**3. Interventional studies**

#### **3.1. Current evidence**

study (CAIDE), the risk of dementia has been evaluated in relation to a score (CAIDE Dementia Risk Score) combining mid-life risk factors, including low education and cardiovascular factors (i.e., hypertension, obesity, hypercholesterolemia, physical inactivity). The risk of dementia increased as the score increased in a dose-response trend, making it possible to identify individuals who can greatly benefit from preventive intervention that targets vascular risk factors [128]. Similar findings have been reported for late-life exposures: in the Swedish Kungsholmen Project, the cumulative effect of vascular risk factors and vascular diseases on dementia/AD risk has been investigated in people aged 75+ years. These factors were aggre‐ gated according to two pathophysiological hypotheses: the brain hypoperfusion profile, defined by chronic heart failure, low pulse pressure, and low diastolic pressure, and the atherosclerosis profile, which included high systolic pressure, diabetes mellitus or prediabetes, and stroke. In both profiles, dementia/AD risk increased with increasing scores in a doseresponse manner, suggesting a synergy of vascular risk factors in promoting dementia/AD also in advanced age [129]. The American Cardiovascular Health Cognition Study developed a Late-life Dementia Risk Index, and also its brief version, which groups older adults in the three categories of low, moderate, and high risk of developing dementia. Both versions of the index support the cumulative effect of different factors in determining the risk of dementia after the age of 65 years. These indices include information from different domains, including demographic factors (age), genetic (presence of the *APOE* ε4 allele), lifestyle (BMI<18.5, lack of alcohol consumption), comorbid vascular conditions (internal carotid artery thickening, angina, coronary artery by-pass surgery, stroke, peripheral artery disease), evidence of brain abnormalities showed by magnetic resonance imaging (MRI) (white matter diseases or

enlarged ventricles), cognitive test scores and physical performances [130, 131].

*APOE* ε4 allele carriers [133].

460 Understanding Alzheimer's Disease

dementia risk due to low education [78].

The combined effect of genetic-environmental or environmental-environmental joint expo‐ sures may also lead to the attenuation of the dementia risk. Population-based studies suggest an effect modification for the *APOE* ε4 allele, the most important genetic risk factor for sporadic AD. *APOE* ε4 carriers seem more vulnerable to risk factors like alcohol drinking, smoking, physical inactivity and high intake of saturate fat, indicating that people with genetic suscept‐ ibility may reduce their initial AD risk by lifestyle interventions (i.e., physical activity, sufficient intake of PUFA, and avoiding excess alcohol drinking and smoking) [33]. The protective effect of lifestyle in *APOE* ε4 carriers seem to be present also in advanced age: in the Swedish Kungsholmen Project, subjects aged 75+ years who were *APOE* ε4 carriers, but with high education, active leisure activities, or good vascular health (i.e., absence of vascular risk factors), had a reduced risk of dementia and AD, as well as a delayed time of onset of the disease [132]. Further, it has been shown that high education may reduce dementia risk among

Regarding the interactions among modifiable risk factors, results from the Kungsholmen Project suggested that complexity of work with data and people was related to a decreased dementia risk and that the highest level of work complexity may modulate the increased

In conclusion, even though the evidence for some risk and protective factors in dementia and AD is still scarce, and their role needs to be further clarified, findings from observational

Different medications, including statins, antihypertensive drugs, estrogens alone or in combination with progestin (hormone replacement therapy, HRT), nonsteroidal anti-inflam‐ matory drugs (NSAIDs), and nutraceuticals (vitamin B12, C, E, folate, Ginkgo biloba) have been tested as primary or secondary prevention measures for dementia and AD in subjects with normal cognition or MCI. In general, for all these compounds the protective effects suggested by observational studies have not been confirmed in RCTs, the results of which are inconsistent or even suggest a detrimental effect on cognition (e.g., NSAIDs, HRT) [120, 134-136]. Few interventional studies implementing non-pharmacological approaches have been carried out. Among them some RCTs on cognitive training and physical activity provided encouraging results, which need further confirmation [134, 137]. It is possible that the negative results from the RCTs done so far reflect the real inefficacy of the tested strategies in preventing dementia and AD. However, the apparent contradiction of results from observational and interventional studies could be explained by several factors:

