Early Markers

Latest Research News

In the past few months, several studies have come out showing the value of three different tests of people's sense of smell for improving the accuracy of MCI and Alzheimer's diagnosis, or pointing to increased risk. The studies also add to growing evidence that a decline in sense of smell is an early marker for mild cognitive impairment and Alzheimer’s. Indeed, it appears that this sensory loss is a very early symptom, preceding even the shrinking of the entorhinal cortex (the first brain region to show signs of atrophy).

Smell test improves accuracy of MCI & Alzheimer's diagnosis

A simple, commercially available test known as the Sniffin' Sticks Odor Identification Test, in which subjects must try to identify 16 different odors, was given to 728 older adults, as well as a standard cognitive test (the Montreal Cognitive Assessment).

The participants had already been evaluated by doctors and classified as being healthy (292 subjects), having MCI (174: 150 aMCI, 24 naMCI), or having Alzheimer's (262).

It was found that, while the cognitive test alone correctly classified 75% of people with MCI, the number rose to 87% when the sniff test results were added. Diagnosis of Alzheimer's, and of subtypes within MCI, was also improved.

The smell test normally takes 5 to 8 minutes to administer; the researchers are trying to get it down to 3 minutes, to encourage greater use.

A new smell test

Another recent study validates a new smell test which is rather more complicated. The test was developed because the standard University of Pennsylvania Smell Identification Test doesn’t take into account the great variation in olfactory ability among healthy individuals. The ability of normal individuals to recognize and discriminate between odors can vary by as much as 40 times!

The new test is actually four tests:

  • In the OPID (Odor Percept IDentification)-10 test, participants are presented with 10 odors (menthol, clove, leather, strawberry, lilac, pineapple, smoke, soap, grape, lemon) for two seconds each. They are then asked whether the scent is familiar and given a choice of four of the 10 words from which are asked to pick the best one that describes the odor.
  • The Odor Awareness Scale (OAS) assesses their overall attention to environmental odors and how they are affected emotionally and behaviorally by scents.
  • The OPID-20 test includes an additional 10 odors (banana, garlic, cherry, baby powder, grass, fruit punch, peach, chocolate, dirt, orange). Participants are first asked whether a presented odor was included in the OPID-10 test and then asked which word best describes the odor. Their ability to remember odors from the first test determines their POEM (Percepts of Odor Episodic Memory) score.
  • In the Odor Discrimination (OD) test, participants are presented with two consecutive odors and asked whether they were different or the same, a process that is repeated 12 times with different paired scents.

The study involved 183 older adults, of whom 70 were cognitively normal, 74 tested normal but were concerned about their cognitive abilities, 29 had MCI and 10 had been diagnosed with possible or probable Alzheimer's disease.

Results of the OPID-20 test significantly differentiated among the four groups of participants, and those results correlated with the thinning of the hippocampus and the entorhinal cortex. Participants' ability to remember a previously presented aroma, as reflected in the POEM score, was also significant, with participants with Alzheimer's disease performing at no better than chance.

POEM scores of the two cognitively normal groups were compared with what would have been predicted based on their ability to identify and differentiate between odors, as reflected in the OAS and OD tests. Poor POEM performers were more likely to have the ‘Alzheimer's gene’ (APOEe4), showed thinning of the entorhinal cortex, and poorer cognitive performance over time.

Validation of UPSIT

However, two 2016 studies support the use of the University of Pennsylvania Smell Identification Test (UPSIT), and suggest it may offer a practical, low-cost alternative to other tests.

In one study, UPSIT was administered to 397 older adults (average age 80) without dementia, who were also given an MRI scan to measure the thickness of the entorhinal cortex (the first brain region to be affected by Alzheimer's disease). After four years, 50 participants (12.6%) had developed dementia, and nearly 20% had signs of cognitive decline.

Low UPSIT scores, but not entorhinal cortical thickness, were significantly associated with dementia and Alzheimer's disease, and with cognitive impairment. Entorhinal cortical thickness was significantly associated with UPSIT score in those who transitioned from MCI to dementia.

In other words, it looks like impairment in odor identification precedes thinning in the entorhinal cortex.

In another study, UPSITwas administered to 84 older adults, of whom 58 had MCI, as well as either beta amyloid PET scanning or analysis of cerebrospinal fluid. After six months, 67% had signs of memory decline, and this was predicted by amyloid-beta levels (assessed by either method), but not UPSIT score. However, participants with a score of less than 35 were more than three times as likely to have memory decline as those with higher UPSIT scores.

The researchers suggest the association wasn’t as strong in this study because of the younger age of participants (median age 71), their higher education, and the short follow-up.




[4209] Quarmley M, Moberg PJ, Mechanic-Hamilton D, Kabadi S, Arnold SE, Wolk DA, Roalf DR. Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease. Journal of Alzheimer's Disease [Internet]. 2017 ;55(4):1497 - 1507. Available from: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160842

[4210] Dhilla AAlefiya, Asafu-Adjei J, Delaney MK, Kelly KE, Gomez-Isla T, Blacker D, Johnson KA, Sperling RA, Hyman BT, Betensky RA, et al. Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly. Annals of Neurology [Internet]. 2016 ;80(6):846 - 857. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ana.24792/abstract

Lee, Seonjoo et al. 2016. Predictive Utility of Entorhinal Cortex Thinning and Odor Identification Test for Transition to Dementia and Cognitive Decline in an Urban Community Population. Presented at the Alzheimer's Association's International Conference in Toronto.

Kreisl, William et al. 2016. Both Odor Identification and Amyloid Status Predict Memory Decline in Older Adults. Presented at the Alzheimer's Association's International Conference in Toronto.

A study comparing the language abilities of 22 healthy young individuals, 24 healthy older individuals and 22 people with MCI, has found that those with MCI:

  • were much less concise in conveying information
  • produced much longer sentences
  • had a hard time staying on point
  • were much more roundabout in getting their point across.

So, for example, when given an exercise in which they had to join up three words (e.g., “pen”, “ink” and “paper”), the healthy volunteers typically joined the three in a simple sentence, while the MCI group gave circuitous accounts such as going to the shop and buying a pen.

Additionally, when asked to repeat phrases read out by the interviewer, those with MCI had trouble when given phrases involving ambiguous pronouns (e.g., “Fred visited Bob after his graduation”), although they had no trouble with more complex sentences.

A caveat: if you're just one of those people who has always talked like this, don't panic! It's a matter of change and deterioration, not a stable personality trait.


Janet Sherman presented the findings at the annual meeting of the American Association for the Advancement of Science in Boston, in February 2017.

A ten-year study involving 2,092 older adults (average age 76) has found that people tended to lose awareness of memory problems two to three years before the onset of dementia.

Being unaware of your own memory problems is common in dementia, but previous research has focused on those already diagnosed with dementia. In this study, participants had no cognitive impairment at the beginning of the study.

Overall, subjective memory ratings taken annually were modestly correlated with performance (only modestly — people tend not to be that great at accurately assessing their own memory!), and this awareness was stable with age. However, in the subset of those who developed dementia (239 participants; 11%), this awareness started to deteriorate an average of 2.6 years before dementia was diagnosed (after which it dropped rapidly).

In a subset of those who died and had their brains examined (385 participants), a decline in memory awareness was associated with three pathologies:

  • tau tangles
  • gross cerebral infarcts
  • transactive response DNA-binding protein 43 pathology (TDP-43 is a protein involved in transcription, the first step in producing proteins from genes; mutations in the gene that produces TDP-43 have been linked to frontotemporal dementia and amyotrophic lateral sclerosis (ALS)).

There was no decline in memory awareness in those who didn't show any of these pathologies.

Those who were older at the beginning of the study were more likely to retain memory awareness longer, perhaps because they were more alert to memory problems.


Last year I reported on a finding that ten lipids in the blood could predict development of MCI or Alzheimer's within 2-3 years, with over 90% accuracy. The hunt for an accurate blood test has been gathering momentum, on the back of the growing belief that any effective treatment of Alzheimer's might have to start early, and the high cost and inconvenience of other means of early diagnosis.

