Chris Corcoran

Vascular factors predict rate of progression in Alzheimer disease.

Background: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. Objective: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. Methods: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. Results: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. Conclusion: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age. GLOSSARY: 3MS = revised Modified Mini-Mental State Examination for epidemiologic studies; AF = atrial fibrillation; CABG = coronary artery bypass graft surgery; CCHS = Copenhagen City Heart Study; CCSMHA = Cache County Study on Memory, Health, and Aging; CDR = Clinical Dementia Rating; CVD = cardiovascular disease; DM = diabetes mellitus; DPS = Dementia Progression Study; MI = myocardial infarction; MMSE = Mini-Mental State Examination; SBP = systolic blood pressure.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah

The role of protein intake in osteoporosis is unclear. In a case‐control study in Utah (n = 2501), increasing level of protein intake was associated with a decreased risk of hip fracture in men and women 50–69 years of age but not in those 70–89 years of age. Protein intake may be important for optimal bone health.

Dementia: The leading predictor of death in a defined elderly population The Cache County Study

Objective: To examine the relative risk and population attributable risk (PAR) of death with dementia of varying type and severity and other risk factors in a population of exceptional longevity. Methods: Deaths were monitored over 5 years using vital statistics records and newspaper obituaries in 355 individuals with prevalent dementia and 4,328 without in Cache County, UT. Mean age was 83.3 (SD 7.0) years with dementia and 73.7 (SD 6.8) years without. History of coronary artery disease, hypertension, diabetes, and other life-shortening illness was ascertained from interviews. Results: Death certificates implicated dementia as an important cause of death, but other data suggested a stronger association. Adjusted Cox relative hazard and PAR of death were higher with dementia than with any other illness studied. Relative hazard of death with dementia was highest at ages 65 to 74, but the high prevalence of dementia after age 85 resulted in 27% PAR among the oldest old. Mortality increased substantially with severity of dementia. Alzheimer disease shortened survival time most dramatically in younger participants, but vascular dementia posed a greater mortality risk among the oldest old. Conclusion: In this population, dementia was the strongest predictor of mortality, with a risk two to three times those of other life-shortening illnesses.

Progression of Cognitive, Functional, and Neuropsychiatric Symptom Domains in a Population Cohort With Alzheimer Dementia: The Cache County Dementia Progression Study

OBJECTIVES Progression of Alzheimer dementia (AD) is highly variable. Most estimates derive from convenience samples from dementia clinics or research centers where there is substantial potential for survival bias and other distortions. In a population-based sample of incident AD cases, we examined progression of impairment in cognition, function, and neuropsychiatric symptoms, and the influence of selected variables on these domains. DESIGN Longitudinal, prospective cohort study. SETTING Cache County (Utah). PARTICIPANTS Three hundred twenty-eight persons with a diagnosis of possible/probable AD. MEASUREMENTS Mini-Mental State Exam (MMSE), Clinical Dementia Rating sum-of-boxes (CDR-sb), and Neuropsychiatric Inventory (NPI). RESULTS Over a mean follow-up of 3.80 (range: 0.07-12.90) years, the mean (SD) annual rates of change were -1.53 (2.69) scale points on the MMSE, 1.44 (1.82) on the CDR-sb, and 2.55 (5.37) on the NPI. Among surviving participants, 30% to 58% progressed less than 1 point per year on these measures, even 5 to 7 years after dementia onset. Rates of change were correlated between MMSE and CDR-sb (r = -0.62, df = 201, p < 0.001) and between the CDR-sb and NPI (r = 0.20, df = 206, p < 0.004). Female subjects (LR χ = 8.7, df = 2, p = 0.013) and those with younger onset (likelihood ratio [LR] χ = 5.7, df = 2, p = 0.058) declined faster on the MMSE. Although one or more apolipoprotein E ε 4 alleles and ever use of FDA-approved antidementia medications were associated with initial MMSE scores, neither was related to the rate of progression in any domain. CONCLUSIONS A significant proportion of persons with AD progresses slowly. The results underscore differences between population-based versus clinic-based samples and suggest ongoing need to identify factors that may slow the progression of AD.

