Faculty Bibliography

A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE epsilon3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Abeta) and tau levels, in cognitively intact elderly subjects. APOE epsilon4 carriers showed significant reductions in Abeta 1-42 levels compared to non-epsilon4 carriers, but no differences were detected across TOMM40 variants. Neither Abeta 1-40 nor tau levels were affected by APOE or TOMM40

Introduction: An important goal of ongoing Alzheimer's disease (AD) research is to identify markers that allow one to predict risk for the development of this type of dementia in cognitively intact elderly. Known cognitive changes associated with AD, possibly reflecting hippocampal pathology, include a worse recall of primacy items and better immediate recall of items learned at the end of a list compared to the middle (recency effect). Aims: The aim of our study was to examine whether learning and recall of primacy and recency words predicted future decline in intact elderly subjects. Methods: Individuals with MMSE of 28 or over at baseline were included in the study. Of these, 211 had at least two successive cognitive evaluations; mean age at baseline was 69.5 (SD=8.0). We regressed MMSE decline on baseline Auditory-Verbal Learning Test (AVLT) memory measures, focusing especially on learning and recall of primacy and recency words, and controlling for baseline age, time since baseline and other variables. Results: Worse learning/delayed recall of primacy words on AVLT trials consistently predicted greater subsequent cognitive decline. Additionally, this effect was stronger among older subjects than among younger ones. APOE e4, a well established genetic risk factor for late-onset AD, was not a significant predictor of MMSE decline in this sample. Conclusions: Decreased learning and poorer recall of primacy words in the AVLT is a predictor of decline in healthy elderly individuals, and future studies should examine if decreased learning and recall can predict conversion to AD

The monoamine hypothesis ascribes an important role to the under activity of brain monoamines such as 5-HT, noradrenaline and dopamine to the pathophysiology of depression. This view emerged more than 50 years ago and has guided development of most medications currently used for the treatment of this disorder. However, large numbers of depressed individuals treated with currently available antidepressant agents, or even with various combinations, do not respond. Residual symptoms, relapses and recurrences are common while receiving adequate doses of these medications. In a recent issue of the BJP, Colaianna et al.describe results suggesting that a new neurobiological mechanism with treatment implications should be considered for the development of depression in humans, namely, elevations in potentially neurotoxic brain amyloid-ss peptides

Retrograde facilitation (RF) of information learned prior to acute oral administration of trihexyphenidyl, a preferential muscarinic M1 receptor antagonist which impairs new learning, was studied in 24 healthy elderly subjects. The relationship between the RF induced by this anticholinergic drug and the APOE epsilon4 allele was also examined. Acute adverse performance effects of trihexyphenidyl (1- and 2mg) were determined using the Buschke Selective Reminding Test administered pre-drug and at 1, 2.5, and 5h post-drug. Recall of pre-drug words at the end of the fifth hour neuropsychological assessment (end-of-session recall) was of primary interest. Words studied before drug administration were better recalled following 2mg trihexyphenidyl compared to placebo, and this RF effect was not affected by the APOE epsilon4 allele. Better recall of pre-drug words following 2-mg trihexyphenidyl was associated with a greater amnestic effect of this dose. Our findings demonstrated that RF induced by trihexyphenidyl was related to anterograde amnestic effects of the drug and resulted in part from drug-induced reduction of retroactive interference