Since that report we have had several more findings. Bear in mind that 90% accuracy still means one in 10 people would get an incorrect result.

Blood proteins predict whether MCI will convert to Alzheimer's with 87% accuracy

Blood from 452 healthy people, 220 people with mild cognitive impairment, and 476 with Alzheimer’s disease, has allowed researchers to identify those whose MCI would progress to Alzheimer's. The study identified 16 proteins that were associated with brain shrinkage in MCI or Alzheimer's. Further testing revealed 10 proteins that could predict, with 87% accuracy, whether MCI would progress to Alzheimer's within the next 12 months.



Blood microRNA predicts Alzheimer's disease

A preliminary study using serum from 49 Australians has found that microRNA in the blood can predict early changes in the brain that are associated with Alzheimer's.

One in five healthy participants with no memory complaints showed the specific microRNA associated with Alzheimer's. Brain imaging then confirmed the presence of early degeneration. The 16-miRNA signature, together with established risk factors such as age, sex and apolipoprotein ε4 gene status, predicted Alzheimer's with 91% accuracy.



Large Danish study links ApoE in blood to Alzheimer's risk

A study using data from nearly 76,000 Danes has shown that the level of the biomarker apolipoprotein E in the blood can predict the risk of developing dementia, with low levels being associated with a higher risk. Apolipoprotein E in the brain is strongly associated with Alzheimer's, with the ApoE4 gene the strongest genetic factor linked to Alzheimer's risk.

The study found that the link between blood plasma level and Alzheimer's and dementia risk existed irrespective of APOE genotype.


[3892] Hye A, Riddoch-Contreras J, Baird AL, Ashton NJ, Bazenet C, Leung R, Westman E, Simmons A, Dobson R, Sattlecker M, et al. Plasma proteins predict conversion to dementia from prodromal disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association [Internet]. 2014 ;10(6):799 - 807.e2. Available from: http://www.alzheimersanddementia.com/article/S1552526014024546/abstract

[3891] Cheng L, Doecke JD, Sharples RA, Villemagne VL, Fowler CJ, Rembach A, Martins RN, Rowe CC, Macaulay SL, Masters CL, et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Molecular Psychiatry [Internet]. 2014 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/abs/mp2014127a.html

[3899] Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Annals of Neurology [Internet]. 2015 ;77(2):301 - 311. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ana.24326/abstract

A brain imaging study of 162 healthy babies (2-25 months) has found that those who carried the ApoE4 gene (60 of the 162) tended to have increased brain growth in areas in the frontal lobe, and decreased growth in several areas in the middle and rear of the brain (precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions) — areas that tend to be affected in Alzheimer’s disease.

While this does not mean that those children are destined to develop Alzheimer’s, the findings do suggest brains of ApoE4 carriers tend to develop differently from those of non-carriers, and perhaps these early changes provide a “foothold” for the development of Alzheimer’s pathologies.


[3567] Dean DC, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset alzheimer disease: A cross-sectional imaging study. JAMA Neurology [Internet]. 2014 ;71(1):11 - 22. Available from: http://dx.doi.org/10.1001/jamaneurol.2013.4544

A gene linked to Alzheimer's has been linked to brain changes in childhood. This gene, SORL1, has two connections to Alzheimer’s: it carries the code for the sortilin-like receptor, which is involved in recycling some molecules before they develop into amyloid-beta; it is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway.

Brain imaging of 186 healthy individuals (aged 8-86) found that, even among the youngest, those with a specific variant of SORL1 showed a reduction in white matter connections. Post-mortem brain tissue from 269 individuals (aged 0-92) without Alzheimer's disease, found that the same SORL1 variant was linked to a disruption in the process by which the gene translated its code to become the sortilin-like receptor, and this was most prominent during childhood and adolescence. Another set of post-mortem brains from 710 individuals (aged 66-108), of whom the majority had mild cognitive impairment or Alzheimer's, found that the SORL1 risk gene was linked with the presence of amyloid-beta.

It may be that, for those carrying this gene variant, lifestyle interventions may be of greatest value early in life.


[3570] Felsky D, Szeszko P, Yu L, Honer WG, De Jager PL, Schneider JA, Malhotra AK, Lencz T, Ikuta T, Pipitone J, et al. The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan. Molecular Psychiatry [Internet]. 2013 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2013142a.html

Analysis of data from 237 patients with mild cognitive impairment (mean age 79.9) has found that, compared to those carrying the ‘normal’ ApoE3 gene (the most common variant of the ApoE gene), the ApoE4 carriers showed markedly greater rates of shrinkage in 13 of 15 brain regions thought to be key components of the brain networks disrupted in Alzheimer’s.


[3578] Hostage CA, Choudhury KR, Doraiswamy MP, Petrella JR. Mapping the Effect of the Apolipoprotein E Genotype on 4-Year Atrophy Rates in an Alzheimer Disease–related Brain Network. Radiology [Internet]. 2013 ;271(1):211 - 219. Available from: http://pubs.rsna.org/doi/abs/10.1148/radiol.13131041

A pilot study involving 94 older adults, of whom 18 had Alzheimer’s, 24 had MCI, 26 other dementias, and 26 were healthy controls, has found those with Alzheimer’s were significantly less able to detect the smell of peanut butter. Peanut butter was chosen because of its purity and accessibility (not because there's something special about its smell!).

The test was undertaken by the patient closing eyes and mouth and blocking one nostril, while the clinician held a ruler next to the open nostril and moved 14g of peanut butter in an open jar up the ruler one centimeter at a time, as the patient breathed out. Those in the early stages of Alzheimer’s disease showed a dramatic difference in detecting odor between the left and right nostril. The average distance at which the peanut butter was detected was 5.1 cm for the left nostril, compared to 17.4 cm for the right. The difference between these (12.4 cm) compares to an average 4.8 cm for other dementias, 1.9 for MCI, and 0 for healthy controls.

Of the 24 patients with MCI, only 10 patients showed a left nostril impairment, suggesting that this may be an indication of who will go on to develop Alzheimer’s.


[3609] Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer's disease. Journal of the Neurological Sciences [Internet]. 2013 ;333(1):19 - 24. Available from: http://www.jns-journal.com/article/S0022-510X(13)00311-0/abstract

Data from 6257 older adults (aged 55-90) evaluated from 2005-2012 has revealed that concerns about memory should be taken seriously, with subjective complaints associated with a doubled risk of developing mild cognitive impairment or dementia, and subjective complaints supported by a loved one being associated with a fourfold risk. Complaints by a loved one alone were also associated with a doubled risk. Among those with MCI, subjective complaints supported by a loved one were associated with a threefold risk of converting to dementia.

Of the 4414 initially cognitively normal, 14% developed MCI or dementia over the course of the study (around 5 years); of the 1843 with MCI, 41% progressed to dementia.


[3573] Gifford KA, Liu D, Lu Z, Tripodis Y, Cantwell NG, Palmisano J, Kowall N, Jefferson AL. The source of cognitive complaints predicts diagnostic conversion differentially among nondemented older adults. Alzheimer's & Dementia [Internet]. 2014 ;10(3):319 - 327. Available from: http://www.alzheimersanddementia.com/article/S1552-5260(13)00082-4/

Analysis of mitochondrial DNA (mtDNA) in the cerebrospinal fluid has found that both symptomatic Alzheimer’s patients and asymptomatic patients at risk of Alzheimer’s showed a significant decrease in levels of circulating cell-free mtDNA in the CSF. Patients with frontotemporal dementia did not display this.

Moreover, this potential biomarker occurred at least a decade before signs of dementia manifested, preceding the appearance of amyloid-beta and tau — suggesting not simply that it might be used as a very early sign of developing Alzheimer’s, but that the pathological process of Alzheimer's disease starts earlier than previously thought.


