July 14, 2009 (Vienna, Austria) — Results of 2 new studies show that both the incidence and prevalence of dementia continue to rise in a linear fashion among the so-called "oldest old," those in their 80s and 90s and even among centenarians.

The results, from the population-based Monzino 80-Plus Study in Italy and the 90+ Study in the United States, would appear to contradict fairly conclusively the previously held idea that conversion to dementia plateaus or even declines in this oldest-old population.

"The prevalence and incidence rates of dementia found in the Monzino 80-Plus study continue to rise also in very advanced ages," Ugo Lucca, MD, from the Laboratory of Geriatric Neuropsychiatry at the Istituto di Ricerche Farmacologiche Mario Negri, in Milan, Italy. "Age remains the most important risk factor for dementia, and we need to further our understanding of its role if effective therapeutic and preventive strategies are to be developed."

Claudia Kawas, MD, from the University of California, Irvine, showed a linear increase in dementia risk from 10% in the 90- to 95-year-olds to a "whopping" 41% for centenarians in the 90+ Study.

"I for one just spent about 2 decades of my career suggesting that the incidence rates of dementia go down after age 85," she said. "This just goes to show that you really don't know what you think you know."

The results of both studies were presented here at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009).

Monzino 80-Plus Study

Patients with dementia included in clinical research are systematically younger than those in the general population, and this may limit the generalizability of the findings to the oldest old, Dr. Lucca told a press conference here. Because the numbers of these older patients who have been studied in epidemiological surveys have been small, incidence estimates fluctuate widely, he noted, "and the evidence is often insufficient to reach confident conclusions."

Dr. Ugo Lucca

There is also growing evidence that the classical pathology of amyloid plaques and neurofibrillary tangles do not correlate with cognitive status in these oldest-old patients. For example, a study published just this year in the New England Journal of Medicine (NEJM) from the Medical Research Council Cognitive Function and Ageing Study found that the association between pathological features of AD and dementia was stronger in "younger-old" subjects than in the older old (Savva GM et al. N Engl J Med 2009;360:2302-2309).

The Monzino 80-Plus study is a prospective, door-to-door population-based survey of all residents 80 years of age and older living in 8 municipalities of Varese province in Italy. Of 2436 eligible residents, information could be gathered for 2138 subjects, a response rate of 87.8%, making this among the largest studies of dementia in this population, Dr. Lucca noted.

On the first visit, prevalent dementia was found in 25% of this population of over-80-year-olds, with an almost 4-fold increase with age, increasing from approximately 14% at 80 to 84 years to about 55% over 90 years of age, he said. More women were affected than men, with dementia seen in 27% of women vs 18% of men.

Of 1085 surviving participants, 995, or 91%, were reevaluated after an average follow-up of 3 years. Incident dementia among those not demented at baseline occurred at a rate of about 8 new cases per 100 persons, he noted, and here the rate also rose with age, from about 6 cases per 100 persons among those aged 80 to 84 years to 19 cases per 100 among those 95 years of age or older. "Thus, from 80 to 95 years of age, the proportion of new cases triples," Dr. Lucca said.

Monzino 80-Plus Study: Prevalence and Incidence of Dementia

Age Group (y)	Prevalence (95% CI)	Incidence (95% CI)
80 – 84	14.6 (12.1 – 17.5)	6.3 (4.6 – 8.4)
85 – 89	32.8 (29.2 – 36.6)	8.2 (6.7 – 10.0)
90 – 94	40.6 (36.7 – 44.6)	15.6 (13.0 – 18.6)
95+	55.5 (47.5 – 63.2)	19.2 (13.7 – 26.2)
80+*	24.3 (22.5 – 26.2)	7.9 (6.9 – 8.9)

*Standardized to the Italian population

Incident dementia was about 30% higher in women than in men, occurring in about 8.5% of women vs 6.5% in men. However, he noted, "Since the number of men at these extreme ages becomes very small, the interpretation of the gender difference should be cautious."

"With almost one-fourth of over-80s and almost half of over-90s affected, the results of our study confirm that dementia is widespread among the older olds and strengthen the need to shift the focus of clinical research to this segment of the elderly population," Dr. Lucca concluded. "In fact, evidence drawn from younger olds cannot necessarily be generalized to the older olds."

Findings of the NEJM paper and other research suggest the pathology of dementia in the oldest old may be different from classical AD, he said. "Probably dementia is a common expression of many diseases, where several rivers flow together into the lake of the disease, and each person has a different river."

