Alzheimers

Alzheimer's & other dementias

Alzheimer's disease symptoms more subtle in people over 80

September, 2011
  • A new study shows that, among the very old, it’s harder to distinguish between normal brain atrophy and cognitive impairment and that indicative of Alzheimer’s.

A study involving 105 people with Alzheimer's disease and 125 healthy older adults has compared cognitive function and brain shrinkage in those aged 60-75 and those aged 80+.

It was found that the association between brain atrophy and cognitive impairment typically found in those with Alzheimer’s disease was less evident in the older group. This is partly because of the level of brain atrophy in healthy controls in that age group — there was less difference between the healthy controls and those with Alzheimer’s. Additionally, when compared to their healthy counterparts, executive function, immediate memory and attention/processing speed were less abnormal in the older group than they were in the younger group.

The finding suggests that mild Alzheimer’s in the very old may go undetected, and emphasize the importance of taking age into account when interpreting test performance and brain measures.

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Sleep apnea and brain injury raise risk of later dementia

August, 2011

Recent studies add to the evidence that sleep apnea and even mild brain injury increase the risk of developing dementia.

Sleep apnea linked to later dementia

A study involving 298 older women with sleep problems found that those who had disordered breathing (such as sleep apnea) were significantly more likely to develop dementia or mild cognitive impairment.

Around a third of the women (average age 82) had disordered breathing (slowing down or stopping breathing during sleep and often having to gasp to catch up). None showed signs of cognitive impairment at the time of the sleep testing. When re-tested some five years later, 45% of those who had disordered breathing had developed dementia or MCI, compared with 31% of those with no breathing irregularities.

Those whose sleep irregularities had been particularly severe (15 or more breathing stoppages per hour and more than 7% of sleep time not breathing) during the earlier part of the study were nearly twice as likely as those without breathing problems to develop dementia or MCI. Other measures of sleep quality — waking after sleep onset, sleep fragmentation, sleep duration — were not associated with cognitive impairment.

The finding adds to the evidence for the importance of treating sleep apnea. Previous research has found that CPAP treatment effectively counteracts cognitive impairment caused by sleep apnea.

Brain injury raises dementia risk

Analysis of medical records on 281,540 U.S. military veterans aged at least 55 at the beginning of the study has found that over the next seven years those who had at one time suffered a traumatic brain injury were more than twice as likely to develop dementia than those who had not suffered such an injury. Around 1.7% (4,902) had incurred a traumatic brain injury, in many cases during the Vietnam War, and over 15% of these developed dementia. In contradiction of the prevailing belief that only moderate or severe brain injuries predispose people to dementia, severity of the injury made no difference.

Injuries due to strokes were weeded out of the study.

In another study, following up on nearly 4,000 retired National Football League players surveyed in 2001, 35% appeared to have significant cognitive problems (as assessed by questionnaire). When 41 of them were tested, they were found to have mild cognitive impairment that resembled a comparison group of much older patients from the general population.

The findings are a reminder of the importance of treating even mild head injuries, and of following a regime designed to mitigate damage: exercising, eating a healthy diet, reducing stress, and so on.

Reference: 

[2444] Yaffe, K., Laffan A. M., Harrison S L., Redline S., Spira A. P., Ensrud K. E., et al.
(2011).  Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women.
JAMA: The Journal of the American Medical Association. 306(6), 613 - 619.

The brain injury studies were reported in July at the Alzheimer's Association International Conference in France. http://www.alz.org/aaic/

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Diagnosis and prevalence of dementia & MCI — recent reports

August, 2011

Several recent reports point to the need for GPs to be better informed about the initial symptoms of dementia and mild cognitive impairment.

