Multimodal Precision Prevention - A New Direction in Alzheimer's Disease.

At least 40% of all dementia has been linked to modifiable risk factors suggesting a clear potential for preventative approaches targeting these factors. Despite the recent promising findings from anti-amyloid monoclonal antibodies, a limited proportion of patients are expected to be eligible for these novel AD treatments. Given the heterogeneous nature of AD and the complex multi-level pathological processes leading to dementia (involving, e.g., shared risk factors, interaction of different pathology mechanisms, and their putative synergistic effects on cognition), targeting a single pathology may not be sufficient to halt or significantly impact disease progression. With exponentially increasing numbers of patients world-wide, in parallel to the unprecedented population ageing, new multimodal therapy approaches targeting several modifiable risk factors and disease mechanisms simultaneously are urgently required. Developing the next generation of combination therapies with lifestyle intervention and pharmacological treatments, implementing the right interventions for the right people at the right time, and defining accessible and sustainable strategies worldwide are crucial. Here, we summarize the state-of-the-art multimodal lifestyle-based approaches, especially findings and lessons learned from the FINGER trial, for prevention and risk reduction of cognitive impairment and dementia. We also discuss some emerging underlying biological mechanisms and the current development of precision prevention approaches. We present an example of a novel trial design combining healthy lifestyle changes with a repurposed putative disease-modifying drug and place this study in the context of the World-Wide FINGERS, the first interdisciplinary network of multimodal trials dedicated to the prevention and risk reduction of cognitive impairment and dementia.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

How can dementia and disability be prevented in older adults: where are we today and where are we going?

Ageing of the population, together with population growth, has brought along an ample increase in the number of older individuals living with dementia and disabilities. Dementia is the main cause of disability in old age, and promoting healthy brain ageing is considered as a key element in diminishing the burden of age-related disabilities. The World Health Organization recently launched the first risk reduction guidelines for cognitive impairment and dementia. According to recent estimates, approximately 40% of dementia cases worldwide could be attributable to 12 modifiable risk factors: low education; midlife hypertension and obesity; diabetes, smoking, excessive alcohol use, physical inactivity, depression, low social contact, hearing loss, traumatic brain injury and air pollution indicating clear prevention potential. Dementia and physical disability are closely linked with shared risk factors and possible shared underlying mechanisms supporting the possibility of integrated preventive interventions. FINGER trial was the first large randomized controlled trial indicating that multidomain lifestyle-based intervention can prevent cognitive and functional decline amongst at-risk older adults from the general population. Within the World-Wide FINGERS network, the multidomain FINGER concept is now tested and adapted worldwide proving evidence and tools for effective and easily implementable preventive strategies. Close collaboration between researchers, policymakers and healthcare practitioners, involvement of older adults and utilization of new technologies to support self-management is needed to facilitate the implementation of the research findings. In this scoping review, we present the current scientific evidence in the field of dementia and disability prevention and discuss future directions in the field.

Multidomain Interventions to Prevent Cognitive Impairment, Alzheimer's Disease, and Dementia: From FINGER to World-Wide FINGERS.

Alzheimer's disease (AD) and dementia are a global public health priority, and prevention has been highlighted as a pivotal component in managing the dementia epidemic. Modifiable risk factors of dementia and AD include lifestyle-related factors, vascular and metabolic disorders, and psychosocial factors. Randomized controlled clinical trials (RCTs) are needed to clarify whether modifying such factors can prevent or postpone cognitive impairment and dementia in older adults. Given the complex, multifactorial, and heterogeneous nature of late-onset AD and dementia, interventions targeting several risk factors and mechanisms simultaneously may be required for optimal preventive effects. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is the first large, long-term RCT to demonstrate that a multidomain lifestyle-based intervention ameliorating vascular and lifestyle-related risk factors can preserve cognitive functioning and reduce the risk of cognitive decline among older adults at increased risk of dementia. To investigate the multidomain intervention in other populations and diverse cultural and geographical settings, the World-Wide FINGERS (WW-FINGERS) network was recently launched (https://alz.org/wwfingers). Within this network, new FINGER-type trials with shared core methodology, but local culture and context-specific adaptations, will be conducted in several countries. The WW-FINGERS initiative facilitates international collaborations, provides a platform for testing multidomain strategies to prevent cognitive impairment and dementia, and aims at generating high-quality scientific evidence to support public health and clinical decision-making. Furthermore, the WW-FINGERS network can support the implementation of preventive strategies and translation of research findings into practice.

Midlife improvements in financial situation are associated with a reduced dementia risk later in life: the CAIDE 30-year study.