[3598] Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, Lleo A, Molinuevo JL, Serra N, Trullas R. Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Annals of Neurology [Internet]. 2013 ;74(5):655 - 668. Available from: http://onlinelibrary.wiley.com/doi/10.1002/ana.23955/abstract

Comparison of the EEGs of 27 healthy older adults, 27 individuals with mild Alzheimer's and 22 individuals with moderate cases of Alzheimer’s, has found statistically significant differences across the three groups, using an algorithm that dissects brain waves of varying frequencies.

In particular, delta modulation of the beta frequency band reliably discriminated between healthy controls and mild Alzheimer’s, and disappeared with an increase in disease severity (from mild to moderate). Increase in disease severity was also marked by the appearance of delta modulation of the theta band.

It’s hoped that the algorithm can be used not only to help detect Alzheimer’s disease early, but also to monitor its progression. The algorithm has been shared on the NeuroAccelerator.org online data analysis portal, to enable it to be used by researchers around the world.


[3572] Fraga FJ, Falk TH, Kanda PAM, Anghinah R. Characterizing Alzheimer’s Disease Severity via Resting-Awake EEG Amplitude Modulation Analysis. PLoS ONE [Internet]. 2013 ;8(8). Available from: http://dx.doi.org/10.1371/journal.pone.0072240

Analysis of 40 spinal marrow samples, 20 of which belonged to Alzheimer’s patients, has identified six proteins in spinal fluid that can be used as markers for Alzheimer's. The analysis focused on 35 proteins that are associated with the lysosomal network — involved in cleaning and recycling beta amyloid. None of the six proteins had previously been linked to Alzheimer’s.


[3551] Armstrong A, Mattsson N, Appelqvist H, Janefjord C, Sandin L, Agholme L, Olsson B, Svensson S, Blennow K, Zetterberg H, et al. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer’s Disease. NeuroMolecular Medicine [Internet]. 2014 ;16(1):150 - 160. Available from: http://link.springer.com/article/10.1007/s12017-013-8269-3

Data from 848 adults of all ages has found that brain volume in the default mode network declined in both healthy and pathological aging, but the greatest decline occurred in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease. Reduced brain volumes in these regions were associated with declines in cognitive ability, the presence of Alzheimer’s biomarkers in the cerebrospinal fluid, and with carrying the “Alzheimer’s gene”, the APOE4 allele.

The findings support the idea that neurodegeneration spreads through networks of connected brain regions, in a disease specific manner.


[3607] Spreng RNathan, Turner GR. Structural Covariance of the Default Network in Healthy and Pathological Aging. The Journal of Neuroscience [Internet]. 2013 ;33(38):15226 - 15234. Available from: http://www.jneurosci.org/content/33/38/15226

New research supports the classification system for preclinical Alzheimer’s proposed two years ago. The classification system divides preclinical Alzheimer's into three stages:

Stage 1: Levels of amyloid beta begin to decrease in the spinal fluid. This indicates that the substance is beginning to form plaques in the brain.

Stage 2: Levels of tau protein start to increase in the spinal fluid, indicating that brain cells are beginning to die. Amyloid beta levels are still abnormal and may continue to fall.

Stage 3: In the presence of abnormal amyloid and tau biomarker levels, subtle cognitive changes can be detected by neuropsychological testing.

Long-term evaluation of 311 cognitively healthy older adults (65+) found 31% with preclinical Alzheimer’s, of whom 15% were at stage 1, 12% at stage 2, and 4% at stage 3. This is consistent with autopsy studies, which have shown that around 30% of cognitively normal older adults die with some preclinical Alzheimer's pathology in their brain. Additionally, 23% were diagnosed with suspected non-Alzheimer pathophysiology (SNAP), 41% as cognitively normal, and 5% as unclassified.

Five years later, 2% of the cognitively normal, 5% of those with SNAP, 11% of the stage 1 group, 26% of the stage 2 group, and 56% of the stage 3 group had been diagnosed with symptomatic Alzheimer's.


[3614] Vos SJB, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. The Lancet Neurology [Internet]. 2013 ;12(10):957 - 965. Available from: http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70194-7/abstract

Initial findings from an analysis of cerebrospinal fluid taken between 1995 and 2005 from 265 middle-aged healthy volunteers, of whom 75% had a close family member with Alzheimer’s disease, has found that the ratios of phosphorylated tau and amyloid-beta could predict mild cognitive impairment more than five years before symptom onset — the more tau and less amyloid-beta, the more likely MCI will develop. The rate of change in the ratio over time was also predictive — the more rapidly the ratio of tau to amyloid-beta went up, the more likely the eventual development of MCI.

The drop in amyloid-beta is thought to be because it is getting trapped in the plaques characteristic of Alzheimer’s.


[3592] Moghekar A, Li S, Lu Y, Li M, Wang M-C, Albert M, O’Brien R. CSF biomarker changes precede symptom onset of mild cognitive impairment. Neurology [Internet]. 2013 . Available from: http://www.neurology.org/content/early/2013/10/16/01.wnl.0000435558.98447.17

People with Parkinson’s disease have a six times greater risk of developing dementia than the general population. A new study points to a way of picking out those who are at risk of dementia.

The 20-month study involved 32 patients in the first stages of Parkinson's disease and 18 healthy controls. It found thinning in certain cortical areas (temporal, occipital, parietal and supplementary motor area) as well as subcortical atrophy (amygdala and nucleus accumbens) in the grey matter of those Parkinson’s sufferers with mild cognitive impairments. The rate of cortical thinning mirrored growth in cognitive problems. This pattern of brain degradation associated with the early presence of mild cognitive impairment might serve as a marker for the development of dementia. Parkinson's patients without mild cognitive impairment had only one lateral occipital and one fusiform cluster with increased rate of thinning compared to healthy individuals.


[3575] Hanganu A, Bedetti C, Degroot C, Mejia-Constain B, Lafontaine A-L, Soland V, Chouinard S, Bruneau M-A, Mellah S, Belleville S, et al. Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson’s disease longitudinally. Brain [Internet]. 2014 ;137(4):1120 - 1129. Available from: http://brain.oxfordjournals.org/content/137/4/1120

A five-year study involving 525 older adults (70+) found 46 had Alzheimer’s or aMCI and a further 28 went on to develop the conditions. The blood levels of 10 specific lipids predicted with more than 90% accuracy whether an individual would go on to develop either Alzheimer’s or aMCI within 2-3 years. The researchers speculate that the lower lipid levels could be an early indication that brain cells are beginning to lose their integrity and break down.

The continual failures in human clinical trials of promising therapies has led to a growing belief that once the cognitive symptoms of the Alzheimer’s have emerged, it may be too late to slow or reverse the neurological damage. However, treatments begun early enough may be more effective. This is why early diagnosis of Alzheimer’s risk is so critical.




[3588] Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine [Internet]. 2014 ;20(4):415 - 418. Available from: http://www.nature.com/nm/journal/v20/n4/abs/nm.3466.html

A three-year study involving 152 adults aged 50 and older, of whom 52 had been recently diagnosed with mild cognitive impairment and 31 were diagnosed with Alzheimer's disease, has found that those with mild or no cognitive impairment who initially had amyloid-beta plaques showed greater cognitive decline than those whose brain scans were negative for plaques. Moreover, 35% of plaque-positive participants who started with MCI progressed to Alzheimer's, compared to 10% without plaque, and they were more than twice as likely to be started on cognitive-enhancing medication.

The fact that 90% of those with MCI but no plaque didn’t progress to Alzheimer's (within the three-year period) points to the value of using PET imaging to identify patients unlikely to decline, who can be reassured accordingly. The finding also points to the importance of plaque buildup in cognitive decline.


[3569] Doraiswamy MP, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Joshi AD, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study. Molecular Psychiatry [Internet]. 2014 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/abs/mp20149a.html

More evidence for early changes in the eye in Alzheimer’s disease comes from a study involving both rats and postmortem human retinas. Changes were found in the retinal pigment epithelial layer (which harbors the supportive cells located in the back of the eye) and in the thickness of the choroidal layer that has blood vessels providing nutrients to the retina.

The finding is consistent with growing evidence that glaucoma is a neurodegenerative disorder similar to Alzheimer’s.



