Alzheimer's & other dementias
A clinical trial involving 9361 older adults (50+) with hypertension but without diabetes or history of stroke has found that intensive control of blood pressure significantly reduced the risk of developing mild cognitive impairment.
While there was also a 15% reduction in dementia, this result did not reach statistical significance. This may have been due to the small number of new cases of dementia in the study groups.
Participants were randomly assigned to a systolic blood pressure goal of either less than 120 mm HG (intensive treatment) or less than 140 mm HG (standard treatment). They were then classified after five years as having no cognitive impairment, MCI or probable dementia.
The trial was stopped early due to its success in reducing cardiovascular disease. As a result, participants were on intensive blood pressure lowering treatment for a shorter period than originally planned. This impacted the number of cases of dementia occurring.
Hypertension affects more than half of Americans over age 50 and more than 75% of those older than 65.
The SPRINT MIND Investigators for the SPRINT Research Group. (2019). Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA, 321(6), 553–561.
Survey data from 6,807 Danish older adults (average age 60) in the Copenhagen City Heart Study, has found that being distressed in late midlife is associated with a higher risk of dementia in later life.
The survey measured “vital exhaustion”, which is operationalized as feelings of unusual fatigue, increased irritability and demoralization and can be considered an indicator of psychological distress. Vital exhaustion is suggested to be a response to unsolvable problems in individuals' lives, in particular when being incapable of adapting to prolonged exposure to stressors.
The study found a dose-response relation between symptoms of vital exhaustion reported in late midlife and the risk of dementia later in life:
Results were adjusted for gender, marital status, lower educational level, lifestyle factors and comorbidities.
Full paper available at: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180478
 Islamoska, S., Ishtiak-Ahmed K., Hansen Å. Marie, Grynderup M. Brødsgaar, Mortensen E. Lykke, Garde A. Helene, et al.
(2019). Vital Exhaustion and Incidence of Dementia: Results from the Copenhagen City Heart Study.
Journal of Alzheimer's Disease. 67(1), 369 - 379.
Poor sleep has been associated with Alzheimer's disease risk, but a new study suggests a specific aspect of sleep is important.
The study, involving 119 older adults (60+), of whom 80% were cognitively normal and the remainder very mildly impaired, found that decreased slow-wave sleep coincided with higher levels of tau in the brain and a higher tau-to-amyloid ratio in the cerebrospinal fluid.
Amyloid plaques and tau tangles develop for decades before cognitive symptoms of dementia emerge. Identifying the process at an early stage offers a possible window of opportunity for successful intervention.
Participants’ sleep at home was monitored over the course of a normal week, and participants also kept sleep logs of nighttime sleep and daytime napping. Thirty-eight people underwent PET brain scans for amyloid-beta and tau proteins, and 104 people underwent spinal taps to provide cerebrospinal fluid. Twenty-seven did both.
Those with increased tau pathology actually slept more, during both night and day, but their quality of sleep was poorer. In fact, daytime napping alone was significantly associated with high levels of tau, making it a useful indicator of risk.
 Lucey, B. P., McCullough A., Landsness E. C., Toedebusch C. D., McLeland J. S., Zaza A. M., et al.
(2019). Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease.
Science Translational Medicine. 11(474), eaau6550.
The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, is known to be involved in cholesterol and lipid metabolism. Now the largest ever genetic study of Alzheimer’s disease, using DNA from more than 1.5 million people, has identified 90 points across the genome that were associated with an increased risk of both cardiovascular disease and Alzheimer’s disease.
The study focused on specific risk factors for heart disease (e.g., high BMI, type 2 diabetes, high cholesterol) to see if any were genetically related to Alzheimer’s risk. It was found that only those genes involved in lipid metabolism also related to Alzheimer's risk.
Six of the 90 regions had very strong effects on Alzheimer’s and heightened blood lipid levels, including several points within the CELF1/MTCH2/SPI1 region on chromosome 11 that was previously linked to the immune system.
The same genetic risk factors were also more common in people with a family history of Alzheimer’s, even though they had not themselves developed dementia or MCI.
