Cholesterol, Copper and Aβ in Controls, MCI, AD and the AD Cholesterol- Lowering Treatment Trial (ADCLT)

D.   L.   Sparks; Suzana      Petanceska; Marwan      Sabbagh; Donald      Connor; Holly      Soares; Charles      Adler; Jean      Lopez; Chuck      Ziolkowski; Jeff      Lochhead; Patrick      Browne

Abstract

Cholesterol clearly plays an influential role in promoting the production of amyloid β (Aβ) and possibly the progression of Alzheimers 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 Aβ1-40, Aβ1-42, 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 Aβ 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 Aβ1-40 occurred in low- compared to highfunction controls, with a further significant increase in MCI compared to low-function controls. Circulating Aβ1-40 levels were decreased in AD compared to MCI. Levels of Aβ1-42 were not significantly different between the groups. The slight gradual increase in circulating Ab1-40 and Ab1-42 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 Aβ1-40 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 Aβ or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.

Keywords: MCI, AD, cholesterol, copper, clinical trial

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