[3613] Tsai Y, Lu B, Ljubimov AV, Girman S, Ross-Cisneros FN, Sadun AA, Svendsen CN, Cohen RM, Wang S. Ocular Changes in TgF344-AD Rat Model of Alzheimer's Disease. Investigative Ophthalmology & Visual Science [Internet]. 2014 ;55(1):523 - 534. Available from: http://www.iovs.org/content/55/1/523

A multi-year study involving 207 healthy older adults, in which their spinal fluids were repeatedly sampled and their brains repeatedly scanned, has found that disruptions in the default mode network emerges about the same time as chemical markers of Alzheimer’s appear in the spinal fluid (decreased amyloid-beta and increased tau protein). The finding suggests not only that amyloid-beta and tau pathology affect default mode network integrity early on, but that scans of brain networks may be an equally effective and less invasive way to detect early disease.

The greatest decrease in functional connectivity was found between the posterior cingulate and medial temporal regions. This decrease was not attributable to age or structural atrophy in these regions.


[3617] Wang L, Brier MR, Snyder AZ, et al. Cerebrospinal fluid aβ42, phosphorylated tau181, and resting-state functional connectivity. JAMA Neurology [Internet]. 2013 ;70(10):1242 - 1248. Available from: http://dx.doi.org/10.1001/jamaneurol.2013.3253

An analysis of the anatomical connectivity in the brains of 15 people with Alzheimer's disease, 68 with mild cognitive impairment and 28 healthy older individuals, has found several measures showed disease effects:

  • widespread network disruptions
  • decreases in network nodes
  • neural fiber path length
  • decreased signaling efficiency
  • increased asymmetry in the proportions of fibers that connect the left and right cortical regions


[3565] Daianu M, Jahanshad N, Nir TM, Toga AW, Jack CR, Weiner MW, Thompson PM. Breakdown of Brain Connectivity Between Normal Aging and Alzheimer's Disease: A Structural k-Core Network Analysis. Brain Connectivity [Internet]. 2013 ;3(4):407 - 422. Available from: http://online.liebertpub.com/doi/abs/10.1089/brain.2012.0137

Following on from the evidence that Alzheimer’s brains show higher levels of metals such as iron, copper, and zinc, a mouse study has found that amyloid plaques in Alzheimer’s-like brains with significant neurodegeneration have about 25% more copper than those with little neurodegeneration. This is consistent with a human study showing very high levels of copper in Alzheimer’s plaques.

Iron, though doubled in Alzheimer’s brains compared to controls, was not significantly different as a function of neurodegeneration, and zinc showed very little difference.

The findings suggest that the cellular control of copper is altered in some way in Alzheimer’s brains, while the increase in oxidized iron suggests it might be useful as a biomarker for the early diagnosis of Alzheimer’s.


[3555] Bourassa MW, Leskovjan AC, Tappero RV, Farquhar ER, Colton CA, Van Nostrand WE, Miller LM. Elevated copper in the amyloid plaques and iron in the cortex are observed in mouse models of Alzheimer's disease that exhibit neurodegeneration. Biomedical Spectroscopy and Imaging [Internet]. 2013 ;2(2):129 - 139. Available from: http://dx.doi.org/10.3233/BSI-130041

Providing some support for the finding I recently reported — that problems with semantic knowledge in those with mild cognitive impairment (MCI) and Alzheimer’s might be rooted in an inability to inhibit immediate perceptual information in favor of conceptual information — a small study has found that executive function (and inhibitory control in particular) is impaired in far more of those with MCI than was previously thought.

The study involved 40 patients with amnestic MCI (single or multiple domain) and 32 healthy older adults. Executive function was tested across multiple sub-domains: divided attention, working memory, inhibitory control, verbal fluency, and planning.

As a group, those with MCI performed significantly more poorly in all 5 sub-domains. All MCI patients showed significant impairment in at least one sub-domain of executive functioning, with almost half performing poorly on all of the tests. The sub-domain most frequently and severely impaired was inhibitory control.

The finding is in sharp contrast with standard screening tests and clinical interviews, which have estimated executive function impairment in only 15% of those with MCI.

Executive function is crucial for many aspects of our behavior, from planning and organization to self-control to (as we saw in the previous news report) basic knowledge. It is increasingly believed that inhibitory control might be a principal cause of age-related cognitive decline, through its effect on working memory.

All this adds weight to the idea that we should be focusing our attention on ways to improve inhibitory control when it declines. Although training to improve working memory capacity has not been very successful, specific training targeted at inhibitory control might have more luck. Something to hope for!

A small study shows how those on the road to Alzheimer’s show early semantic problems long before memory problems arise, and that such problems can affect daily life.

The study compared 25 patients with amnestic MCI, 27 patients with mild-to-moderate Alzheimer's and 70 cognitively fit older adults (aged 55-90), on a non-verbal task involving size differences (for example, “What is bigger: a key or a house?”; “What is bigger: a key or an ant?”). The comparisons were presented in three different ways: as words; as images reflecting real-world differences; as incongruent images (e.g., a big ant and a small house).

Both those with MCI and those with AD were significantly less accurate, and significantly slower, in all three conditions compared to healthy controls, and they had disproportionately more difficulty on those comparisons where the size distance was smaller. But MCI and AD patients experienced their biggest problems when the images were incongruent – the ant bigger than the house. Those with MCI performed at a level between that of healthy controls and those with AD.

This suggests that perceptual information is having undue influence in a judgment task that requires conceptual knowledge.

Because semantic memory is organized according to relatedness, and because this sort of basic information has been acquired a long time ago, this simple test is quite a good way to test semantic knowledge. As previous research has indicated, the problem doesn’t seem to be a memory (retrieval) one, but one reflecting an actual loss or corruption of semantic knowledge. But perhaps, rather than a loss of data, it reflects a failure of selective attention/inhibition — an inability to inhibit immediate perceptual information in favor of more relevant conceptual information.

How much does this matter? Poor performance on the semantic distance task correlated with impaired ability to perform everyday tasks, accounting (together with delayed recall) for some 35% of the variance in scores on this task — while other cognitive abilities such as processing speed, executive function, verbal fluency, naming, did not have a significant effect. Everyday functional capacity was assessed using a short form of the UCSD Skills Performance Assessment scale (a tool generally used to identify everyday problems in patients with schizophrenia), which presents scenarios such as planning a trip to the beach, determining a route, dialing a telephone number, and writing a check.

The finding indicates that semantic memory problems are starting to occur early in the deterioration, and may be affecting general cognitive decline. However, if the problems reflect an access difficulty rather than data loss, it may be possible to strengthen these semantic processing connections through training — and thus improve general cognitive processing (and ability to perform everyday tasks).

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

[2997] Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, et al. Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease. New England Journal of Medicine [Internet]. 2012 :120723122607004 - 120723122607004. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1202753

Another study adds to the evidence that changes in the brain that may lead eventually to Alzheimer’s begin many years before Alzheimer’s is diagnosed. The findings also add to the evidence that what we regard as “normal” age-related cognitive decline is really one end of a continuum of which the other end is dementia.

In the study, brain scans were taken of 137 highly educated people aged 30-89 (participants in the Dallas Lifespan Brain Study). The amount of amyloid-beta (characteristic of Alzheimer’s) was found to increase with age, and around a fifth of those over 60 had significantly elevated levels of the protein. These higher amounts were linked with worse performance on tests of working memory, reasoning and processing speed.

More specifically, across the whole sample, amyloid-beta levels affected processing speed and fluid intelligence (in a dose-dependent relationship — that is, as levels increased, these functions became more impaired), but not working memory, episodic memory, or crystallized intelligence. Among the elevated-levels group, increased amyloid-beta was significantly associated with poorer performance for processing speed, working memory, and fluid intelligence, but not episodic memory or crystallized intelligence. Among the group without elevated levels of the protein, increasing amyloid-beta only affected fluid intelligence.

These task differences aren’t surprising: processing speed, working memory, and fluid intelligence are the domains that show the most decline in normal aging.