The findings suggest that cardiovascular and Alzheimer's risk co-occur because of a shared genetic basis.
They also suggest a therapeutic target — namely, pathways involved in lipid metabolism.
Broce I, Karch C, Desikan R, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica, published online Nov. 9, 2018.
Data from 1,215 older adults, of whom 173 (14%) were African-American, has found that, although brain scans showed no significant differences between black and white participants, cerebrospinal fluid (CSF) showed significantly lower levels of the brain protein tau in African-Americans.
While both groups showed the same (expected) pattern of higher tau levels being associated with greater chance of cognitive impairment, the absolute amounts of tau protein were consistently lower in African-Americans.
However, when APOE status was taken into account, it was found that those who held the low-risk variants of the “Alzheimer’s gene” had similar levels of tau, regardless of race. It was only African-Americans with the APOE4 gene variant that showed lower levels of tau.
This suggests that the APOE4 risk factor has different effects in African-Americans compared to non-Hispanic white Americans, and points to the need for more investigation into how Alzheimer’s develops in various populations.
Interestingly, another study, using data from 1798 patients (of whom 1690 were white), found that there was a strong gender difference in the association between APOE status and tau levels in the CSF.
Previous research has shown that the link between APOE4 and Alzheimer's is stronger in women than men. This study points to a connection with tau levels, as there was no gender difference in the association between APOE and amyloid-beta levels, amyloid plaques, or tau tangles.
Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. Published online January 07, 2019. doi:10.1001/jamaneurol.2018.4249
Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018;75(8):989–998. doi:10.1001/jamaneurol.2018.0821
A number of studies have found that physical exercise can help delay the onset of dementia, however the ability of exercise to slow the decline once dementia has set in is a more equivocal question. A large new study answers this question in the negative.
The study involved 494 people with mild-to-moderate dementia (average age 77; 61% male), of whom 329 were randomly assigned to a four-month aerobic and strength exercise programme and 165 were assigned to usual care. The exercise program was personalized, and involved two 60-90 minute gym sessions every week, plus a further hour at home. Nearly two-thirds of the exercise group attended more than three-quarters of the gym sessions.
While the exercise group did get physically fitter, their cognitive fitness (as measured by ADAS-cog score) actually worsened slightly.
The researchers emphasize that this was a specialized and intense exercise program, and in no way should it be taken to mean that gentle exercise, which is good for dementia sufferers, should be avoided.
 Lamb, S. E., Sheehan B., Atherton N., Nichols V., Collins H., Mistry D., et al.
(2018). Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial.
BMJ. 361, k1675.
A small Japanese study has found evidence that those with amnestic mild cognitive impairment (aMCI) show a specific decline in their ability to recognize faces, and this is accompanied by changes in the way they scan faces.
The study involved 18 patients with aMCI and 18 age-matched healthy controls. Participants were tested on their ability to perceive and remember images of faces and houses.
Those with aMCI showed poorer memory for faces compared to their memory for houses, while control participants showed no difference between the two. Moreover, compared with controls, those with aMCI spent less time looking at the eyes in the image, while increasing the time they spent looking at the mouths of faces.
In general, people have an excellent memory for faces compared to other visual stimuli, and the eyes are particularly useful in helping us remember the face. The researchers suggest that damage to the brain region known as the fusiform face area (FFA) is responsible for the abnormal processing of faces. It is worth noting that a case study of a patient with acquired prosopagnosia revealed the same pattern of fixating on the mouth rather than the eyes.
The finding is consistent with several other studies showing impaired face processing in those with aMCI, but there is some controversy about that conclusion.
Full text available at https://www.nature.com/articles/s41598-017-14585-5
 Kawagoe, T., Matsushita M., Hashimoto M., Ikeda M., & Sekiyama K.
(2017). Face-specific memory deficits and changes in eye scanning patterns among patients with amnestic mild cognitive impairment.
Scientific Reports. 7(1), 14344.
Mild cognitive impairment (MCI) is a precursor of Alzheimer's disease, although having MCI does not mean you are definitely going to progress to Alzheimer's. A new study suggests that one sign of MCI development might be personality changes.