Functional impairment good indicator of mild cognitive impairment

Evaluation of 816 older adults, of whom 229 had no cognitive problems, 394 had a diagnosis of amnestic mild cognitive impairment, and 193 had a diagnosis of mild Alzheimer’s, has revealed that most of those with aMCI (72%) or AD (97%) had trouble with at least one type of function on the Pfeffer Functional Activities Questionnaire. Only 8% of controls had any difficulty. In both impaired groups, those who had the most difficulty functioning also tended to score worse on cognition tests, have smaller hippocampal volumes, and carry the APOe4 gene.

Two of the ten items in the questionnaire were specific in differentiating the control group from the impaired groups. Those items concerned "remembering appointments, family occasions, holidays, and medications” and "assembling tax records, business affairs, or other papers." Only 34% of those with aMCI and 3.6% of those with AD had no difficulty with these items.

The findings suggest that even mild disruptions in daily functioning may be an important clinical indicator of disease.

Early-onset Alzheimer’s poorly diagnosed when initial symptoms aren’t memory related

Post-mortem analysis of 40 people diagnosed  with early-onset Alzheimer’s has revealed that about 38% experienced initial symptoms other than memory problems, such as behavior, vision or language problems and a decline in executive function, or the ability to carry out tasks. Of these, 53% were incorrectly diagnosed when first seen by a doctor, compared to 4% of those who had memory problems. Of those with unusual initial symptoms, 47% were still incorrectly diagnosed at the time of their death.

The mean age at onset was 54.5 years (range 46-60). The average duration of the disease was 11 years, with an average diagnostic delay of 3 years.

GPs misidentify and fail to identify early dementia and MCI

A review of 30 studies involving 15,277 people seen in primary care for cognitive disorders, has found that while GPs managed to identify eight out of ten people with moderate to severe dementia, they only identified 45% of those with early dementia and mild cognitive impairment. Moreover, they were very poor at recording such diagnoses. Thus, though they recognized 45% of the MCI cases, they only recorded 11% of these cases in their medical notes. Although they identified 73% of people with dementia, they made correct annotations in medical records in only 38% of cases.

But the problem is not simply one of failing to diagnose — they were even more likely to misidentify dementia, and this was particularly true for those with depression or hearing problems.

The findings point to the need for more widespread use of simple cognitive screening tests.

Prevalence of dementia & MCI in 'oldest old' women

Data from 1,299 women enrolled in the Women Cognitive Impairment Study of Exceptional Aging suggests that the incidence of dementia almost doubles with every 5 years of age and prevalence rises from approximately 2-3% in those 65 to 75 years to 35% in those 85+.

Among those with mild cognitive impairment, amnestic multiple domain was most common (34%), followed by non-amnestic single domain (29%). Amnestic single domain (affecting only one type of cognitive function, including memory difficulty) affected 22%.

Alzheimer's disease and mixed dementia accounted for nearly 80% of dementia cases, and vascular dementia for 12.1%.

Those with dementia tended to be older, less likely to have completed high school, more likely to have reported depression, a history of stroke, and to have the APOEe4 gene.

The women in the study had an average age of 88.2 years and 27% were older than 90. 41% had clinical cognitive impairment (17.8% with dementia and 23.2% with mild cognitive impairment).

The high prevalence of cognitive impairment in this age group points to the importance of screening for cognitive disorders, particularly among high-risk groups.

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Discovery of more risky genes reveals more about the paths to Alzheimer’s

June, 2011

New genetic studies implicate myelin development, the immune system, inflammation, and lipid metabolism as critical pathways in the development of Alzheimer’s.

I commonly refer to ApoE4 as the ‘Alzheimer’s gene’, because it is the main genetic risk factor, tripling the risk for getting Alzheimer's. But it is not the only risky gene.

A mammoth genetic study has identified four new genes linked to late-onset Alzheimer's disease. The new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells, pointing to three new pathways that are critically related to the disease.

Genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of healthy older adults, plus additional data from another 32,000, has identified MS4A, CD2AP, CD33, and EPHA1 genes linked to Alzheimer’s risk, and confirmed two other genes, BIN1 and ABCA7.