Those with the Alzheimer’s gene APOE4 were significantly more likely to have elevated levels of amyloid-beta. While 38% of the group with high levels of the protein had the risky gene variant, only 15% of those who didn’t have high levels carried the gene.

Note that, while the prevalence of carriers of the gene variant matched population estimates (24%), the proportion was higher among those in the younger age group — 33% of those under 60, compared to 19.5% of those aged 60 or older. It seems likely that many older carriers have already developed MCI or Alzheimer’s, and thus been ineligible for the study.

The average age of the participants was 64, and the average years of education 16.4.

Amyloid deposits varied as a function of age and region: the precuneus, temporal cortex, anterior cingulate and posterior cingulate showed the greatest increase with age, while the dorsolateral prefrontal cortex, orbitofrontal cortex, parietal and occipital cortices showed smaller increases with age. However, when only those aged 60+ were analyzed, the effect of age was no longer significant. This is consistent with previous research, and adds to evidence that age-related cognitive impairment, including Alzheimer’s, has its roots in damage occurring earlier in life.

In another study, brain scans of 408 participants in the Mayo Clinic Study of Aging also found that higher levels of amyloid-beta were associated with poorer cognitive performance — but that this interacted with APOE status. Specifically, carriers of the Alzheimer’s gene variant were significantly more affected by having higher levels of the protein.

This may explain the inconsistent findings of previous research concerning whether or not amyloid-beta has significant effects on cognition in normal adults.

As the researchers of the first study point out, what’s needed is information on the long-term course of these brain changes, and they are planning to follow these participants.

In the meantime, all in all, the findings do provide more strength to the argument that your lifestyle in mid-life (and perhaps even younger) may have long-term consequences for your brain in old age — particularly for those with a genetic susceptibility to Alzheimer’s.

A small study of the sleep patterns of 100 people aged 45-80 has found a link between sleep disruption and level of amyloid plaques (characteristic of Alzheimer’s disease). The participants were recruited from the Adult Children Study, of whom half have a family history of Alzheimer’s disease.

Sleep was monitored for two weeks. Those who woke frequently (more than five times an hour!) and those who spent less than 85% of their time in bed actually asleep, were more likely to have amyloid plaques. A quarter of the participants had evidence of amyloid plaques.

The study doesn’t tell us whether disrupted sleep leads to the production of amyloid plaques, or whether brain changes in early Alzheimer's disease lead to changes in sleep, but evidence from other studies do, I think, give some weight to the first idea. At the least, this adds yet another reason for making an effort to improve your sleep!

The abstract for this not-yet-given conference presentation, or the press release, don’t mention any differences between those with a family history of Alzheimer’s and those without, suggesting there was none — but since the researchers made no mention either way, I wouldn’t take that for granted. Hopefully we’ll one day see a journal paper providing more information.

The main findings are supported by another recent study. A Polish study involving 150 older adults found that those diagnosed with Alzheimer’s after a seven-year observation period were more likely to have experienced sleep disturbances more often and with greater intensity, compared to those who did not develop Alzheimer’s.

Ju, Y., Duntley, S., Fagan, A., Morris, J. & Holtzman, D. 2012. Sleep Disruption and Risk of Preclinical Alzheimer Disease. To be presented April 23 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

Bidzan L, Grabowski J, Dutczak B, Bidzan M. 2011. [Sleep disorders in the preclinical period of the Alzheimer's disease]. Psychiatria Polska, 45(6), 851-60. http://www.ncbi.nlm.nih.gov/pubmed/22335128

Following on from research showing an association between lower walking speed and increased risk of dementia, and weaker hand grip strength and increased dementia risk, a large study has explored whether this association extends to middle-aged and younger-old adults.

Part of the long-running Framingham study, the study involved 2,410 men and women with an average age of 62, who underwent brain scans and tests for walking speed, hand grip strength and cognitive function. During the follow-up period of up to 11 years, 34 people (1.4%) developed dementia (28 Alzheimer’s) and 79 people (3.3%) had a stroke.

Those who had a slower walking speed at the start of the study were one-and-a-half times more likely to develop dementia compared to people with faster walking speed, while stronger hand grip strength was associated with a 42% lower risk of stroke or transient ischemic attack in people over age 65.

Slower walking speed and weaker hand grip strength were also associated with lower brain volume and poorer cognitive performance. Specifically, those with slower walking speed scored significantly worse on tests of visual reproduction, paired associate learning, executive function, visual organization, and language (Boston Naming test). Higher hand grip strength was associated with higher scores on tests of visual reproduction, executive function, visual organization, language and abstraction (similarities test).

While the nature of the association is not yet understood, the findings do seem to support the benefits of physical fitness. At the least, these physical attributes can serve as pointers to the need for more investigation of an older person’s brain health. But they might also serve as a warning to improve physical fitness.

Camargo, E.C., Beiser, A., Tan, Z.S., Au, R., DeCarli, C., Pikula, A., Kelly-Hayes, M., Kase, C., Wolf, P. & Seshadri, S. 2012. Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham Offspring Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

A study involving 159 older adults (average age 76) has confirmed that the amount of brain tissue in specific regions is a predictor of Alzheimer’s disease development. Of the 159 people, 19 were classified as at high risk on the basis of the smaller size of nine small regions previously shown to be vulnerable to Alzheimer's), and 24 as low risk. The regions, in order of importance, are the medial temporal, inferior temporal, temporal pole, angular gyrus, superior parietal, superior frontal, inferior frontal cortex, supramarginal gyrus, precuneus.

There was no difference between the three risk groups at the beginning of the study on global cognitive measures (MMSE; Alzheimer’s Disease Assessment Scale—cognitive subscale; Clinical Dementia Rating—sum of boxes), or in episodic memory. The high-risk group did perform significantly more slowly on the Trail-making test part B, with similar trends on the Digit Symbol and Verbal Fluency tests.

After three years, 125 participants were re-tested. Nine met the criteria for cognitive decline. Of these, 21% were from the small high-risk group (3/14) and 7% from the much larger average-risk group (6/90). None were from the low-risk group.

The results were even more marked when less stringent criteria were used. On the basis of an increase on the Clinical Dementia Rating, 28.5% of the high-risk group and 9.7% of the average-risk group showed decline. On the basis of declining at least one standard deviation on any one of the three neuropsychological tests, half the high-risk group, 35% of the average risk group, and 14% (3/21) of the low-risk group showed decline. (The composite criteria required both of these criteria.)

Analysis estimated that every standard deviation of cortical thinning (reduced brain tissue) was associated with a nearly tripled risk of cognitive decline.

The 84 individuals for whom amyloid-beta levels in the cerebrospinal fluid were available also revealed that 60% of the high-risk group had levels consistent with the presence of Alzheimer's pathology, compared to 36% of those at average risk and 19% of those at low risk.

The findings extend and confirm the evidence that brain atrophy in specific regions is a biomarker for developing Alzheimer’s.

[2709] Dickerson BC, Wolk DA. MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology [Internet]. 2012 ;78(2):84 - 90. Available from: http://www.neurology.org/content/78/2/84.abstract

Dickerson BC, Bakkour A, Salat DH, et al. 2009. The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloidpositive individuals. Cereb Cortex;19:497–510.

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.

In a study in which 78 healthy elders were given 5 different tests and then tested for cognitive performance 18 months later, two tests combined to correctly predict nearly 80% of those who developed significant cognitive decline. These tests were a blood test to identify presence of the ‘Alzheimer’s gene’ (APOE4), and a 5-minute fMRI imaging scan showing brain activity during mental tasks.

The gene test in itself correctly classified 61.5% of participants (aged 65-88; mean age 73), showing what a strong risk factor this is, but when taken with activity on the fMRI test, the two together correctly classified 78.9% of participants. Age, years of education, gender and family history of dementia were not accurate predictors of future cognitive decline. A smaller hippocampus was also associated with a greater risk of cognitive decline.

These two tests are readily available and not time-consuming, and may be useful in identifying those at risk of MCI and dementia.