The study involved 277 cognitively healthy residents of a U.S. County, who had the apolipoprotein E (APOE) ɛ4 gene (otherwise known as the ‘Alzheimer’s gene’). Over the study period (around 7 years), 25 developed MCI. Their performance on the Neuroticism, Extraversion, and Openness Personality Inventory—Revised (delivered at the beginning of the study, as well as at other times during the study) was compared with that of the other 252 participants.
Neuroticism increased significantly more in those developing MCI, and openness decreased more. Those developing MCI also showed significantly greater depression, somatization, irritability, anxiety, and aggressive attitude. (Somatization refers to the tendency to generate physical manifestations in response to psychological distress.)
While such personality changes may be barely noticeable at this stage, it may be that diagnosing such early personality changes could help experts develop earlier, safer, and more effective treatments — or even prevention options — for the more severe types of behavior challenges that affect people with Alzheimer's disease.
 Caselli, R. J., Langlais B. T., Dueck A. C., Henslin B. R., Johnson T. A., Woodruff B. K., et al.
(2018). Personality Changes During the Transition from Cognitive Health to Mild Cognitive Impairment.
Journal of the American Geriatrics Society. 66(4), 671 - 678.
A large study using data from the famous Framingham Heart Study has compared changes in dementia onset over the last three decades. The study found that over time the age of onset has increased while the length of time spent with dementia has decreased.
The study involved 5,205 participants from the Framingham Original and Offspring cohorts. Four 5-year periods anchored to different baseline examinations (participants have been examined every four years) were compared. These baseline years are (on average, because participants’ schedules are different): 1978, 1989, 1996, 2006. Participants were those who were aged 60 or older and dementia-free at the start of a time period. There were at least 2000 participants in each time period. In total, there were 371 cases of dementia, and 43% of dementia cases survived more than 5 years after diagnosis.
It was found that the mean age of dementia onset increased by around two years per time period, while age at death increased by around one year. Length of survival after diagnosis decreased over time for everyone, taken as a whole, and also for each gender and education level, taken separately. Survival was almost 6 years in the first time period, and only three years in the last. But the mean age of onset was 80 in the first period, compared to over 86 in the last.
However, the changes haven’t been steady over the 30 years, but rather occurred mostly in those with dementia in 1986–1991 compared to 1977–1983.
Part of the reason for the changes is thought to be because of the reduced risk of stroke (largely because of better blood pressure management), and the better stroke treatments available. Stroke is a major risk factor for dementia. Other reasons might include lower burdens of multiple infections, better education, and better nutrition.
 Dufouil, C., Beiser A., Chêne G., & Seshadri S.
(2018). Are Trends in Dementia Incidence Associated With Compression in Morbidity? Evidence From The Framingham Heart Study.
The Journals of Gerontology: Series B. 73(suppl_1), S65 - S72.
Data from over 11,500 participants in the Atherosclerosis Risk in Communities (ARIC) cohort has found evidence that orthostatic hypotension in middle age may increase the risk of cognitive impairment and dementia 20 years later.
Orthostatic hypotension is the name for the experience of dizziness or light-headedness on standing up. Previous research has suggested an association between orthostatic hypotension and cognitive decline in older adults.
In this study, participants aged 45-64 were tested for orthostatic hypotension in 1987. Those with it (703, around 6%) were 40% more likely to develop dementia in the next 20 years. They also had some 15% more cognitive decline.
Orthostatic hypotension was defined as a drop of 20 mmHg or more in systolic blood pressure or 10 mmHg or more in diastolic blood pressure, when the individual stood up after 20 minutes lying down.
More work is needed to understand the reason for the association.
Rawlings, Andreea. 2017. Orthostatic Hypotension is Associated with 20-year Cognitive Decline and Incident Dementia: The Atherosclerosis Risk in Communities (ARIC) Study. Presented March 10 at the American Heart Association's EPI|LIFESTYLE 2017 Scientific Sessions in Portland, Oregon.
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