A second meta-analysis of genetic data has also found another location within the MS4A gene cluster which is associated with Alzheimer's disease. Several of the 16 genes within the cluster are implicated in the activities of the immune system and are probably involved in allergies and autoimmune disease. The finding adds to evidence for a role of the immune system in the development of Alzheimer's.

Another study adds to our understanding of how one of the earlier-known gene factors works. A variant of the clusterin gene is known to increase the risk of Alzheimer’s by 16%. But unlike the ApoE4 gene, we didn’t know how, because we didn’t know what the CLU gene did. A new study has now found that the most common form of the gene, the C-allele, impairs the development of myelin.

The study involved 398 healthy adults in their twenties. Those carrying the CLU-C gene had poorer white-matter integrity in multiple brain regions. The finding is consistent with increasing evidence that degeneration of myelin in white-matter tracts is a key component of Alzheimer’s and another possible pathway to the disease. But this gene is damaging your brain (in ways only detectible on a brain scan) a good 50 years before any clinical symptoms are evident.

Moreover, this allele is present in 88% of Caucasians. So you could say it’s not so much that this gene variant is increasing your risk, as that having the other allele (T) is protective.

Reference: 

[2257] Naj, A. C., Jun G., Beecham G. W., Wang L-S., Vardarajan B. N., Buros J., et al.
(2011).  Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.
Nat Genet. 43(5), 436 - 441.

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at http://genomemedicine.com/content/3/5/33/abstract

[2254] Braskie, M. N., Jahanshad N., Stein J. L., Barysheva M., McMahon K. L., de Zubicaray G. I., et al.
(2011).  Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults.
The Journal of Neuroscience. 31(18), 6764 - 6770.

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Alzheimer's diagnostic guidelines updated

June, 2011
  • Updated clinical guidelines now cover three distinct stages of Alzheimer's disease.

For the first time in 27 years, clinical diagnostic criteria for Alzheimer's disease dementia have been revised, and research guidelines updated. They mark a major change in how experts think about and study Alzheimer's disease.

The updated guidelines now cover three distinct stages of Alzheimer's disease:

  • Preclinical – is currently relevant only for research. It describes the use of biomarkers that may precede the development of Alzheimer’s.
  • Mild Cognitive Impairment– Current biomarkers include elevated levels of tau or decreased levels of beta-amyloid in the cerebrospinal fluid, reduced glucose uptake in the brain, and atrophy of certain brain regions. Primarily for researchers, these may be used in specialized clinical settings.
  • Alzheimer's Dementia – Criteria outline ways clinicians should approach evaluating causes and progression of cognitive decline, and expand the concept of Alzheimer's dementia beyond memory loss to other aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment.

The criteria are available at http://www.alzheimersanddementia.org/content/ncg

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Brain starts shrinking long before Alzheimer's appears

June, 2011

A study following older adults for more than a decade has found that neural volume in specific brain regions markedly predicted later development of Alzheimer’s.

A long-term study of older adults with similar levels of education has found that those with the thinnest cerebral cortex in specific brain regions were the most likely to develop dementia. Among those in whom these signature brain areas were the thinnest at the beginning of the study, 55% developed dementia over the next decade, compared with 20% of those with average cortical thickness and none of those in whom cortical thickness was above average. Those with the thinnest cortical areas also developed Alzheimer's significantly faster.

The study involved two independent samples. In the first group, 33 people were followed for an average of 11 years, during which time eight developed Alzheimer's. In the second group, 32 people were followed for an average of seven years, and seven of them developed the disease. (So 23% developed Alzheimer’s in total.) Participants were divided into three groups based on cortical thickness in the key areas: 11 had the lowest levels, 9 had the highest, and 45 were average.

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Tobacco-derived compound prevents memory loss in Alzheimer's mice

June, 2011

A mouse study has found that a compound derived from tobacco reduced plaques associated with dementia and prevented memory loss.

