels associated with frailty and preclinical AD. This may explain the difference with our findings for incident AD.
Lipid-lowering agents (LLAs) have previously been associated with slower cognitive decline among AD patients 33
. Nonetheless, consistent with others 13
, we found no association between LLAs and cognitive decline.
Among the medical history variables, only diabetes was associated with faster cognitive decline. Diabetes may influence AD progression via an inflammatory mechanism, or by contributing to amyloid plaque and neurofibrillary tangle formation 34
. Stroke, heart disease, hypertension, and smoking history were not associated with disease progression in the overall sample.
The ApoE-ε4 genotype may contribute both to vascular disease and AD neuropathology, with effects of vascular risk factors more pronounced among ε4 carriers35
. A previous study of this cohort found faster cognitive decline among participants with mild AD who were ε4 carriers36
. In our ε4-stratified models, higher total cholesterol and higher LDL-C predicted faster decline in both groups, while history of heart disease and/or stroke predicted faster decline among ε4 carriers only.
Few studies have examined the simultaneous effects of multiple vascular risk factors on AD progression. A study of prevalent AD found stroke, but not other vascular factors, was associated with faster decline on the MMSE 13
. A study of incident cases found faster decline on the Clinical Dementia Rating and the MMSE among those with a history of atrial fibrillation, systolic hypertension and angina at baseline, while diabetes was associated with slower decline 14
. Our findings may differ from these studies for several reasons: we measured cognitive change using a comprehensive battery of cognitive tests, which is potentially more sensitive than the MMSE; one of the previous studies13
included some participants with relatively advanced AD; and both of the previous studies were limited to Caucasian participants who, on average, were more highly educated than our multiethnic sample. In our post-hoc model, only higher LDL emerged as an independent predictor. The negative finding for diabetes as an independent predictor may be due to reduced power in the post-hoc analysis, since the beta value associated with diabetes-related cognitive change was similar to the diabetes-specific model.
This study has limitations. Since disease history (stroke, heart disease, diabetes) was self-reported, the prevalence of these conditions in our sample was likely underestimated. Further, 44 of the participants with incident AD were not included in this analysis since they died before the next follow-up assessment. Cause of death was unavailable, however it is likely that many of these deaths were due to vascular disease. If so, the effect size we found may be an underestimate. We had only one lipid assessment, potentially resulting in measurement error. Although lipids were measured prior to diagnosis, some participants may have been in the prodromal phase of AD. We attempted to account for this by adjusting for the interval between lipid measurement and diagnosis; results were unchanged. Similarly, AD-associated reductions in blood pressure may have masked an association between hypertension and disease progression that might have been seen had blood pressure been measured at mid-life. In future longitudinal studies, it would be better to measure these factors earlier in life. Our AD diagnoses were not neuropathologically confirmed, and imaging was not consistently used as part of diagnosis. Previous studies using MRI and neuropathogy data suggest that, especially among the oldest old, mixed dementia (AD + Vascular dementia) is the most common cause of dementia 37
Therefore, it is likely that some of our AD patients actually had mixed dementia. Finally, there is always the possibility that our findings could be due to chance.
Despite these limitations, clinical diagnosis was based on uniform application of widely accepted criteria, and unlike cognitive screening instruments used in some studies, our cognitive assessment comprised a comprehensive battery of tests evaluating a range of cognitive domains. Our use of a population-based sample limited to incident cases reduced biases associated with convenience samples (disease registries, hospital- or clinic-based samples) that may not accurately reflect the course of the disease in the general population.
In conclusion, we found that higher pre-diagnosis cholesterol levels (total cholesterol and LDL-C) and prevalent diabetes were associated with accelerated post-diagnostic cognitive decline. Heart disease history and stroke history predicted faster decline among ε4 carriers only. Prevention or treatment of these conditions can potentially slow the course of AD.