Woodard, J.L.  et al. 2010. Prediction of Cognitive Decline in Healthy Older Adults using fMRI. Journal of Alzheimer’s Disease, 21 (3), 871-885.

A six-year study involving over 1200 older women (70+) has found that low amounts of albumin in the urine, at levels not traditionally considered clinically significant, strongly predict faster cognitive decline in older women. Participants with a urinary albumin-to-creatinine ratio of >5 mcg/mg at the start of the study experienced cognitive decline at a rate 2 to 7 times faster in all cognitive measures than that attributed to aging alone over an average 6 years of follow-up. The ability most affected was verbal fluency. Albuminuria may be an early marker of diffuse vascular disease.

Data from 19,399 individuals participating in the Renal Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, of whom 1,184 (6.1%) developed cognitive impairment over an average follow-up of 3.8 years, has found that those with albuminuria were 1.31-1.57 times more likely to develop cognitive impairment compared to individuals without albuminuria. This association was strongest for individuals with normal kidney function. Conversely, low kidney function was associated with a higher risk for developing cognitive impairment only among individuals without albuminuria. Surprisingly, individuals with albuminuria and normal kidney function had a higher probability for developing cognitive impairment as compared to individuals with moderate reductions in kidney function in the absence of albuminuria.

Both albuminuria and low kidney function are characteristics of kidney disease.

Lin, J., Grodstein, F., Kang, J.H. & Curhan, G. 2010. A Prospective Study of Albuminuria and Cognitive Decline in Women. Presented at ASN Renal Week 2010 on November 20 in Denver, CO.

Tamura, M.K. et al. 2010. Albuminuria, Kidney Function and the Incidence of Cognitive Impairment in US Adults. Presented at ASN Renal Week 2010 on November 20 in Denver, CO.

Confirming earlier research, a study involving 257 older adults (average age 75) has found that a two-minute questionnaire filled out by a close friend or family member is more accurate that standard cognitive tests in detecting early signs of Alzheimer’s.

The AD8 asks questions about changes in everyday activities:

  • Problems with judgment, such as bad financial decisions;
  • Reduced interest in hobbies and other activities;
  • Repeating of questions, stories or statements;
  • Trouble learning how to use a tool or appliance, such as a television remote control or a microwave;
  • Forgetting the month or year;
  • Difficulty handling complicated financial affairs, such as balancing a checkbook;
  • Difficulty remembering appointments; and
  • Consistent problems with thinking and memory.

Problems with two or more of these are grounds for further evaluation. The study found those with AD8 scores of 2 or more were very significantly more likely to have early biomarkers of Alzheimer’s (abnormal Pittsburgh compound B binding and cerebrospinal fluid biomarkers), and was better at detecting early stages of dementia than the MMSE. The AD8 has now been validated in several languages and is used in clinics around the world.

A three-year study involving 169 people with mild cognitive impairment has found that those who later developed Alzheimer's disease showed 10-30% greater atrophy in two specific locations within the hippocampus, the cornu ammonis (CA1) and the subiculum. A second study comparing the brains of 10 cognitively normal elderly people and seven who were diagnosed with MCI between two and three years after their initial brain scan and with Alzheimer's some seven years after the initial scan, has confirmed the same pattern of hippocampal atrophy, from the CA1 to the subiculum, and then other regions of the hippocampus.

Apostolova, L.G. et al. In press. Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal. Neurobiology of Aging, Available online 24 September 2008.

[392] Apostolova LG, Thompson PM, Green AE, Hwang KS, Zoumalan C, Jack, Jr CR, Harvey DJ, Petersen RC, Thal LJ, Aisen PS, et al. 3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI. Human Brain Mapping [Internet]. 2010 ;9999(9999):NA - NA. Available from: http://dx.doi.org/10.1002/hbm.20905

A study involving 511 older adults (average age 78) has found that 11.6% of those with very mild or mild Alzheimer’s (43% of the participants) had mental lapses, compared to only 2 of the 295 without Alzheimer’s. Those with mental lapses also tended to have more severe Alzheimer’s. Although mental lapses are characteristic of dementia with Lewy bodies, this is the first study to look at them in connection with Alzheimer’s. Having mental lapses was defined as having three or four of the following symptoms:

  • Feeling drowsy or lethargic all the time or several times per day despite getting enough sleep the night before
  • Sleeping two or more hours before 7 p.m.
  • Having times when the person's flow of ideas seems disorganized, unclear, or not logical
  • Staring into space for long periods

Previous research suggesting loss of smell function may serve as an early marker of Alzheimer's disease has now been supported by a finding that in genetically engineered mice, loss of smell function is associated with amyloid-beta accumulation in the brain, and that amyloid pathology occurs first in the olfactory region. It was striking how sensitive olfactory performance was to even the smallest amount of amyloid presence in the brain as early as three months of age (equivalent to a young adult).

A study involving 57 cognitively healthy older adults has found that those who showed decreased memory performance two years later (20 of the 57) had higher baseline levels of phosphorylated tau231 in the cerebrospinal fluid, and more atrophy in the medial temporal lobe. Higher levels of damaged tau protein were associated with reductions in medial temporal lobe gray matter. The finding may be useful in early diagnosis of Alzheimer’s disease.

Previous research has found that unexplained weight loss is an early sign of Alzheimer's. Now a study involving 140 older adults (60+), of whom half had early-stage Alzheimer's disease, has revealed that it is not the overall weight or fat levels that are important, but the loss of lean mass (weight of an individual's bones, muscles and organs without body fat). This directly correlated with reductions in the volume of the whole brain and of white matter only, along with declines in cognitive performance. The finding is consistent with research suggesting that brain pathology contributes to a decline in body composition, perhaps by disrupting the regulation of energy metabolism and food intake, perhaps through behavioral changes (there is a strong association between loss of muscle mass and reductions in physical activity), or perhaps through a common underlying mechanism, such as inflammation.

Older news items (pre-2010) brought over from the old website

Measuring brain atrophy in patients with mild cognitive impairment

A study involving 269 patients with mild cognitive impairment provides evidence that a fully automated procedure called Volumetric MRI (that can be done in a clinical setting) can accurately and quickly measure parts of the medial temporal lobe and compare them to expected size. It also found that not only atrophy in the hippocampus but also the amygdala is associated with a greater risk of conversion to Alzheimer’s.

Kovacevic, S. et al. 2009. High-throughput, Fully Automated Volumetry for Prediction of MMSE and CDR Decline in Mild Cognitive Impairment. Alzheimer Disease & Associated Disorders, 23 (2), 139-145.


Cerebrospinal fluid shows Alzheimer's disease deterioration much earlier

A study involving 60 patients with subjective cognitive impairment, 37 patients with non-amnestic mild cognitive impairment, and 71 with amnestic mild cognitive impairment, has found that 52% of those with SCI, 68% of those with naMCI, and 79% of those with aMCI showed decreased concentrations of Aβ42 and increased concentrations of tau protein in the cerebrospinal fluid. The findings confirm the use of biomarkers in the CSF for very early diagnosis

Visser, P.J. et al. 2009. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment and mild cognitive impairment in the DESCRIPA study: a prospective, case-control study. The Lancet Neurology, 8 (7), 619–627.


Weight loss in old age may signal dementia

An 8-year study involving over 1,800 older Japanese Americans has found that those with lower body mass index (BMI) scores at the beginning of the study were 79% more likely to develop dementia than those with higher scores. In addition, those who lost weight over the study period at a faster rate were nearly three times more likely to develop dementia than those who lost weight more slowly, and this association was stronger in those who were overweight or obese to start.

Hughes, T.F. et al. 2009. Association between late-life body mass index and dementia: The Kame Project. Neurology, 72, 1741-1746.


New tool can help predict Alzheimer's risks

A new 15-point scale of risk factors for Alzheimer's has been developed and correctly classified 88% of the 3,375 older adults in the study. 56% of those with scores of 8 or higher developed dementia within six years, compared to 23% with moderate scores and just 4% with low scores. The risk factors include poor cognitive test performance (2–4 points), body mass index below 18.5 (2 points), older age (1–2 points), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point), presence of the ApoE4 gene (1 point), MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point).