Some epidemiological studies have showed that people who smoke tend to have lower incidences of Parkinson's disease and Alzheimer's disease; this has been widely attributed to nicotine. However, nicotine's harmful effects make it a poor drug candidate.

Cotinine, a byproduct of nicotine metabolism, is nontoxic and longer lasting than nicotine.

In the study, genetically engineered 2-month-old mice were given cotinine daily for five months. When tested, those treated with cotinine performed at the same level as normal mice on spatial memory tests, and showed a 26% reduction in deposits of amyloid plaques, compared to the genetically engineered mice who had not received the treatment. Cotinine also inhibited the accumulation of the amyloid peptide oligomers, and stimulated the signaling factor Akt, which promotes the survival of neurons and enhances attention and memory.

The researchers are hoping to carry out a pilot clinical trial to investigate cotinine's effectiveness in preventing progression to Alzheimer's dementia in patients with mild cognitive impairment.

Reference: 

Echeverria, V. et al. In press. Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice. Journal of Alzheimer's Disease, 24 (4).

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Treating high blood pressure, cholesterol, diabetes may lower risk of Alzheimer's disease

May, 2011

New findings reveal that mild cognitive impairment is more likely to develop into Alzheimer’s if vascular risk factors are present, especially if untreated.

A study following 837 people with MCI, of whom 414 (49.5%) had at least one vascular risk factor, has found that those with risk factors such as high blood pressure, diabetes, cerebrovascular disease and high cholesterol were twice as likely to develop Alzheimer's disease. Over five years, 52% of those with risk factors developed Alzheimer's, compared to 36% of those with no risk factors In total, 298 people (35.6%) developed Alzheimer's.

However, of those with vascular risk factors, those receiving full treatment for their vascular problems were 39% less likely to develop Alzheimer's disease than those receiving no treatment, and those receiving some treatments were 26% less likely to develop the disease.

Treatment of risk factors included using high blood pressure medicines, insulin, cholesterol-lowering drugs and diet control. Smoking and drinking were considered treated if the person stopped smoking or drinking at the start of the study.

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More evidence moderate alcohol consumption helps stave off dementia

April, 2011

More evidence that a moderate amount of alcohol helps protect against Alzheimer’s —but not vascular dementia or age-related cognitive decline.

A review of 23 longitudinal studies of older adults (65+) has found that small amounts of alcohol were associated with lower incidence rates of overall dementia and Alzheimer dementia, but not of vascular dementia or age-related cognitive decline. A three-year German study involving 3,327 adults aged 75+ extends the evidence to the older-old.

The study found alcohol consumption was significantly associated with 3 other factors that helped protect against dementia: better education, not living alone, and absence of depression. Nevertheless, the lower risk remained after accounting for these factors.

The ‘magic’ amount of alcohol was between 20-29g, roughly 2-3 drinks a day. As in other studies, a U-shaped effect was found, with higher risk found among both those who consumed less than this amount of alcohol, and those who consumed more.

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More evidence that Alzheimer's disease may be inherited from your mother

March, 2011
  • A new study adds to growing evidence that having a mother with Alzheimer's disease is a greater risk factor than if your father suffered the disease.

A two-year study involving 53 older adults (60+) has found that those with a mother who had Alzheimer's disease had significantly more brain atrophy than those with a father or no parent with Alzheimer's disease. More specifically, they had twice as much gray matter shrinkage, and about one and a half times more whole brain shrinkage per year.

This atrophy was particularly concentrated in the precuneus and parahippocampal gyrus. Those with the APOE4 gene also had more atrophy in the frontal cortex than those who didn’t carry the ‘Alzheimer’s gene’.

This adds to evidence indicating that maternal history is a far greater risk factor for Alzheimer’s than paternal history. Eleven participants reported having a mother with Alzheimer's disease, 10 had a father with Alzheimer's disease and 32 had no family history of the disease. It has been estimated that people who have first-degree relatives with Alzheimer's disease are four to 10 times more likely to develop the disease.

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