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As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD). Analogous characteristics of DLB offer a provisional rationale for pharmacologic therapy based on remediating cholinergic and dopaminergic deficits, respectively. However, the distinct clinical manifestations and pathophysiologic substrates of DLB pose unique therapeutic opportunities and challenges. More severe cholinergic deficits in DLB relative to AD support clinical evidence that cholinergic therapy may be particularly beneficial in DLB patients. In contrast, DLB patients are generally more sensitive to the adverse effects of antipsychotic agents, warranting caution in treating visual hallucinations and other psychotic symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity and bradykinesia, may be less amenable to dopaminergic therapies than in PD. Increasing recognition of DLB as a common form of dementia in the elderly underscores the need for large-scale, placebo-controlled therapeutic trials.

Psychotic symptoms occurring in Alzheimer's disease (AD + psychosis, AD + P) are a marker for a more rapidly deteriorating phenotype. We have developed a polygenic model of AD + P risk, conditioned on the presence of AD. Whether risk genes for AD itself contribute to AD + P risk is not established, although our model predicts they will not. The most important identified genetic determinant of sporadic, late-onset AD is the apolipoprotein E epsilon 4 allele (APOE4). The effect of APOE4 on AD phenotype is to reduce the age of onset of AD. Prior studies examining the association of APOE4 with AD + P have reported conflicting results. However, no prior studies have examined if APOE4 reduces time to onset of psychosis in AD. The objective of this study was to examine the effect of APOE4 and alpha1-antichymotrypsin/AA (ACT/AA) genotypes on time to psychosis onset in subjects with AD. A longitudinal study of psychosis incidence in 316 subjects with AD with no history of current or prior psychotic symptoms at entry was undertaken. APOE and ACT genotyping was conducted per established protocols. Data were analyzed by survival analysis and Cox proportional hazards models. There were no significant associations of APOE or ACT genotypes with time to psychosis onset and no significant interaction of these genotypes with time to psychosis onset. There remained no significant associations after covarying for age, age of AD onset, degree of cognitive impairment, gender, race, and education. This is the first study to examine the genetic prediction of psychosis onset in AD. The findings support the hypothesis that these two genetic determinants of AD risk do not contribute to the risk of development of psychotic symptoms in AD.

We conducted an open-label study designed to assess the effects of tacrine on behavioral changes in patients with Alzheimer's disease (AD). Twenty-eight subjects completed a baseline evaluation and at least one assessment during treatment. Behavioral symptoms and cognitive function were assessed with the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examination (MMSE), respectively. The mean NPI score at the maximum individual dose of tacrine attained was markedly decreased (behavior improved, compared to baseline). Symptoms of anxiety, apathy, hallucinations, aberrant motor behaviors, and disinhibition were most responsive. Subject stratification by dementia severity revealed a substantially reduced mean NPI score only in the group with moderate dementia, independent of cognitive response. Over half of the subjects with cognitive improvement had a marked reduction in behavioral symptoms, particularly apathetic behaviors. These data suggest that tacrine may be beneficial for selected behavioral symptoms in AD patients, particularly at higher doses and in those with moderate cognitive deficits.