Late-life depression, mild cognitive impairment, and dementia: possible continuum?

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms.

Drugs currently used in the treatment of cognitive impairment and dementia have a very limited therapeutic value, suggesting the necessity to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. An increasing body of epidemiological evidence suggested that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI). Furthermore, a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. Epidemiological findings demonstrated that high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. Several hypotheses could explain the association between dietary unsaturated fatty acids and cognitive functioning, including mechanisms through the co-presence of antioxidant compounds in food groups rich in fatty acids, via atherosclerosis and thrombosis, inflammation, accumulation of b-amyloid, or via an effect in maintaining the structural integrity of neuronal membranes, determining the fluidity of synaptosomal membranes that thereby regulate neuronal transmission. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms only in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimer's disease (AD) subgroups, MCI patients, and cognitively unimpaired subjects non-APOE epsilon4 carriers. These data together with epidemiological evidence support a possible role of fatty acid intake in maintaining adequate cognitive functioning and possibly for the prevention and management of cognitive decline and dementia, but not when the AD process has already taken over.

All-cause mortality and competing risks of fatal and nonfatal vascular events in the Italian longitudinal study on aging: impact of lipoprotein(a).

Among possible determinants of vascular events, the role of high lipoprotein(a) (Lp[a]) serum levels represents a still uncertain independent risk factor in elderly populations. Moreover, the cumulative incidence of nonfatal vascular events due to high Lp(a) serum levels is conditioned by the competing risk of death from any causes that are a function of age. After a 6.3-year median follow up, we tested the competing risks of all-cause mortality, cumulative fatal-nonfatal stroke events, cumulative fatal-nonfatal coronary artery disease (CAD) events, and nonfatal stroke or CAD events due to high Lp(a) serum levels in a population-based, prospective study conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Of 704 elderly individuals (65-84 years), 372 (169 women and 203 men) agreed to participate in the study. As compared with those in the lowest Lp(a) tertile serum levels, subjects in the highest tertile (>20 mg/dL) had a higher partially adjusted risk of nonfatal CAD (hazard ratio, 4.19; 95% confidence interval [CI], 1.36-12.94) and nonfatal stroke (hazard ratio, 3.38; 95% CI, 1.00-11.56). Compared with those in the lowest tertile, subjects in the highest tertile had a higher fully adjusted risk of nonfatal CAD (hazard ratio, 3.41; 95% CI, 1.08-10.78). Finally, overall no statistically significant association was found between Lp(a) and the risk of all-cause mortality, cumulative fatal-nonfatal stroke, and cumulative fatal-nonfatal CAD events. In our population, Lp(a) was not a significant independent predictor of stroke and death from all causes, but it was an independent predictor of nonfatal CAD. Finally competing risk, conditioning the timing and occurrence of vascular events in our study population, could be a correct approach for evaluating the role of Lp(a) lipoprotein in vascular disease among elderly people.

Disease-modifying approach to the treatment of Alzheimer's disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators.

In the last decade, advances in understanding the neurobiology of Alzheimer's disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of beta-amyloid (A beta) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating A beta formation from amyloid precursor protein (APP). Compounds that stimulate alpha-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of beta-secretase (memapsin-2, beta-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta, have been identified, the most advanced being LY-450139 (semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of tarenflurbil, a compound believed to modulate the activity of gamma-secretase, after encouraging phase II findings. Nevertheless, other promising gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years.

Dietary fatty acids and predementia syndromes.

An increasing body of epidemiological evidence suggests that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD). Furthermore, a reduction of risk for cognitive decline and mild cognitive impairment (MCI) has been found in population samples with elevated fish consumption, and high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimer's disease (AD) subgroups, MCI patients, and cognitively unimpaired non-APOE epsilon4 carriers. These data, together with epidemiological evidence, support the idea that n-3 PUFA may play a role in maintaining adequate cognitive functioning in predementia syndromes, but not when the AD process has already taken over. Therefore, at present, no definitive dietary recommendations on fish and unsaturated fatty acids consumption, or lower intake of saturated fat, in relation to the risk for dementia and cognitive decline are possible.

Alcohol drinking, cognitive functions in older age, predementia, and dementia syndromes.

Among lifestyle-related factors, low to moderate alcohol drinking has been proposed as a protective factor against the development of age-related changes in cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD) in several longitudinal studies, but contrasting findings also exist. Furthermore, many of these studies were limited by cross-sectional design, restriction by age or sex, or incomplete ascertainment. Different outcomes, beverages, drinking patterns, or follow-up periods, or possible interactions with other lifestyle-related (i.e., smoking) or genetic factors [i.e., apolipoprotein E (APOE) genotyping] may be sources of great variability. Light to moderate alcohol use may be associated with a reduced risk of unspecified incident dementia and AD, while for VaD, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. In conclusion, as intervention studies are not feasible in this area, the best evidence comes from an overview of epidemiological studies, suggesting that the protective effects are more likely with wine consumption and the absence of an APOE e4 allele. At present, there is no indication that light to moderate alcohol drinking would be harmful to cognition and dementia, and it is not possible to define a specific beneficial level of alcohol intake.

