Phosphatidylserine and the Human Brain

Nutrition. 2015 Jun;31(6):781-786. doi: 10.1016/j.nut.2014.10.014. Epub 2014 Nov 4.

Phosphatidylserine and the human brain.

Glade MJ1, Smith K2.



The aim of this study was to assess the roles and importance of phosphatidylserine (PS), an endogenous phospholipid and dietary nutrient, in human brain biochemistry, physiology, and function.


A scientific literature search was conducted on MEDLINE for relevant articles regarding PS and the human brain published before June 2014. Additional publications were identified from references provided in original papers; 127 articles were selected for inclusion in this review.


A large body of scientific evidence describes the interactions among PS, cognitive activity, cognitive aging, and retention of cognitive functioning ability.


Phosphatidylserine is required for healthy nerve cell membranes and myelin. Aging of the human brain is associated with biochemical alterations and structural deterioration that impair neurotransmission.

Exogenous PS (300-800 mg/d) is absorbed efficiently in humans, crosses the blood-brain barrier, and safely slows, halts, or reverses biochemical alterations and structural deterioration in nerve cells.

It supports human cognitive functions, including the formation of short-term memory, the consolidation of long-term memory, the ability to create new memories, the ability to retrieve memories, the ability to learn and recall information, the ability to focus attention and concentrate, the ability to reason and solve problems, language skills, and the ability to communicate.

It also supports locomotor functions, especially rapid reactions and reflexes.


Copyright © 2015 Elsevier Inc. All rights reserved.

National Center for Biotechnology Information, U.S. National Library of Medicine


Lower Risk of Alzheimer’s Disease Mortality with Exercise, Statin, and Fruit Intake

J Alzheimers Dis. 2014 Nov 14. [Epub ahead of print]

Lower Risk of Alzheimer’s Disease Mortality with Exercise, Statin, and Fruit Intake.

Williams PT1.



Whether lifestyle affects Alzheimer’s disease (AD) risk remains controversial.


Test whether exercise, diet, or statins affect AD mortality in 153,536 participants of the National Runners’ and Walkers’ Health Studies.


Hazard ratios (HR) and 95% confidence intervals (95% CI) were obtained from Cox proportional hazard analyses for AD mortality versus baseline metabolic equivalent (MET) hours/d of exercise energy expenditure (1 MET equals approximately 1 km run), statin use, and fruit intake when adjusted for age, race, gender, education, and exercise mode.


The National Death Index identified 175 subjects who died with AD listed as an underlying (n = 116) or contributing (n = 59) cause of death during 11.6-year average mortality surveillance.

Relative to exercising <1.07 MET-hours/d, AD mortality was 6.0% lower for 1.07 to 1.8 MET-hours/d (HR: 0.94, 95% CI: 0.59 to 1.46, p = 0.79), 24.8% lower for 1.8 to 3.6 MET-hours/d (HR: 0.75, 95% CI: 0.50 to 1.13, p = 0.17), and 40.1% lower for ≥3.6 MET-hours/d (HR: 0.60, 95% CI: 0.37 to 0.97, p = 0.04).

Relative to non-use, statin use was associated with 61% lower AD mortality (HR: 0.39, 95% CI: 0.15 to 0.82, p = 0.01), whereas use of other cholesterol-lowering medications was not (HR: 0.78, 95% CI: 0.40 to 1.38, p = 0.42).

Relative to <1 piece of fruit/day, consuming 2 to 3 pieces daily was associated with 39.7% lower AD mortality (HR: 0.60, 95% CI: 0.39 to 0.91, p = 0.02) and ≥3 pieces/day with 60.7% lower AD mortality (HR: 0.39, 95% CI: 0.22 to 0.67, p = 0.0004).


Exercise, statin, and fruit intake were associated with lower risk for AD mortality.


Copyright ©2014 IOS Press All rights reserved.


Effect of Depression and Diabetes Mellitus on the Risk for Dementia

JAMA Psychiatry. 2015 Apr 15. doi: 10.1001/jamapsychiatry.2015.0082. [Epub ahead of print]

Effect of Depression and Diabetes Mellitus on the Risk for Dementia: A National Population-Based Cohort Study.

Katon W1, Pedersen HS2, Ribe AR2, Fenger-Grøn M2, Davydow D1, Waldorff FB3, Vestergaard M2.

  • 1Division of Health Services Research and Psychiatric Epidemiology, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
  • 2Department of Public Health, Research Unit for General Practice, Aarhus University, Aarhus, Denmark.
  • 3Department of Public Health, Research Unit for General Practice, Section of General Practice, University of Copenhagen, Copenhagen, Denmark.



Although depression and type 2 diabetes mellitus (DM) may independently increase the risk for dementia, no studies have examined whether the risk for dementia among people with comorbid depression and DM is higher than the sum of each exposure individually.


To examine the risk for all-cause dementia among persons with depression, DM, or both compared with persons with neither exposure.