90+ Study: Epidemiology and Autopsy Findings

Dr. Kawas similarly reported a high incidence of dementia in the oldest old, particularly centenarians, with results from the 90+ Study, also a population-based study of the oldest old. In this study, 330 participants underwent in-person neurological examination and were determined to be nondemented at baseline. Blood and DNA were also collected, and over follow-up, many of the participants agreed to donate their brain upon their death. "We now have over 100 brains in the brain bank," Dr. Kawas noted.

Dr. Claudia Kawas [Source: University of California, Irvine]

They were followed from January 2003 through December 2007, for a total of 770 person-years. Assessments in this study were done every 6 months. There were 140 cases of incident dementia identified over 770 person-years, for an overall incidence rate of 18.2% per year. Of these cases, 20 occurred among the centenarians, she noted.

Interestingly, she noted, men and women had almost identical rates of incident dementia: 17.9% in men and 18.3% in women. Their previous findings in this same cohort showed a prevalence of dementia among women that was double that of men, Dr. Kawas noted.

"The fact that we have an identical incidence rate for men and women in the incidence study I think tells us that the risk for dementia in women is not higher, but once they become demented, they live longer than men who are demented, just as women without dementia live longer than men without dementia," she said.

The effect of age on incidence was linear on the log scale, such that dementia incidence doubled every 5.5 years overall and in both sexes, strikingly similar to what has been seen for those under 85 years of age. "Essentially the rate goes from 10% for the 90- to 94-year-olds to 20% in the 95- to 99-year-olds and a whopping 41% for our centenarians, unfortunately," she said.

"I'm very convinced by these results," Dr. Kawas concluded. "I think the doubling time being completely consistent with younger ages and the dead-on similar rate for men and women are very striking and convince me that unfortunately the risk of this dreadful disorder does not go down with age."

In an interview with Medscape, Dr. Kawas speculated that the difference between their findings of no sex difference in incident dementia and those of Dr. Lucca's group may relate to the sampling frequency, which was 6 months in their study and 3 years in the Monzino 80-Plus study. "The longer your interval, the greater the likelihood of missing short-duration cases, and the short-duration cases are going to be the men," she said. This same issue may also explain why previous studies have suggested dementia declines in older age, she added.

Poor Correlation

Also at this meeting, Dr. Kawas presented autopsy data of the brains donated to date in the 90+ Study. Interestingly, there was again very little correlation between the clinical assessment of dementia or no dementia and what was found at autopsy. "If we said somebody was demented who came to autopsy, there was a 50% chance that the pathologist would call them normal elderly brain," she said.

There is a very poor relationship of cognition with amyloid measures, Dr. Kawas added, and only a slightly better relationship with neurofibrillary tangles and tau. "Far and away the best correlation for cognition in this sample turned out to be, so far, synaptophysin," she said, a way of measuring the integrity of synapses, that had an almost linear correlation with cognition. However, the actual disease process is unclear. "That's the million-dollar question — what is the pathology?" she said.

Pathologists are now examining a variety of measures, including other isomers of amyloid and tau, to see whether these other specific forms might be related to cognition. Their group is also doing neuronal counting in the hippocampus of these brains, as well as looking at the size of the neurons to see if this is relevant. "It might be that you might not lose neurons but lose size, and that could account for brain shrinkage." Finally, they are looking at other types of vascular pathology.

Work Just Beginning

Dr. Kristine Yaffe

Asked for comment on these findings, Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology and associate chair of research for the department of psychiatry at the University of California, San Francisco, pointed out that work among the oldest old is still a burgeoning area of research.

Until recently, there were not that many people of this age around, and now it is actually the fastest-growing segment of the population, she said. "You don't see that many people in their 90s as a physician, but I think what we're talking about here is, what is it about the pathology in that group, and is the dementia in that group different from dementia in the earlier group?"

These people are not even generally included in trials, Dr. Yaffe noted. "If we're understanding that the neuropathology is different, maybe we need a trial of the oldest old."

There may also be differences in risk factors for dementia in this group, she added. "So, for example, whether this is due to survival bias or other reasons — we don't know — it looks like some of the traditional risk factors that we think of for dementia don't bear out in the oldest old. And again, I think we're just starting to understand why that is."

Dr. Yaffe added that she has just been funded by the Alzheimer's Association to look at risk factors in this group of oldest old.

The 90+ Study was funded by the National Institute on Aging. Dr. Kawas reports no conflicts of interest. The Monzino 80-Plus Study is supported by the nonprofit Monzino Foundation. Dr. Lucca reports no conflict of interest.

2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009): Abstracts P3-168, 02-02-08. Presented July 14, and 13, 2009.