Barnes, D.E. et al. 2009. Predicting risk of dementia in older adults. The late-life dementia risk index. Neurology, published May 13, 2009.


Eye tracking test detects mild cognitive impairment

A test first developed for use with nonhuman primates is now being used to detect mild cognitive impairment (MCI) in humans. The infrared eye-tracking test involves showing one image and then another after a 2-second delay, and then repeating the test 2 minutes later. Those without cognitive impairment spend most of their time looking at the new image, but it was found that those with MCI spent less time looking at the new picture, presumably because they have less memory of seeing the original image before. Those with Alzheimer's disease look at both images equally. It’s hoped that this test may allow dementia to be spotted much earlier.

Crutcher, M.D. et al. 2009. Eye Tracking During a Visual Paired Comparison Task as a Predictor of Early Dementia. American Journal of Alzheimer's Disease and Other Dementias, Published online February 26 2009.


Shrinking in hippocampus precedes Alzheimer's

An imaging study of 64 Alzheimer's patients, 44 people with mild cognitive impairment, and 34 people with no memory or thinking problems, has found that those with smaller hippocampal volumes and higher rates of shrinkage were two to four times as likely to develop dementia over the study period (average 18 months) as those with larger volumes and a slower rate of atrophy. During that time, 23 of the people with MCI developed Alzheimer's, and three of the healthy participants.

Henneman, W.J.P. et al. 2009. Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology, 72, 999-1007.


Brain atrophy pattern in some MCI patients predicts Alzheimer's

A study of 84 patients with mild Alzheimer's, 175 patients with MCI and 139 healthy controls has revealed a pattern of regional brain atrophy in patients with MCI that indicates a greater likelihood of progression to Alzheimer's. Brain scans results showed widespread cortical atrophy in some patients with MCI, most importantly, atrophy in parts of the medial and lateral temporal lobes and in the frontal lobes — a pattern also present in the patients with mild Alzheimer's disease. Those exhibiting such atrophy declined significantly over a year and were more likely to progress to a probable diagnosis of Alzheimer's. MCI patients without that pattern of atrophy remained stable after a year. It should be noted that such atrophy affects not only memory, but also planning, organization, problem solving and language.

McEvoy, L.K. et al. 2009. Alzheimer Disease: Quantitative Structural Neuroimaging for Detection and Prediction of Clinical and Structural Changes in Mild Cognitive Impairment. Radiology, Published online February 6.


Blood test could give early warning of Alzheimer’s risk

A simple blood test may enable us to predict whether someone will soon develop Alzheimer’s, allowing them to take action that might delay its development. In the study of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed Alzheimer’s over 4.6 years of follow-up. Higher blood levels of amyloid-beta 42 peptide at the onset of the study were associated with a threefold increased risk of Alzheimer’s, with the levels significantly declining at the onset of Alzheimer’s (perhaps because it has started accumulating in the brain).

Schupf, N. et al. 2008. Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease. PNAS, 105 (37), 14052-14057.


Women lose weight at least a decade before developing dementia

Another study has come out associating weight loss with later dementia. The study found that women who later developed dementia started losing weight up to 20 years before the disease was diagnosed. On average, those with dementia weighed 12 pounds less than those without the disease the year the disease was diagnosed. The association may be related to a loss in the sense of smell, and increasing apathy. The association was not found with men, probably because older men were less likely to be preparing their own food. The findings do of course conflict with others suggesting that obesity in middle-age may be a risk factor for dementia. More research is needed to clarify the situation.

Knopman, D.S. et al. 2007. Incident dementia in women is preceded by weight loss by at least a decade. Neurology, 69, 739-746.


Simple test predicts 6-year risk of dementia

A 14-point index combining medical history, cognitive testing, and physical examination — a simple test that can be given by any physician — has been found to predict a person’s risk for developing dementia within six years with 87% accuracy. As measured by the index, the risk factors for developing dementia are an age of 70 or older, poor scores on two simple cognitive tests, slow physical functioning on everyday tasks such as buttoning a shirt or walking 15 feet, a history of coronary artery bypass surgery, a body mass index of less than 18, and current non-consumption of alcohol. The results do need to be validated in other populations — for example, they have not yet been tested on Hispanics or Asian-Americans.

The tests were described in a presentation at the 2007 International Conference on Prevention of Dementia, in Washington, DC.


Brain structure changes years before memory loss begins

Another study provides evidence that people who develop dementia or Alzheimer's disease experience brain structure changes years before any signs of memory loss begin. The study involved 136 people over the age of 65 who were considered cognitively normal at the beginning of the five-year study. By the end of the study, 23 people had developed MCI, and nine of the 23 went on to be diagnosed with Alzheimer's disease. Compared to the group that didn't develop memory problems, the 23 who developed MCI or Alzheimer's disease had less gray matter in key memory processing areas (specifically, anteromedial temporal lobes and left angular gyrus) even at the beginning of the study when they were cognitively normal. They also had lower cognitive test scores, though these scores were still within normal range.

Smith, C.D. et al. 2007. Brain structural alterations before mild cognitive impairment. Neurology, 68, 1268-1273.


Memory complaints early warning for Alzheimer's

A post-mortem study of 90 older adults from the Rush Memory and Aging Project found that those who had yet to have any clinical symptoms of Alzheimer's disease still showed a strong link between their self-reported memory complaints and brain pathology associated with Alzheimer's disease.

Barnes, L.L., Schneider, J.A., Boyle, P.A., Bienias, J.L. & Bennett, D.A. 2006. Memory complaints are related to Alzheimer disease pathology in older persons. Neurology, 67, 1581-1585.


New early diagnostic test trialed

A mouse study has used a laser scan of the eyes to accurately diagnose Alzheimer's well before the disease was evident in the brain. The study follows on from earlier research revealing that beta-amyloid protein is evident in the eyes of Alzheimer’s patients. The test, which is a very quick and simple procedure, is now in the first stage of experimental trials in people.

The findings were announced at the annual meeting of the Optical Society of America.


Link between increased weight-loss rate and dementia

Confirming earlier indications, a long-term study of the elderly has revealed that their average rate of weight loss doubles (from 0.6 pounds per year to 1.2 pounds per year) in the year before symptoms of Alzheimer's-type dementia first become detectable. The finding may be useful as one of several early biomarkers. The study analyzed data on 449 seniors, of whom 125 were eventually diagnosed with mild dementia. Interestingly, at the beginning of the study, this group weighed about 8lb less on average than the other participants, although the two groups lost weight at the same rate for four to five years, before weight loss increased in the group that would eventually be diagnosed with mild dementia. It is not yet known why there should be this connection between weight loss and dementia.

Johnson, D.K., Wilkins, C.H. & Morris, J.C. 2006. Accelerated weight loss in Alzheimer's disease precedes diagnosis. Archives of Neurology, 63, 1312-1317.


Weight Loss Precedes Dementia Diagnosis In Women

A study has come out finding that, in women, declining weight precedes dementia by many years.
The retrospective study analyzed the medical records of 560 patients diagnosed with the onset of dementia between 1990 and 1994. The patients were matched with 560 controls. Among the women, average weight increased slightly over the preceding 30 years for the control group, but drifted downwards over the 30 years for those who developed dementia. The researchers suggest that changes in the brain interfered somehow with maintenance of body weight. The trend was not observed in men.

Findings were presented July 16 at the Alzheimer's Association International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain.


Link between size of hippocampus and progression to Alzheimer's

A study of 20 older adults with mild cognitive impairment has found that the hippocampus was smaller in those who developed into Alzheimer's during the 3 year period.

Apostolova, L.G. et al. 2006. Conversion of Mild Cognitive Impairment to Alzheimer Disease Predicted by Hippocampal Atrophy Maps. Archives of Neurology, 63, 693-699.