Design, Setting, and Participants

We performed a national population-based cohort study of 2 454 532 adults, including 477 133 (19.4%) with depression, 223 174 (9.1%) with DM, and 95 691 (3.9%) with both. We included all living Danish citizens 50 years or older who were free of dementia from January 1, 2007, through December 31, 2013 (followed up through December 31, 2013). Dementia was ascertained by physician diagnosis from the Danish National Patient Register or the Danish Psychiatric Central Register and/or by prescription of a cholinesterase inhibitor or memantine hydrochloride from the Danish National Prescription Registry. Depression was ascertained by psychiatrist diagnosis from the Danish Psychiatric Central Research Register or by prescription of an antidepressant from the Danish National Prescription Registry. Diabetes mellitus was identified using the National Diabetes Register.

Main Outcomes and Measures

We estimated the risk for all-cause dementia associated with DM, depression, or both using Cox proportional hazards regression models that adjusted for potential confounding factors (eg, demographics) and potential intermediates (eg, medical comorbidities).


During 13 834 645 person-years of follow-up, 59 663 participants (2.4%) developed dementia; of these, 6466 (10.8%) had DM, 15 729 (26.4%) had depression, and 4022 (6.7%) had both. The adjusted hazard ratio for developing all-cause dementia was 1.83 (95% CI, 1.80-1.87) for persons with depression, 1.20 (95% CI, 1.17-1.23) for persons with DM, and 2.17 (95% CI, 2.10-2.24) for those with both compared with persons who had neither exposure. The excess risk for all-cause dementia observed for individuals with comorbid depression and DM surpassed the summed risk associated with each exposure individually, especially for persons younger than 65 years (hazard ratio, 4.84 [95% CI, 4.21-5.55]). The corresponding attributable proportion due to the interaction of comorbid depression and DM was 0.25 (95% CI, 0.13-0.36; P < .001) for those younger than 65 years and 0.06 (95% CI, 0.02-0.10; P = .001) for those 65 years or older.

Conclusions and Relevance

Depression and DM were independently associated with a greater risk for dementia, and the combined association of both exposures with the risk for all-cause dementia was stronger than the additive association.



The Continuing Failure of Bexarotene in Alzheimer’s Disease Mice

J Alzheimers Dis. 2015 Mar 16. [Epub ahead of print]

The Continuing Failure of Bexarotene in Alzheimer’s Disease Mice.

Balducci C1, Paladini A1, Micotti E1, Tolomeo D1, La Vitola P1, Grigoli E1, Richardson JC2, Forloni G1.


Alzheimer’s disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance.

Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist, that increases ApoE expression and microglia phagocytosis and has been proposed as a promising therapy for AD, resolving both the amyloid pathology and memory loss.

Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD.

To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation.

No differences were found when specifically investigating the microglial phagocytic state in vivo. In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice.

These results suggest that BEXA has no beneficial effect on the multi-factorial pathologic phenotype of AD mice.



Divalent Copper as a Major Triggering Agent in Alzheimer’s Disease

J Alzheimers Dis. 2015 Apr 8. [Epub ahead of print]

Divalent Copper as a Major Triggering Agent in Alzheimer’s Disease.

Brewer GJ1.


Alzheimer’s disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries.

This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper.

Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition.

Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates.

An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury.

Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.



Smoking is Associated with an Increased Risk of Dementia: A Meta-Analysis of Prospective Cohort Studies

PLoS One. 2015 Mar 12;10(3):e0118333. doi: 10.1371/journal.pone.0118333. eCollection 2015.

Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies with investigation of potential effect modifiers.

Zhong G1, Wang Y1, Zhang Y2, Guo JJ3, Zhao Y2.

  • 1The Second College of Clinical Medicine, Chongqing Medical University, Chongqing, China.
  • 2School of Public Health and Management, Chongqing Medical University, Chongqing, China.
  • 3Division of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45221, United States of America.



Previous studies showed inconsistent results on the association of smoking with all-cause dementia and vascular dementia (VaD), and are limited by inclusion of a small number of studies and unexplained heterogeneity. Our review aimed to assess the risk of all-cause dementia, Alzheimer’s disease (AD) and VaD associated with smoking, and to identify potential effect modifiers.

Methods and Findings

The PubMed, Embase, Cochrane Library and Psychinfo databases were searched to identify studies that provided risk estimates on smoking and incidence of dementia. A random-effects model was used to yield pooled results. Thirty-seven studies were included.

Compared with never smokers, current smokers showed an increased risk of all-cause dementia (risk ratio (RR) 1.30, 95% confidence interval (CI) 1.18-1.45), AD (RR 1.40, 95% CI 1.13-1.73) and VaD (RR 1.38, 95% CI 1.15-1.66). For all-cause dementia, the risk increased by 34% for every 20 cigarettes per day (RR 1.34, 95% CI 1.25-1.43).

Former smokers did not show an increased risk of all-cause dementia (RR 1.01, 95% CI 0.96-1.06), AD (RR 1.04, 95% CI 0.96-1.13) and VaD (RR 0.97, 95% CI 0.83-1.13).