Conversion to dementia from mild cognitive disorder The Cache County Study

Objective: To examine 3-year rates of conversion to dementia, and risk factors for such conversion, in a population-based sample with diverse types of cognitive impairment. Methods: All elderly (aged 65 or older) residents of Cache County, UT, were invited to undergo two waves of dementia screening and assessment. Three-year follow-up data were available for 120 participants who had some form of mild cognitive impairment at baseline. Of these, 51 had been classified at baseline with prodromal Alzheimer disease (proAD), and 69 with other cognitive syndromes (CS). Results: Three-year rates of conversion to dementia were 46% among those with cognitive impairment at baseline. By comparison, 3.3% without impairment converted to dementia in the interval. Among converters, AD was the most common type of dementia. In individuals with at least one APOE ε4 allele, those with proAD or CS exhibited a 22- to 25-fold higher risk of dementia than cognitively unimpaired individuals (vs 5- to 10-fold higher risk in those without ε4). Conclusions: Individuals with all types of mild cognitive impairment have an elevated risk of dementia over 3 years, more so in those with an APOE ε4 allele. These results suggest value in dementia surveillance for broad groups of cognitively impaired individuals beyond any specific category, and utility of APOE genotyping as a prognostic method.

Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study

Background: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. Methods: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. Results: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE ε4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more ε4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more ε4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an ε4 allele who started NSAID use after age 65 showed greater decline than nonusers (−0.16 points per year; p = 0.02). Conclusions: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE ε4 alleles.

Prospective study of Dietary Approaches to Stop Hypertension– and Mediterranean-style dietary patterns and age-related cognitive change: the Cache County Study on Memory, Health and Aging

BACKGROUND Healthy dietary patterns may protect against age-related cognitive decline, but results of studies have been inconsistent. OBJECTIVE We examined associations between Dietary Approaches to Stop Hypertension (DASH)- and Mediterranean-style dietary patterns and age-related cognitive change in a prospective, population-based study. DESIGN Participants included 3831 men and women ≥65 y of age who were residents of Cache County, UT, in 1995. Cognitive function was assessed by using the Modified Mini-Mental State Examination (3MS) ≤4 times over 11 y. Diet-adherence scores were computed by summing across the energy-adjusted rank-order of individual food and nutrient components and categorizing participants into quintiles of the distribution of the diet accordance score. Mixed-effects repeated-measures models were used to examine 3MS scores over time across increasing quintiles of dietary accordance scores and individual food components that comprised each score. RESULTS The range of rank-order DASH and Mediterranean diet scores was 1661-25,596 and 2407-26,947, respectively. Higher DASH and Mediterranean diet scores were associated with higher average 3MS scores. People in quintile 5 of DASH averaged 0.97 points higher than those in quintile 1 (P = 0.001). The corresponding difference for Mediterranean quintiles was 0.94 (P = 0.001). These differences were consistent over 11 y. Higher intakes of whole grains and nuts and legumes were also associated with higher average 3MS scores [mean quintile 5 compared with 1 differences: 1.19 (P < 0.001), 1.22 (P < 0.001), respectively]. CONCLUSIONS Higher levels of accordance with both the DASH and Mediterranean dietary patterns were associated with consistently higher levels of cognitive function in elderly men and women over an 11-y period. Whole grains and nuts and legumes were positively associated with higher cognitive functions and may be core neuroprotective foods common to various healthy plant-centered diets around the globe.

Effects of Cardiovascular Medications on Rate of Functional Decline in Alzheimer Disease

BACKGROUND Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Caregiver–Recipient Closeness and Symptom Progression in Alzheimer Disease. The Cache County Dementia Progression Study

Applying Rusbults investment model of dyadic relationships, we examined the effect of caregiver-care recipient relationship closeness (RC) on cognitive and functional decline in Alzheimers disease. After diagnosis, 167 participants completed up to six visits, observed over an average of 20 months. Participants were 64% women, had a mean age of 86 years, and mean dementia duration of 4 years. Caregiver-rated closeness was measured using a six-item scale. In mixed models adjusted for dementia severity, dyads with higher levels of closeness (p < .05) and with spouse caregivers (p = .01) had slower cognitive decline. Effect of higher RC on functional decline was greater with spouse caregivers (p = .007). These findings of attenuated Alzheimers dementia (AD) decline with closer relationships, particularly with spouse caregivers, are consistent with investment theory. Future interventions designed to enhance the caregiving dyadic relationship may help slow decline in AD.