The average age at first evaluation of the 938 participants in The 90+ Study was 94 years (range: 90–106) and 77% were women. While many of them still lived at home alone (28%) a significant portion lived in assisted living or other group quarters (29%) and 15% lived in a nursing home.
A history of high blood pressure was present in almost half of the participants (47%), heart disease (coronary artery disease, myocardial infarction, atrial fibrillation, or congestive heart failure) in 40%, thyroid disease in about one quarter (26%), and clinical stroke in 15%. Depression was reported by 19% and anxiety only by 8% of 90+ participants. While diabetes was relatively infrequent (6%) a history of cancer was reported by more than one third (39%) of 90+ year olds.
More than half of 90+ participants reported having suffered a fall in the previous year (53%) and most participants reported using an assistive device for walking (71%). Half of all 90+ year olds used the help of a paid caregiver, either full- or part-time (51%).
In terms of cognitive performance, about one third of all participants were considered to have normal cognition (32%), another third met criteria for dementia (32%), and the remaining third had cognitive deficits that were not severe enough to meet criteria for dementia (36%). The most common type of dementia, as judged by a neurological examiner, was AD (71%).
Apolipoprotein E as a Risk Factor for Dementia or AD
Previously published studies of Caucasian populations have reported allelic frequencies for the APOE gene at about 8%, 76%, and 16% for the alleles e2, e3, and e4, respectively. In addition, the presence of the e4 allele has been described as a strong risk factor for Alzheimer’s disease and dementia in general. Most studies, however, have included very small numbers of very old subjects. In our study, we found the APOE-e4 allele to be a risk factor in women, but not in men, with clinically-diagnosed AD1
. Our study was done in the first 403 participants examined in-person in The 90+ Study. Dementia was determined by the neurological examiner applying DSM-IV criteria for dementia [43
] and NINCDS-ADRDA criteria for AD [44
APOE genotype was available for 342 of the 403 participants (85%). Most participants were women (70%) and Caucasian (100%). The average age was 94.7 years (range: 90 to 105). The APOE allelic frequencies were e2 = 8.2%, e3 = 81.6%, e4 = 10.2%. In the overall sample, the presence of an e4 allele was not associated with the prevalence of dementia or AD (). When stratified analyses were performed according to sex, the presence of an e4 allele was significantly associated with the prevalence of dementia and AD in women but not in men.
Association of the Apolipoprotein E - e4 allele with Prevalent Dementia and Alzheimer’s Disease, The 90+ Study
Our study showed the e4 allelic frequency to be lower in this sample of oldest-old participants with an equivalent increase in the e3 allelic frequency, when compared to studies of younger subjects. Moreover, the e4 allele appears to be a risk factor for dementia and AD only in oldest-old women. Additional clinical and pathological studies in relation to APOE in the oldest-old will be of interest.
Clinical and Pathological Agreement
Braak & Braak [45
] staging of β-amyloid plaques and neurofibrillary tangles (NFT) has been associated with the presence and severity of dementia in older individuals, but the few studies in the oldest-old do not consistently support this finding. Our initial results2
showed a poor correlation between a clinical diagnosis of dementia and pathological abnormalities.
Preliminary results in the first 29 participants to come to autopsy are shown below. All available data was reviewed to arrive at a consensus clinical diagnosis, using DSM-IV criteria for dementia [43
] and NINCDS-ADRDA criteria for AD [44
]. Plaque and tangle staging was done with Braak & Braak criteria [45
]. The 29 participants (7 men and 22 women) died between the ages of 92 and 105 (mean: 96.3). Nineteen of these participants were diagnosed as having dementia at the time of their last evaluation, which was on average 3.7 months before death (range: 0.2–16.1). The interval from last evaluation to death and age at death were similar in the demented and non-demented groups. Brain weight was lower in the demented group as were cognitive scores at last evaluation.
shows the distribution of plaque and tangle scores for the demented and non-demented groups. Great overlap is seen in the distributions of plaques and tangle scores of the two groups and statistical analyses showed no differences in the plaque and tangle scores of demented and non-demented participants. Of interest, all participants had some degree of NFT and none had a tangle stage less than II.
Distribution of Braak & Braak Plaque and Tangle Scores for Demented and Non-Demented Participants, The 90+ Study
When participants were classified according to agreement between clinical and pathological diagnosis, we had three similar sized groups (). None of the participants in the non-demented group had sufficient pathology to meet any of the standard pathological criteria, and thus are designated as “Not-Demented Insufficient Pathology” (NDIP). In the demented group, there were two distinct groups. The first group did not have sufficient pathology to meet any of the pathological criteria, designated here as “Demented Insufficient Pathology” (DIP). The second group met pathological criteria for Alzheimer’s disease, designated here as “Demented Alzheimer Pathology” (DAP). Thus, 9 out of 20 (45%) demented participants did not have pathology that would account for their dementia.
Classification of Autopsied Participants by Clinical and Pathological Diagnosis, The 90+ Study
To identify features that could help distinguish the groups, we compared clinical characteristics and past medical histories, including hypertension, diabetes, thyroid disease, cardiac diseases (myocardial infarction, arrhythmia, congestive heart failure), stroke, and transient ischemic attack (TIA)) (). Clinical dementia diagnoses were more varied in the DIP group, perhaps reflecting atypical features and the difficulty of diagnosing dementia in this group. Mini-Mental scores [46
] were very different in the 3 groups, with the DAP group having more severe dementia (median score = 0) as compared to the DIP group (median score = 17). There was also a difference in duration of disease, with the DIP group dying sooner after a diagnosis than those in the DAP group, even though age at death was not different. A very interesting finding was that the brain weight of the two demented groups was very similar, and lower, than the NDIP group, even when the NDIP and the DIP groups had similar levels of pathology. There were no significant differences in any of the medical histories except for a self-report of TIA’s, which were more frequent in the DIP group than the DAP group.
Characteristics of Autopsied Participants by Clinical Pathological Groups, The 90+ Study
There are several possible interpretations for our findings. First, early AD may take less pathology in 90+ year olds and the DIP group may represent early AD. Perhaps if these individuals had lived longer, they would have developed sufficient pathology to meet current AD pathologic criteria. Another interpretation may be that the DIP group represents a dementia etiology not yet identified. Finally, there are always concerns that we may be misclassifying the DIP group as demented because they were not performing or functioning as well due to various physical problems. Against this last interpretation is the observation that there were no major differences in vision, hearing, or medical histories, and that brain weight in the DIP group was similar to the DAP group. This difference in brain weight suggests to us the presence of a degenerative process.