OBJECTIVES: Perceived financial strain is associated with various health conditions, but it is unknown whether it is associated with an increased risk for dementia. The goal is to examine the associations between midlife perceptions of financial situation and dementia risk later in life. METHODS: Participants were derived from the Cardiovascular Risk Factors, Aging, and Dementia population-based cohort study (n = 2000) (between 1972 and 1987, baseline mean age 50 years) in Finland. Participants returned for two re-examinations in late life (in 1998 and 2005-2008, mean age 71 and 78 years). In this study, 1442 subjects that participated in at least one re-examination (mean total follow-up 25 years) were included in analyses. Financial strain was measured using two questions in midlife on perceptions of financial situation and perceptions of changes in financial situation. For each question, participants were categorized into three groups reporting improvement, worsening, or stability, with the latter set as the reference group. Analyses were adjusted for potential confounding factors. RESULTS: The group reporting better financial situation had a reduced risk for dementia (fully adjusted model: odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33-0.86). In contrast, the group reporting worse financial situation did not have an increased risk for dementia (OR: 1.04, 95% CI: 0.53-2.02). Analyses on perceptions of current financial situation showed that the groups reporting satisfaction or dissatisfaction with financial situation did not differ in risk for dementia. CONCLUSION: This study is the first to show that midlife improvements in financial situation are associated with a reduced dementia risk later in life. Potential pathways related to stress reduction, improved lifestyle, and potential biological mechanisms are discussed.

Brain ß-Amyloid and Atrophy in Individuals at Increased Risk of Cognitive Decline.

BACKGROUND AND PURPOSE: The relationship between brain ß-amyloid and regional atrophy is still incompletely understood in elderly individuals at risk of dementia. Here, we studied the associations between brain ß-amyloid load and regional GM and WM volumes in older adults who were clinically evaluated as being at increased risk of cognitive decline based on cardiovascular risk factors. MATERIALS AND METHODS: Forty subjects (63-81 years of age) were recruited as part of a larger study, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. Neuroimaging consisted of PET using 11C Pittsburgh compound-B and T1-weighted 3D MR imaging for the measurement of brain ß-amyloid and GM and WM volumes, respectively. All subjects underwent clinical, genetic, and neuropsychological evaluations for the assessment of cognitive function and the identification of cardiovascular risk factors. RESULTS: Sixteen subjects were visually evaluated as showing cortical ß-amyloid (positive for ß-amyloid). In the voxel-by-voxel analyses, no significant differences were found in GM and WM volumes between the samples positive and negative for ß-amyloid. However, in the sample positive for ß-amyloid, increases in 11C Pittsburgh compound-B uptake were associated with reductions in GM volume in the left prefrontal (P = .02) and right temporal lobes (P = .04). CONCLUSIONS: Our results show a significant association between increases in brain ß-amyloid and reductions in regional GM volume in individuals at increased risk of cognitive decline. This evidence is consistent with a model in which increases in ß-amyloid incite neurodegeneration in memory systems before cognitive impairment manifests.

Self-rated physical fitness and estimated maximal oxygen uptake in relation to all-cause and cause-specific mortality.

This study investigated the longitudinal associations of self-rated physical fitness and estimated maximal oxygen uptake (VO2max) with all-cause and cause-specific mortality. A total of 59 741 participants in the Finnish National FINRISK Study Cohort had data on self-rated physical fitness and covariates. A subsample of 4823 participants had estimated VO2max data. Follow-up ranged from 3 to 38 years. Associations of self-rated physical fitness and VO2max with mortality were analyzed using multivariate Cox proportional hazard models. The study showed that poor self-rated physical fitness was related to all-cause mortality (hazard ratio [HR] 1.9; 95% confidence interval [CI] 1.8-2.0) and mortality due to cardiovascular (HR 2.0, 95% CI 1.9-2.2), cerebrovascular (HR 1.9, 95% CI 1.6-2.2) and respiratory diseases (HR 2.1, 95% CI 1.9-2.4), trauma (HR 1.7, 95% CI 1.3-2.0), infections (HR 1.8, 95% CI 1.3-2.7), dementia (HR 1.9, 95% CI 1.6-2.3), and cancer (HR 1.7, 95% CI 1.5-1.9). Coexisting higher age, physical inactivity, male gender, and severe chronic conditions further increased the risk. In men, higher VO2max was associated with a lower risk of lung cancer mortality (HR 0.8, 95% CI 0.7-0.96). Based on the results, self-rated physical fitness reflects a combination of unfavorable biological and lifestyle-related factors, which increase mortality risk. A simple question about perceived physical fitness may reveal at-risk individuals who would benefit from more intensive treatment of chronic conditions and other interventions aiming to promote better fitness and well-being.

