Alzheimer Disease: Connor D

Griffin-Pierce T, Silverberg N, Connor D, Jim M, Peters J, Kaszniak A, Sabbagh MN. · Department of Anthropology, University of Arizona, Tucson, AZ, USA. · Alzheimers Dement. · Pubmed #18631981 No free full text.

Abstract: Little is known about Alzheimer's disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Sparks DL, Sabbagh M, Connor D, Soares H, Lopez J, Stankovic G, Johnson-Traver S, Ziolkowski C, Browne P. · Robert Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · Acta Neurol Scand Suppl. · Pubmed #16866915 No free full text.

Abstract: Previous studies have suggested that statin therapy may be of benefit in treating Alzheimer's disease (AD). We initiated a double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo among individuals with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score of 12-28]. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of most other medications in the treatment of co-morbidities. We demonstrated that atorvastatin treatment produced significantly (P = 0.003) improved performance on cognition and memory after 6 months of treatment (ADAS-cog) among patients with mild-to-moderate AD. This superior effect persisted at 1 year (P = 0.055). This positive effect on the ADAS-cog performance after 6 months of treatment was more prominent among individuals entering the trial with higher MMSE scores (P = 0.054). Benefit on other clinical measures was identified in the atorvastatin-treated population compared with placebo. Accordingly, atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment. Evidence also suggests that atorvastatin may slow the progression of mild-to-moderate AD, thereby prolonging the quality of an afflicted individual's life.

Sparks DL, Lopez J, Connor D, Sabbagh M, Seward J, Browne P, Anonymous00354. · Ralph and Murial Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ 95351, USA. · J Mol Neurosci. · Pubmed #14501025 No free full text.

Abstract: Recruitment for the inaugural double-blind placebo-controlled trial investigating a cholesterol-lowering treatment for benefit in Alzheimer's disease (AD) (ADCLT) ended after obtaining 98 informed consents. Suspension of recruitment of the ADCLT occurred in concert with initiation of two separate multicenter trials testing similar hypotheses. Although occurring at very low rates (<2%), altered-chemistry adverse events requiring discontinuation of therapy (withdrawal AEs) are not unexpected with use of cholesterol-lowering statins. We suggest that exceptionally close monitoring for altered chemistry among individuals with AD should be undertaken in future statin treatment trials, as limited data from the ADCLT indicate that chemically based withdrawal AEs could be more prevalent among female AD patients. There was no apparent correlation between the occurrence of withdrawal-AE incidence and lower body mass among the female AD trial subjects and, therefore, probably was not a dose-related resultant. This might indicate that cognitively intact elderly women at risk for heart disease and those with clinically documented AD should not be presumed to be pharmocodynamically equivalent. Lipid profiles obtained at screening in the ADCLT are consistent with a possible difference between patients with current AD and those at risk for heart disease. Elevated cholesterol, increased cholesterol/high-density lipid (HDL) ratios, and elevated triglycerides are routinely observed among those at risk for heart disease; however, among ADCLT study participants, only cholesterol levels were increased while cholesterol/HDL ratio and triglyceride levels remained within normal limits.

Ignatov I, Belden C, Jacobson S, Connor D, Sabbagh MN. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. · J Alzheimers Dis. · Pubmed #19158419 No free full text.

Abstract: The objective of this study was to describe a case of Alzheimer's disease in an ApoE epsilon2/epsilon2 homozygote. ApoE epsilon2/epsilon2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE epsilon2/epsilon2 female who meets clinical criteria for Alzheimer's disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer's disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer's disease is rare in Apo E2 homozygotes but can occur.

Sparks DL, Petanceska S, Sabbagh M, Connor D, Soares H, Adler C, Lopez J, Ziolkowski C, Lochhead J, Browne P. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA. · Curr Alzheimer Res. · Pubmed #16375656 No free full text.

Abstract: Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.

Sabbagh M, Zahiri HR, Ceimo J, Cooper K, Gaul W, Connor D, Sparks DL. · The Cleo Roberts Center for Clinical Research, USA. · J Alzheimers Dis. · Pubmed #15665398 No free full text.

Abstract: OBJECTIVE: To characterize the lipid profile in Alzheimer's Disease (AD) and to determine whether it differs from the cardiac risk profile. BACKGROUND: Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the lipid profile characteristics in AD. METHODS: We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 153 subjects with probable/possible AD (mean age 77.2 +/- 8.6 years, mean MMSE 19.9 +/- 5.6) and 25 non-demented subjects with atherosclerotic heart disease (ASHD) (mean age 73.8 +/- 7.2 years); neither on lipid lowering therapy. RESULTS: Subjects with TC > 200 mg/dl composed 69% of AD and 72% of ASHD groups. Mean TC was 218.9 +/- 38.9 mg/dl and 218.5 +/- 9.2 mg/dl for AD and ASHD subjects respectively. AD subjects exhibited significantly higher HDL and lower TG and TC/HDL ratios. MMSE did not correlate with any lipid parameters in AD. DISCUSSION: Elevated TC, LDL and TG with normal HDL and TC/HDL ratio characterize the lipid profile in AD, which somewhat overlaps with but may be distinct from the cardiac risk profile. MMSE does not correlate with lipid parameters suggesting no interaction between cholesterol and cognition in AD.

Beach TG, Sue L, Scott S, Layne K, Newell A, Walker D, Baker M, Sahara N, Yen SH, Hutton M, Caselli R, Adler C, Connor D, Sabbagh M. · W. H. Civin Laboratory for Neuropathology, Sun Health Research Institute, Sun City, Ariz 85372, USA. · Brain Pathol. · Pubmed #12946017 No free full text.

Abstract: In some elderly individuals with dementia, hippocampal sclerosis (HS) is the only remarkable autopsy finding. The cause of HS in this setting is puzzling, since known causes of HS such as seizures or global hypoxic-ischemic episodes are rarely present. We here describe a series of HS cases that have a widespread neuronal and/or glial tauopathy. Of 14 consecutive cases of HS, 12 had been clinically diagnosed with dementia and/or Alzheimer's disease (AD) while 2 were non-demented; 7 cases had also been clinically diagnosed with parkinsonism. In addition to HS, 6 cases also met pathologic diagnostic criteria for AD. Gallyas silver staining and immunohistochemistry with the AT8 antibody revealed a glial and/or neuronal tauopathy in 12 of 14 cases, with frequent positive neurons and/or glial cells in the neocortex, basal ganglia, thalamus and/or limbic regions; in addition, 8 of the 14 cases had argyrophilic grains. Screening for known tau mutations was negative in all cases. Western blots of sarkosyl-insoluble tau protein showed a mixture of 3- and 4-repeat forms. The results suggest that most cases of HS dementia are sporadic multisystem tauopathies; we suggest the term "hippocampal sclerosis dementia with tauopathy" (HSDT) for these.