Alzheimer's disease onset tied to lapses in attention

A new finding may lead to another tool to detect Alzheimer’s early, and also offers support for the idea that breakdowns in attention may be at the heart of many of the memory problems experienced by Alzheimer’s sufferers. The study, involving 94 older adults (average age mid-70s) who were either healthy controls or in the early stages of Alzheimer’s, found those in the early stages of Alzheimer's disease had greater difficulty shifting attention back and forth between competing sources of information in a dichotic listening task. The finding may also explain why early-stage patients start to struggle with everyday tasks that call for processing a lot of information, such as driving. Prior research has found that performance on dichotic listening predicts accident rates in commercial bus drivers.
[note: this study was briefly reported on in September, but only mentioning its use as an early test]

Duchek, J.M. & Balota, D.A. 2005. Failure to Control Prepotent Pathways in Early Stage Dementia of the Alzheimer's Type: Evidence from Dichotic Listening. Neuropsychology, 19 (5).


A new analysis of a standard brain test may help predict dementia

A new study gives promise of early diagnosis of Alzheimer’s. A computer analysis of an EEG (electroencephalograph) test was almost 95% accurate in predicting those people in their 60s and 70s who would develop dementia over the next 7 to 10 years. There were several distinctive features in the brain waves of those who would later show cognitive impairment. The study now needs to be replicated with a larger sample.

Prichep, L.S., John, E.R., Ferris, S.H., Rausch, L., Fang, Z., Cancro, R., Torossian, C. & Reisberg, B. 2005. Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging. Neurobiology of Aging, In Press, Corrected Proof, Available online 6 October 2005.


Biosensor reveals new information about ADDLs

A new method using nanoscale optical biosensors allows researchers to detect and estimate the size and structure of ADDLs in cerebrospinal fluid. It’s believed that only ADDLs of a certain size cause problems for neurons in the early stages of Alzheimer’s disease. It is hoped that eventually this technology will help us diagnose Alzheimer’s accurately in living people, and aid our understanding of how ADDLs are involved in Alzheimer’s.

Haes, A.J., van Duyne, R.P., Klein, W.L. & Chang, L. 2005. The paper, ANYL 396, was presented at 9:00 a.m., Wednesday, Aug. 31, during the "New Frontiers in Ultrasensitive Analysis: Nanobiotech, Single Molecule Detection, and Single Cell Analysis" symposium.


Protein studies may lead to new Alzheimer's test

A new technique has identified more than 400 proteins in human spinal fluid — 40 times more than previously known. On average, one of every five proteins identified was substantially changed in patients with Alzheimer's disease compared to older people without neurological disease. The finding may lead to a new test for diagnosing Alzheimer’s.

Zhang, J., Goodlett, D.R., Quinn, J.F., Peskind, E., Kaye, J.A., Zhou, Y., Pan, C., Yi, E., Eng, J., Wang, Q., Aebersold, R.H. & Montine, T.J. 2005. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease Journal of Alzheimer's Disease, 7(2), 125-133.


New test is first step in early detection of Alzheimer's disease

A new technique called bio-bar-code amplification (BCA) technology has been found to be able to detect miniscule amounts of ADDL in human cerebrospinal fluid, bringing promise of an early diagnostic test for Alzheimer’s. The researchers hope to develop the technology so that the test could be done using a blood or urine sample instead of cerebrospinal fluid, which is more difficult to obtain.

Georganopoulou, D.G., Chang, L., Nam, J.M., Thaxton, C.S., Mufson, E.J., Klein, W.L. & Mirkin, C.A. 2005. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proceedings of the National Academy of Sciences, 102, 2273-2276.


Smell test to help early diagnosis

One of the first types of memory affected by Alzheimer’s is olfactory memory – our database of smells. Researchers have now developed a simple scratch-and-sniff test that may enable Alzheimer’s to be detected in its very early stages. On the basis of a five-year study tracking 150 people with mild memory loss and Alzheimer's disease and 63 healthy adults, 10 specific odors proved to be the best predictors for Alzheimer's Disease: strawberry, smoke, soap, menthol, clove, pineapple, natural gas, lilac, lemon and leather. The test takes only 5 to 8 minutes, and seems to have comparable predictive ability as detailed memory and neuropsychological testing.

The findings were presented at the 2004 meeting of the American College of Neuropsychopharmacology.


Antibody detection in Alzheimer's may improve diagnosis, treatment

A study has found that people with Alzheimer’s disease have three to four times more antibodies to RAGE (receptor for advanced glycation end products) and beta amyloid — both major players in Alzheimer’s — than their healthy counterparts. The ability to measure these specific antibody levels could lead to a method for very early diagnosis. The finding may also point to a new treatment approach. The study supports the theory that autoimmunity and resulting inflammation play a big role in Alzheimer’s.

Mruthinti, S., Buccafusco, J.J., Hill, W.D., Waller, J.L., Jackson, T.W., Zamrini, E.Y. & Schade, R.F. 2004. Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Ab and RAGE peptides. Neurobiology of Aging, 25 (8), 1023-1032.


Loss of smell linked to key protein in Alzheimer's disease

Loss of smell is one of the first clinical signs of Alzheimer’s and Parkinson’s disease. Now researchers have linked smell loss in genetically altered mice with excessive levels of a key protein associated with these diseases. If smell function declines as the levels of this protein increase in brain regions associated with smelling, the research could validate the use of smell tests for diagnosing Alzheimer's disease.

Macknin, J.B., Higuchi, M., Lee, V.M-Y., Trojanowski, J.Q. & Doty, R.L. 2004. Olfactory dysfunction occurs in transgenic mice overexpressing human t protein. Brain Research, 1000, 174-178.


Diagnosing Alzheimer's disease may soon be possible earlier

Diagnosing Alzheimer's disease is problematic because we have had no definitive tests for the disease (other than after death, by examining the brain). Recent research suggests that two markers in cerebrospinal fluid may indicate the presence of Alzheimers. This is exciting not only because it would make diagnosis easier, but because it might enable us to diagnose it much earlier. However, to be clinically useful, they will need to develop tests that use more readily available fluids (such as urine).

Praticò, D., Clark, C. M., Lee, V. M.-Y., Trojanowski, J. Q., Rokach, J., & FitzGerald, G. A. (2000). Increased 8,12-iso-iPF2α-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity. Annals of Neurology, 48(5), 809–812. doi:10.1002/1531-8249(200011)48:5<809::AID-ANA19>3.0.CO;2-9

Gene marker for late-onset Alzheimer's disease nearer discovery

Three independent studies have linked late-onset Alzheimer's disease to a locus on chromosome 10 that affects processing of the amyloid-beta protein, a peptide important in the formation of the characteristic amyloid plaques found in the brains of people with Alzheimer's disease. Researchers are optimistic the precise gene will be found in the next few years.
Before this, a particular form of the apolipoprotein E (APOE) gene on chromosome 19 has been the only widely recognized genetic risk factor in late onset Alzheimer’s disease. There is also some evidence of a risk factor gene on a region of chromosome 12.
So far, three genes have been found that are linked to the rare early-onset Alzheimer's (when symptoms appear before age 60).

Bertram, L., Blacker, D., Mullin, K., Keeney, D., Jones, J., Basu, S., … Tanzi, R. E. (2000). Evidence for Genetic Linkage of Alzheimer’s Disease to Chromosome 10q. Science, 290(5500), 2302–2303. doi:10.1126/science.290.5500.2302

Ertekin-Taner, N., Graff-Radford, N., Younkin, L. H., Eckman, C., Baker, M., Adamson, J., … Younkin, S. G. (2000). Linkage of Plasma Aβ42 to a Quantitative Locus on Chromosome 10 in Late-Onset Alzheimer’s Disease Pedigrees. Science, 290(5500), 2303–2304. doi:10.1126/science.290.5500.2303

Myers, A., Holmans, P., Marshall, H., Kwon, J., Meyer, D., Ramic, D., … Goate, A. M. (2000). Susceptibility Locus for Alzheimer’s Disease on Chromosome 10. Science, 290(5500), 2304–2305. doi:10.1126/science.290.5500.2304