Association of Long-Term Dietary Fat Intake, Exercise, and Weight with Later Cognitive Function in the Finnish Diabetes Prevention Study.

OBJECTIVES: To investigate associations of long-term nutrient intake, physical activity and obesity with later cognitive function among the participants in the Finnish Diabetes Prevention Study, in which a lifestyle intervention was successful in diabetes prevention. DESIGN: An active lifestyle intervention phase during middle age (mean duration 4 years) and extended follow-up (additional 9 years) with annual lifestyle measurements, followed by an ancillary cognition assessment. SETTING: 5 research centers in Finland. PARTICIPANTS: Of the 522 middle-aged, overweight participants with impaired glucose tolerance recruited to the study, 364 (70%) participated in the cognition assessment (mean age 68 years). MEASUREMENTS: A cognitive assessment was executed with the CERAD test battery and the Trail Making Test A on average 13 years after baseline. Lifestyle measurements included annual clinical measurements, food records, and exercise questionnaires during both the intervention and follow-up phase. RESULTS: Lower intake of total fat (p=0.021) and saturated fatty acids (p=0.010), and frequent physical activity (p=0.040) during the whole study period were associated with better cognitive performance. Higher BMI (p=0.012) and waist circumference (p=0.012) were also associated with worse performance, but weight reduction prior to the cognition assessment predicted worse performance as well (decrease vs. increase, p=0.008 for BMI and p=0.002 for waist). CONCLUSIONS: Long-term dietary fat intake, BMI, and waist circumference have an inverse association with cognitive function in later life among people with IGT. However, decreases in BMI and waist prior to cognitive assessment are associated with worse cognitive performance, which could be explained by reverse causality.

Association between mid- to late life physical fitness and dementia: evidence from the CAIDE study.

OBJECTIVES: This study investigated the association between perceived physical fitness at midlife, changes in perceived fitness during the three decades from mid- to late life and dementia risk. DESIGN: Prospective cohort study. SETTING: Cardiovascular risk factors, ageing and incidence of dementia (CAIDE) study. SUBJECTS: Subjects were selected from four independent, random samples of population-based cardiovascular surveys and were first examined in 1972, 1977, 1982 or 1987, when they were on average 50 years old. The CAIDE target population included 3559 individuals. A random sample of 2000 individuals still alive in 1997 was drawn for re-examinations (performed in 1998 and 2005-2008) that consisted of cognitive assessments, with 1511 subjects participating in at least one re-examination. Dementia diagnoses were also confirmed from national registers for the entire target population. MAIN OUTCOME MEASURE: All-cause dementia. RESULTS: Poor physical fitness at midlife was associated with increased dementia risk in the entire target population [hazard ratio (HR), 1.5; 95% confidence interval (CI), 1.1-2.0]. In participants, odds ratio (OR) was 2.0 (95% CI, 0.9-4.0). This association was significant in apolipoprotein E ε4 allele (APOEε4) noncarriers (OR, 4.3; 95% CI, 1.4-13.3), men (HR, 1.8; 95% CI, 1.1-3.0) and people with chronic conditions (HR, 2.9; 95% CI, 1.3-6.6). A decline in fitness after midlife was also associated with dementia (OR, 3.0; 95% CI, 1.7-5.1), which was significant amongst both men and women and more pronounced in APOEε4 carriers (OR, 4.4; 95% CI, 2.1-9.1). CONCLUSIONS: Perceived poor physical fitness reflects a combination of biological and lifestyle-related factors that can increase dementia risk. A simple question about perceived physical fitness may reveal at-risk individuals who could benefit from preventive interventions.

Midlife smoking, apolipoprotein E and risk of dementia and Alzheimer's disease: a population-based cardiovascular risk factors, aging and dementia study.

AIM: To elucidate the effect of midlife smoking on the risk of dementia and Alzheimer's disease (AD), and the possible modification of this relation by the apolipoprotein E (APOE) ε4. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were randomly selected from population-based samples originally studied in midlife (1972, 1977, 1982 or 1988). After an average follow-up of 21 years, 1,449 persons (73%) aged 65-79 years took part in a reexamination in 1998. RESULTS: Smoking in midlife increased the risk of dementia (odds ratio, OR: 4.93; 95% CI: 1.51-16.11) and AD (OR: 6.56; 95% CI: 1.80-23.94) among the APOE ε4 carriers, but not among the APOE ε4 noncarriers. CONCLUSION: Midlife smoking was associated with an increased risk of dementia and AD later in life only among those individuals carrying the APOE ε4 allele. These results suggest that the association between smoking and AD may be complex and vary according to genotype.

