Accelerated forgetting has been proposed as the first sign in preclinical and early Alzheimer's disease (AD). The authors investigated learning and retention in participants who later developed AD with free and cued selective reminding (FCSR; H. Buschke, 1984; E. Grober & H. Buschke, 1987), a test that maximizes learning by inducing deep semantic processing and by controlling study and test conditions. AD patients in the preclinical stage recalled significantly fewer words than did matched control participants, indicating an impairment of learning; nonetheless, patients' retention was identical to that of control participants. A retention deficit was documented 3 years later for AD patients but not for control participants, whose retention was still perfect. Thus, a retention deficit is not present in preclinical AD when hallmark learning deficits can be documented. Detection of preclinical and very early AD may be best accomplished by using robust learning tests that control cognitive processing.

In most of the world, the oldest old are the fastest growing segment of the population and the individuals most affected by cognitive decline and dementia. The 90+ Study, a population-based sample of more than 1600 people aged 90 years and older (Laguna Woods, California), comprises one of the largest longitudinal studies of oldest old in the world. Participants (76% women; mean age 97 years) are followed every 6 months with neuropsychological and neurological examinations, medical record review, informant questionnaires and interviews. DNA and brain donation are also requested. Our study, similar to other investigations, shows high prevalence and incidence rates of dementia that continue to increase with age in oldest old individuals. However, most individuals without dementia also show significant age-associated declines in cognitive performance. The underlying biological mechanisms of these declines in the oldest old are poorly understood. Amyloid and other pathologies are frequently present in both demented and non-demented 90+ year olds, and distinguish poorly between the groups. Moreover, rates of cognitive decline do not appear to differ in non-demented oldest old with and those without significant amyloid and AD pathology. These results have called into question the relevance of amyloid in the expression of cognitive loss and dementia in oldest old. More recent results however from the 90+ Study suggest that the relationship between pathology and cognition may be more complex, and that the number as well as the types of pathologies may indeed be relevant for cognitive performance in aging. The relationship of cognitive declines in 90+ individuals to cerebral amyloid and other pathologies (identified by imaging and by autopsy) will be presented. Implications for the understanding of dementia and cognition at all ages will be considered.

In the past decade, studies of Alzheimer disease risk and medication exposures, supplement intake, and dietary factors have grown in number. Typically identified in case-control and cross-sectional studies, many of these exposures have also been replicated in prospective studies. These observational studies have provided the foundation for the development of several prevention trials. This brief review focuses on exposures that have been identified in multiple studies. Observational studies of medications suggesting protection for Alzheimer disease include estrogen hormonal therapy, nonsteroidal anti-inflammatory drugs, and cholesterol-lowering statins. Evidence regarding dietary and supplemental intake of vitamins E, C, and folate, and studies of alcohol and wine intake are also reviewed. At present, there is insufficient evidence to make public health recommendations, but these studies can provide potentially important clues and new avenues for clinical and laboratory research.

Memories are the gifts from friends and family that stay with us forever, unless a person develops Alzheimer's disease. Leon J. Thal left many, many memories, along with his desire to create a world where people did not lose them to the ravages of dementing illnesses. Working from the bench to the clinic, he was an incomparable leader, scientist, and educator to whom many, including myself, owe much. The present description of a clinical, genetic, and pathologic study of the oldest old contains much of Leon's influence. With data from >950 subjects, a brain repository, and our collection of DNA, the investigators of the 90+ Study are receptive to collaborations. Through our collective efforts, we will continue the scientific work that Leon so strongly supported.