Temporal relationship between depressive symptoms and cognitive impairment: the Italian Longitudinal Study on Aging.

The temporal relationship between depression and cognitive decline has not been extensively investigated in prospective population-based studies, and most of these have only looked in one direction. We estimated the bidirectional temporal relationship between depressive symptoms and cognitive function in older subjects, excluding subjects with a clinical diagnosis of dementia or mild cognitive impairment (MCI). In a total of 2,963 individuals from the Italian Longitudinal Study on Aging, depressive symptoms, global cognitive function, and episodic memory were measured. Dementia, Alzheimer's disease, vascular dementia, and MCI were classified using current clinical criteria. Depressive symptoms at baseline were associated with an accelerated global cognitive function decline and an accelerated rate of episodic memory delayed recall decline in a 3.5-year follow-up. Finally, an accelerated increase with time of depressive symptoms during the same follow-up period was not associated with global cognitive function and episodic memory (immediate and delayed recall). In older subjects non-cognitively impaired, depressive symptoms at baseline predicted change over time of global cognitive decline and episodic memory delayed recall. Global cognitive function and episodic memory at baseline were not associated with the course of depressive symptoms during the follow-up.

Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimer's disease: a review.

A growing body of evidence indicates that nutritional supplements can improve cognition; however, which supplements are effective remains controversial. In this review article, we focus on dietary supplementation suggested for predementia syndromes and Alzheimer's disease (AD), with particular emphasis on S-adenosylmethionine (SAM) and polyunsaturated fatty acids (PUFA). Very recent findings confirmed that SAM can exert a direct effect on glutathione S-transferase (GST) activity. AD is accompanied by reduced GST activity, diminished SAM, and increased S-adenosylhomocysteine (SAH), the downstream metabolic product resulting from SAM-mediated transmethylation reactions, when deprived of folate. Therefore, these findings underscored the critical role of SAM in maintenance of neuronal health, suggesting a possible role of SAM as a neuroprotective dietary supplement for AD patients. In fact, very recent studies on early-stage AD patients and moderate- to late-stage AD patients were conducted with a nutriceutical supplementation that included SAM, with promising results. Given recent findings from randomized clinical trials (RCTs) in which n-3 PUFA supplementation was effective only in very mild AD subgroups or mild cognitive impairment (MCI), we suggest future intervention trials using measures of dietary supplementation (dietary n-3 PUFA and SAM plus B vitamin supplementation) to determine if such supplements will reduce the risk for cognitive decline in very mild AD and MCI. Therefore, key supplements are not necessarily working in isolation and the most profound impact, or in some cases the only impact, is noted very early in the course of AD, suggesting that nutriceutical supplements may bolster pharmacological approaches well past the window where supplements can work on their own. Recommendations regarding future research on the effects of SAM or n-3 PUFA supplementation on predementia syndromes and very mild AD include properly designed RCTs that are sufficiently powered and with an adequate length (e.g., 3-5 years of follow-up).

Possible role of S-adenosylmethionine, S-adenosylhomocysteine, and polyunsaturated fatty acids in predementia syndromes and Alzheimer's disease.

Very recent findings confirmed that S-adenosylmethionine (SAM) can exert a direct effect on glutathione S-transferase (GST) activity. Alzheimer's disease (AD) is accompanied by reduced GST activity, diminished SAM, and increased S-adenosyl homocysteine (SAH), the downstream metabolic product resulting from SAM-mediated transmethylation reactions, when deprived of folate. Therefore, these findings underscored the critical role of SAM in maintenance of neuronal health, suggesting a possible role of SAM as a neuroprotective dietary supplement in AD. Given recent findings from clinical trials in which omega-3 polyunsturated fatty acids (PUFA) supplementation was effective only in very mild AD subgroups or mild cognitive impairment (MCI), we suggest intervention trials using measures of dietary supplementation (dietary omega-3 PUFA and SAM plus B vitamin supplementation) to determine if such supplements will reduce the risk for cognitive decline in very mild AD and MCI. Therefore, key supplements are not necessarily working in isolation, and the most profound impact, or in some cases the only impact, is noted very early in the course of AD, suggesting that nutriceutical supplements may bolster pharmacological approaches well past the window where supplements can work on their own.

Beyond the neurotransmitter-focused approach in treating Alzheimer's disease: drugs targeting beta-amyloid and tau protein.

Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Abeta is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of beta-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against tau protein include inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for tau phosphorylation and tau protein aggregation inhibitors. NP-12, a promising GSK-3 inhibitor, is being tested in a Phase II study, and methylthioninium chloride, a tau protein aggregation inhibitor, has given initial encouraging results in a 50-week study. With all these approaches on their way, the hope for disease-modifying therapy in this devastating disease may become a reality in the next 5 years.