Subgroup analyses indicated that (1) the significantly increased risk of AD from current smoking was seen only in apolipoprotein E ε4 noncarriers; (2) current smokers aged 65 to 75 years at baseline showed increased risk of all-cause dementia and AD compared to those aged over 75 or under 65 years; and (3) sex, race, study location and diagnostic criteria difference in risk of dementia was not found.


Smokers show an increased risk of dementia, and smoking cessation decreases the risk to that of never smokers. The increased risk of AD from smoking is more pronounced in apolipoprotein E ε4 noncarriers. Survival bias and competing risk reduce the risk of dementia from smoking at extreme age.



Do Physical Activity, Smoking, Drinking, or Depression Modify Transitions from Cognitive Impairment to Functional Disability?

J Alzheimers Dis. 2015 Jan 1;44(4):1171-80. doi: 10.3233/JAD-141866.

Do physical activity, smoking, drinking, or depression modify transitions from cognitive impairment to functional disability?

Rist PM1, Marden JR2, Capistrant BD3, Wu Q4, Glymour MM5.

  • 1Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA, USA Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
  • 2Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA, USA.
  • 3Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA Minnesota Population Center, University of Minnesota, Minneapolis, MN, USA.
  • 4Institute of Social Science Survey, Peking University, Peking, China.
  • 5Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA, USA Department of Epidemiology & Biostatistics, University of California, San Francisco, USA.



Individual-level modifiers can delay onset of limitations in basic activities of daily living (ADLs) among cognitively impaired individuals. We assessed whether these modifiers also delayed onset of limitations in instrumental ADLs (IADLs) among individuals at elevated dementia risk.


To determine whether modifiable individual-level factors delay incident IADL limitations among adults stratified by dementia risk.


Health and Retirement Study participants aged 65+ without activity limitations in 1998 or 2000 (n = 5,219) were interviewed biennially through 2010. Dementia probability, categorized in quartiles, was used to predict incident IADL limitations with Poisson regression. We estimated relative (risk ratio) and absolute (number of limitations) effects from models including dementia, individual-level modifiers (physical inactivity, smoking, no alcohol consumption, and depression) and interaction terms between dementia and individual-level modifiers.


Dementia probability quartile predicted incident IADL limitations (relative risk for highest versus lowest quartile = 0.44; 95% CI: 0.28-0.70). Most modifiers did not significantly increase risk of IADL limitations among the cognitively impaired. Physical inactivity (RR = 1.60; 95% CI: 1.16, 2.19) increased the risk of IADL limitations among the cognitively impaired. The interaction between physical inactivity and low dementia probability was statistically significant (p = 0.009) indicating that physical inactivity had significantly larger effects on incident IADLs among cognitively normal than among those with high dementia probability.


Physical activity may protect against IADL limitations while not smoking, alcohol consumption, and not being depressed do not afford substantial protection among the cognitively impaired. RESULTS highlight the need for extra support for IADLs among individuals with cognitive losses.



Multidomain Intervention of Diet, Exercise, Cognitive Training, and Vascular Risk Monitoring Versus Control to Prevent Cognitive Decline in At-Risk Elderly People

The Lancet, 2015 March (Online first)

DOI: 10.1016/S0140-6736(15)60461-5

A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial

Ngandu, Tiia et al.


Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a proof-of-concept randomised controlled trial, we aimed to assess a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population.


In a double-blind randomised controlled trial we enrolled individuals aged 60–77 years recruited from previous national surveys. Inclusion criteria were CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age.

We randomly assigned participants in a 1:1 ratio to a 2 year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring), or a control group (general health advice). Computer-generated allocation was done in blocks of four (two individuals randomly allocated to each group) at each site. Group allocation was not actively disclosed to participants and outcome assessors were masked to group allocation.

The primary outcome was change in cognition as measured through comprehensive neuropsychological test battery (NTB) Z score. Analysis was by modified intention to treat (all participants with at least one post-baseline observation). This trial is registered at, number NCT01041989.


Between Sept 7, 2009, and Nov 24, 2011, we screened 2654 individuals and randomly assigned 1260 to the intervention group (n=631) or control group (n=629). 591 (94%) participants in the intervention group and 599 (95%) in the control group had at least one post-baseline assessment and were included in the modified intention-to-treat analysis. Estimated mean change in NTB total Z score at 2 years was 0·20 (SE 0·02, SD 0·51) in the intervention group and 0·16 (0·01, 0·51) in the control group. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002–0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control).


Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.


Academy of Finland, La Carita Foundation, Alzheimer Association, Alzheimer’s Research and Prevention Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Finnish Social Insurance Institution, Ministry of Education and Culture, Salama bint Hamdan Al Nahyan Foundation, Axa Research Fund, EVO funding for University Hospitals of Kuopio, Oulu, and Turku and for Seinäjoki Central Hospital and Oulu City Hospital, Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, and af Jochnick Foundation.


Copyright © 2015 Elsevier Limited except certain content provided by third parties.