Cognitive Functioning in Patients With Alzheimer Disease
Felicia C. Goldstein, PhD,* Angela V. Ashley, MD,* Yohannes W. Endeshaw, MD, w John Hanfelt, PhD, z James J. Lah, MD, PhD,* and Allan I. Levey, MD, PhD*
Research has examined whether vascular comorbidities (VCs) including high and low blood pressure and hypercholesterolemia are associated with an increased risk of Alzheimer disease (AD). A number of epidemiologic studies support this relationship,1–8 but have found that these eﬀects may be stronger in midlife as opposed to closer to the disease onset, and may be modiﬁed by thepresence of the apolipoprotein E e4 allele, a genetic risk factor for AD.2–4,6,8 Animal models have reported associations between high cholesterol diets and increased accumulation of brain amyloid b in rabbits and transgenic mice,9,10 and clinical trials with the cholesterol lowering agent Simvastatin have found reduced cerebrospinalﬂuid amyloid b in mild AD patients.11–13 On the other hand, conﬂicting ﬁndings exist as well concerning a relationship between hypertension and hypercholesterolemia and the risk of AD.14–17 Hayden and colleagues14 recently reported that neither hypertension nor hypercholesterolemia were risk factors for AD in a sample of over 3000 elderly participants in the Cache County Study. They raised the possibility that the use of self-report or informant measurement of these comorbidities may have weakened the association, either owing to the unawareness of persons that they had these conditions or conversely, better medical follow-up of these conditions
in persons who were aware.
These studies have led to an appreciation of the potential contribution of VCs to the pathogenesis of AD. However, little is known about the eﬀects of these comorbidities on the clinical features of the disease, despite evidence that VCs are quite prevalent in this patient group.18,19 Research in nondemented older adults has established relationships between hypertension and poorer cognitive performance on measures of memory and executive functioning, including working memory. 20–23 Relationships between hypercholesterolemia and cognitive functioning, speciﬁcally memory performance, have been less consistent.24–26 Zhang et al26 found a U-shaped relationship between serum cholesterol values and memory performance, suggesting that the assumption of a monotonic association may account for some of the discrepancies.
A previous investigation by our group27 in African American AD patients found that those with stage 3 hypertension (systolic BP>160mm Hg, diastolic BP >90mm Hg)28 performed worse than normotensive patients on the Conceptualization and Initiation/Perseveration subscales of the Mattis Dementia Rating Scale.29 These patients did not have a history of stroke or transient ischemic attacks, or evidence of large vessel strokes on neuroimaging. The results suggested the subtle eﬀects of hypertension on executive functioning. The above sample was limited to patients with severe hypertension versus nomotensive patients and also did not examine the presence of other comorbidities.
Patients with mild-to-moderate AD were prospectively recruited from the outpatient memory assessment clinics at The Wesley Woods Center on Aging and Grady Memorial Hospital. The study was approved by the Emory University Institutional Review Board, and signed informed consent was obtained from all participants and their representatives including spouses and adult children. Patients had probable AD33 diagnosed by experienced neurologists and geriatricians in the Emory Alzheimer’s Disease Research Center. Patients were not selected to participate in the current study on the basis of the presence or absence of hypertension and hypercholesterolemia.
Patients were excluded if they had a history of psychiatric (Axis I) disorders, alcohol or substancerelated abuse, and coexisting neurologic conditions such as Parkinson disease and seizures. We excluded participants with large-vessel strokes based on history or imaging. The documented history of stroke included a review of medical records indicating presentation to a
hospital for a newly acquired focal neurologic deﬁcit that lasted >24 h and a discharge diagnosis of acute stroke. Participants with a history of transient ischemic attacks via self-report or medical records were also excluded.
The ﬁnal sample consisted of 74 probable AD patients with MMSE scores Z9 points (mean=19.5
points, SD=4.7). The average age was 75.5 years (SD=10.0; range, 50 to 94) and average education was 12.4 years (SD=3.4; range, 2 to 20). Sixty-two percent of the sample was female. There were 45 (61%) white and 29 (39%) African American patients.
Measurement of VCs
Patients arrived in the morning and underwent measurement of their blood pressure and cholesterol levels by the clinical research nurse. Patients were seated for at least 5 min in a chair with their feet on the ﬂoor and their arm supported at heart level. Blood pressure was determined by averaging 2 readings separated by 2 min, with additional readings taken if they diﬀered by more than 5mm Hg.28 Serum lipid proﬁles were obtained. Sixty-one of the 74 patients came in fasting (no caloric intake for at least 8 h). Published guidelines were used to deﬁne the presence or absence of hypertension and hypercholesterolemia.28,34 Hypertension was deﬁned as systolic BP Z140mm Hg, diastolic BP Z90mm Hg, or taking antihypertensive medication. Hypercholesterolemia was deﬁned as a fasting total cholesterol level of 240 mg/dL or greater, or taking cholesterol lowering agents (eg, statins).
Measurement of Cognitive Functioning
Patients underwent testing of their cognitive functioning by a psychometrist who was unaware of the patients’ vascular status. Fifty-ﬁve patients were tested on the same day as the assessment of their VCs, and they were given a light meal before receiving the measures. The remaining 19 patients had a mean interval of 28.6 days (SD=18.2) between the measurement of their VCs and
their cognitive evaluation.
Five cognitive domains were evaluated involving attention, language, memory, visuomotor/visuospatial performance, and executive functioning. Attention was assessed by the maximum number of digits forward35 and the number of seconds needed to sequence numbers using a pencil (Trails A).36 Language was examined via the 15-item Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) version of the Boston Naming Test.37 The evaluation of memory included verbal and visual episodic memory (CERAD word list recall and design recall) and semantic memory (timed generation of animal names in 60 s).37 Visuomotor/visuospatial performance was evaluated by having participants copy the 4 CERAD designs and determine the angular orientation of lines on the 5 practice trials of the Judgment of Line Orientation Test.38 Finally, executive functioning was measured via the Similarities subtest of the Wechsler Adult Intelligence Test-III39 and the maximum number of digits backwards. 35 Trails B was administered as well, but only 13 patients could complete this measure, and therefore the results were not analyzed owing to ﬂoor eﬀects in this population.