Daniel J. Berlau

Dementia Incidence Continues to Increase with Age in the Oldest Old The 90+ Study

The oldest old are the fastest growing segment of the US population, and accurate estimates of dementia incidence in this group are crucial for healthcare planning. Although dementia incidence doubles every 5 years from ages 65 to 90 years, it is unknown if this exponential increase continues past age 90 years. Here, we estimate age‐ and sex‐specific incidence rates of all‐cause dementia in people aged 90 years and older, including estimates for centenarians.

Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala.

Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present experiments investigated whether the same modulatory influences are involved in regulating the extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC) task and 24 and 48 h later were given extinction training. Immediately following each extinction session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the beta-adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3, 1.0, and 3.0 microg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA activation during extinction, other animals were given infusions of muscimol (500 ng) via an ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The findings also suggest that the BLA influence on extinction is not mediated by an interaction with the dorsal hippocampus.

Basolateral amygdala noradrenergic activity mediates corticosterone-induced enhancement of auditory fear conditioning

The present experiment examined whether posttraining noradrenergic activity within the basolateral complex of the amygdala (BLA) is required for mediating the facilitating effects of acutely administered glucocorticoids on memory for auditory-cue classical fear conditioning. Male Sprague-Dawley rats received five pairings of a single-frequency auditory stimulus and footshock, followed immediately by bilateral infusions of the beta1-adrenoceptor antagonist atenolol (0.5 microg in 0.2 microl) or saline into the BLA together with a subcutaneous injection of either corticosterone (3.0 mg/kg) or vehicle. Retention was tested 24 h later in a novel test chamber and suppression of ongoing motor behavior served as the measure of conditioned fear. Corticosterone facilitated memory as assessed by suppression of motor activity during the 10-s presentation of the auditory stimulus and intra-BLA administration of atenolol selectively blocked this corticosterone-induced memory enhancement. These findings provide evidence that, as found with other emotionally arousing tasks, the enhancing effects of corticosterone on memory consolidation of auditory-cue fear conditioning require posttraining noradrenergic activity within the BLA.

Prevalence of dementia after age 90 Results from The 90+ Study

Background: Although the prevalence of dementia increases with age from ages 65 to 85, whether this increase continues after age 90 is unclear. Most studies reporting on dementia prevalence do not have sufficient participants to estimate prevalence for specific ages and sexes above age 90. Here, we estimate age- and sex-specific prevalence of all-cause dementia in the oldest-old, those aged 90 and older. Methods: Participants are 911 elderly from The 90+ Study, a population-based study of aging and dementia in people aged 90 and above. Dementia was diagnosed using in-person examinations as well as telephone and informant questionnaires. Results: The overall prevalence of all-cause dementia was higher in women (45%, 95% CI = 41.5–49.0) than men (28%, 95% CI = 21.7–34.2). Among women, prevalence increased with age after age 90, essentially doubling every 5 years. A lower prevalence of dementia was significantly associated with higher education in women but not in men. Conclusions: In a very large sample of participants aged 90 and older, prevalence of all-cause dementia doubled every 5 years for women but not men.

APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old

Background: Many studies have examined the role of APOE genotype in the development of dementia, specifically Alzheimer disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathologic AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathologic criteria for AD. Methods: The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using National Institute of Neurological and Communicative Disorders and Stroke–Alzheimers Disease and Related Disorders Association criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurologic examination, and medical records. Neuropathologic examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathologic AD using National Institute on Aging–Reagan criteria. Results: Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathologic criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE3/3), APOE4 carriers were more likely to be diagnosed with dementia (odds ratio [OR] = 12.2, 95% confidence interval [CI] = 1.5–102.0), whereas APOE2 carriers were not (OR = 0.3, 95% CI = 0.1–1.3). Surprisingly, both APOE4 (OR = 4.6, 95% CI = 1.3–16.5) and APOE2 (OR = 7.8, 95% CI = 1.5–40.2) carriers were more likely to meet neuropathologic criteria for AD than those with APOE3/3 genotype. Conclusions: In the oldest old, the presence of the APOE ε2 allele (APOE2) was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased Alzheimer disease (AD) neuropathology. Therefore, oldest old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.

A population-based clinicopathological study in the oldest-old: the 90+ study.

Population-based longitudinal clinicopathological studies provide an ideal opportunity to study a variety of risk and protective factors in relation to pathology associated with dementia in individuals who are representative of the general population. The 90+ Study is a population-based study designed specifically to study aging and dementia as well as its neuropathological correlates in participants 90 years of age and older. We present demographic and pathological data on the first 104 participants to come to autopsy from the brain donation component of the study, The 90+ Autopsy Study. Cognitive diagnosis was assigned according to diagnostic and statistical manual 4th edition criteria for dementia and neuropathological diagnoses were made according to the Consortium to Establish a Registry for Alzheimers Disease protocol. Dementia was present in 61% of autopsied participants, the majority of whom were diagnosed with Alzheimers disease (85%). Many different types of pathology typically associated with dementia were common in the oldest-old, and included neurofibrillary tangles, neuritic plaques, diffuse plaques, Lewy bodies, hippocampal sclerosis, and cerebral infarctions. Most types of pathology were more frequently found in participants suffering from dementia but there was extensive overlap in pathology among those with and without dementia. In addition, 22% of demented participants did not have sufficient pathology to account for their cognitive loss. Our results highlight the poor associations between these common pathological lesions and dementia in the oldest-old and the importance of considering many different types of pathology, possibly including some yet to be identified, in order to account for all dementias in the oldest-old.

Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old

The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimers disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology.

The Prevalence of Disability in the Oldest-old is High and Continues to Increase with Age: Findings from The 90+ Study

To examine the prevalence and type of disability in the oldest‐old (90+), the fastest growing age group in the United States.

Apolipoprotein e genotype, dementia, and mortality in the oldest old: The 90+ Study

Although the apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimers disease (AD), it is not clear whether this relationship persists among the oldest old. Several European studies suggest that the effect of the APOE ε4 allele on dementia and mortality disappears in very old age. We describe the APOE allele and genotype frequencies and examine whether the presence of the APOE ε4 or APOE ε2 alleles is related to prevalent dementia, incident dementia, and mortality in a population‐based cohort of oldest‐old participants in the United States.

Cognitive impairment in nondemented oldest-old: prevalence and relationship to cardiovascular risk factors.

To determine the prevalence and types of cognitive impairment in a sample of nondemented participants aged ≥90 (the oldest‐old) and to examine the relationships between cognitive impairment and cardiovascular risk factors.