Serum total cholesterol, statins and cognition in non-demented elderly.

BACKGROUND: The association between serum total cholesterol (TC), lipid-lowering drugs and cognition in the elderly is currently controversial. OBJECTIVE: To investigate the relationship between TC, lipid-lowering drugs and cognitive functions in non-demented elderly. DESIGN AND SETTING: Participants of the Cardiovascular risk factors, aging and dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. Analyses are based on 1382 non-demented participants re-examined in 1998 after an average follow-up of 21 years. RESULTS: High midlife TC was associated with poorer late-life episodic memory and category fluency. TC decreased in most individuals over time. A more pronounced decrease was related to poorer late-life episodic memory and psychomotor speed, but not if subjects used statins. CONCLUSIONS: The TC-cognition relationship seems bidirectional. High midlife TC is associated with poorer late-life cognition, but decreasing TC after midlife may reflect poorer cognitive status. Statins may be beneficial for cognition in non-demented elderly.

Education and dementia: what lies behind the association?

BACKGROUND: Low education seems to be associated with an increased risk of dementia and Alzheimer disease (AD). People with low education have unhealthier lifestyles and more cardiovascular risk factors, but it is unclear how this affects the association between education and dementia. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals (72%) aged 65 to 79 participated in a re-examination in 1998. RESULTS: Compared to individuals with formal education of 5 years or less, those with 6 to 8 years of education had OR of 0.57 (95% CI 0.29 to 1.13), and those with 9 years of education or more had OR of 0.16 (95% CI 0.06 to 0.41) for dementia. The corresponding ORs for AD were 0.49 (0.24 to 1.00) and 0.15 (0.05 to 0.40). The associations remained unchanged after adjustments for several demographic, socioeconomic, vascular, and lifestyle characteristics. The results were similar among both men and women. ApoE4 did not modify the association, but the risk of dementia and AD was very low among ApoE4 noncarriers with high education. CONCLUSIONS: The association between low education and dementia is probably not explained by the unhealthy lifestyles of the less educated compared with higher educated persons. Higher educated persons may have a greater cognitive reserve that can postpone the clinical manifestation of dementia. Unhealthy lifestyles may independently contribute to the depletion of this reserve or directly influence the underlying pathologic processes.

Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study.

BACKGROUND: Longitudinal studies have shown that high serum total cholesterol (TC) at midlife is a risk factor for dementia/Alzheimer disease. The significance of TC later in life is unclear. OBJECTIVE: To investigate changes in serum TC from midlife to late life and their relationship with late-life cognition. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were derived from random, population-based samples previously studied in a survey in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1,449 individuals aged 65 to 79 were reexamined in 1998. RESULTS: Serum TC levels decreased in most individuals. High midlife TC represented a risk factor for more severe cognitive impairment later in life, and the values were significantly different between the control, mild cognitive impairment, and dementia groups. There were no significant differences in serum TC at reexamination. A moderate decrease in serum TC from midlife to late life (0.5 to 2 mmol/L) was significantly associated with the risk of a more impaired late-life cognitive status, even after adjusting for age, follow-up time, sex, years of formal education, midlife cholesterol, changes in body mass index, APOE epsilon4 genotype, history of myocardial infarction/stroke/diabetes, and lipid-lowering treatment. CONCLUSIONS: The relationship between serum total cholesterol (TC) and dementia seems to be bidirectional. High midlife serum TC is a risk factor for subsequent dementia/Alzheimer disease, but decreasing serum TC after midlife may reflect ongoing disease processes and may represent a risk marker for late-life cognitive impairment.

Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study.

BACKGROUND: Lifestyle and vascular factors have been linked to dementia and Alzheimer's disease (AD), but the role of dietary fats in the development of dementia is less clear. METHODS: Participants were derived from random, population-based samples initially studied in midlife (1972, 1977, 1982, or 1987). Fat intake from spreads and milk products was assessed using a structured questionnaire and an interview. After an average follow-up of 21 years, a total of 1,449 (73%) individuals aged 65-80 years participated in the re-examination in 1998. Altogether 117 persons had dementia. RESULTS: Moderate intake of polyunsaturated fats at midlife decreased the risk of dementia even after adjustment for demographic variables, other subtypes of fats, vascular risk factors and disorders, and apolipoprotein E (ApoE) genotype (OR 0.40, CI 0.17-0.94 for the 2nd quartile vs. 1st quartile), whereas saturated fat intake was associated with an increased risk (OR 2.45, CI 1.10-5.47 for the 2nd quartile). The associations were seen only among the ApoE epsilon4 carriers. CONCLUSIONS: Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE epsilon4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.