**1.** The intervention was done outside the time-window when management of a risk factor would reduce dementia risk: several risk factors exert their effect mainly during mid-life, whereas RCTs have been done in older adults. This is the case for vascular risk factors, which seem to be more relevant when the exposure occurs during mid-life. Moreover, the HRT research suggests that estrogens may have beneficial, neutral, or detrimental effects on the brain depending on age at treatment, type of menopause (natural versus medically or surgically induced) or stage of menopause [138]. This concept, called the "window of opportunity hypothesis" is in agreement with the life-course approach model. There is evidence of neuroprotective effects of estrogens in women before the age of natural menopause and in the early postmenopausal stage (50-60 years), while estrogens initiated in late postmenopause (65-79 years) increase the risk of cognitive impairment and dementia [138-142]. The large-scale RCT of the Women's Health Initiative Memory Study (WHI-MS) showed that estrogens therapy alone or in combination with progestin was associated with a two-fold increased risk for dementia and MCI [139, 140]. The WHI-MS study enrolled women aged 65-79 years, who were given the HRT many years after the onset of natural or surgical menopause. In contrast, the Kronos Early Estrogen Prevention Study (KEEPS) tested the HRT in recently menopausal women (mean age 53 years; enrolment within three years after menopause), reporting beneficial effects [141]. In fact, the use of the HRT in the KEEPS participants has been associated with the improvement of markers of cardiovascular risk, anxiety and depression, without adverse effects on cognition [141]. Overall these results suggest that the role of the HRT in age-related cognition and dementia needs to be further investigated, taking into account the timewindow when the treatment is administered.

are also important, as placebo-controlled trials for high blood pressure and cholesterol are not possible due to their known protective effects regarding cardio- and cerebrovascular disease. Furthermore, a critical aspect that needs to be taken into account when planning preventive measures for dementia and AD, is the multifactorial nature of these disorders, which require multiple prevention approaches. Intervention studies combining several different approaches have not been conducted for AD so far, and the knowledge derived from the previously described observational and interventional studies has paved the way for some ongoing RCTs on prevention of cognitive decline and dementia. In Europe there are three large ongoing RCTs: FINGER, MAPT and PreDIVA [145, 146] (Table 2). The common denominator of these studies is the multidomain approach, which aims to target simultaneously several risk factors for dementia and AD in older adults, mainly by promoting lifestyle changes and adherence to medical treatments for vascular risk factors and vascular diseases. All RCTs exclude individ‐ uals with dementia or substantial cognitive decline, and use clinical evaluation and neuro‐ psychological tests to detect cognitive changes and dementia incidence as main outcomes. Further, secondary outcomes include functional status, mood disorders, quality of life, adherence to the intervention programs and health resources utilization. These two latter aspects are essential from a public health perspective, since they provide information on feasibility and cost effectiveness of prevention strategies. Additionally, both FINGER and MAPT include ancillary studies on neuroimaging (morphological and functional), CSF and blood markers related to AD pathophysiology in order to investigate the effect of the inter‐ ventions on brain morphology and metabolism, clarify mechanisms underlying preventive measures and identify biomarkers that can be used to monitor effects of interventions.

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The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER, NCT01041989) is a multicenter RCT aiming to prevent cognitive impairment, dementia and disability in 60-77 year-old people. The study population is represented by 1282 individuals at increased risk of dementia, selected according to the CAIDE Dementia Risk Score and the CERAD neuropsychological test battery [128, 145]. The 2-year multidomain intervention includes nutritional guidance, physical activity, cognitive training, increased social activity and intensive monitoring and management of metabolic and vascular risk factors (hypertension, dyslipidemia, obesity, impaired glucose tolerance). Individuals in the reference group are given general public health advice on lifestyle and vascular risk factors. FINGER participants are recruited from previous population-based observational surveys (i.e., FINRISK, FIN-D2D) with detailed retrospective information on lifestyle and vascular factors [145]. Thus, differences in these variables can be taken into account, which is normally not possible in RCTs. The primary outcome is cognitive decline measured by a sensitive Neuro‐ psychological Test Battery (NTB) and the Stroop and Trail Making tests, which can depict early cognitive impairment typical for AD and VaD. The planned 7-year extended follow-up will allow detection of differences in dementia/AD incidence. Two earlier intervention trials in Finland were important sources of inspiration for the FINGER study. The Diabetes Prevention Study (now completed) is a landmark RCT showing the effectiveness and feasibility of physical exercise and dietary interventions as preventive measures in people with impaired glucose tolerance. In this RCT lifestyle intervention in people at high risk for type 2 diabetes resulted in sustained lifestyle changes and a reduction in diabetes incidence, which remained after the


In conclusion, despite the discrepancies between findings of observational and interventional studies and the disappointing results of intervention studies on dementia and AD, methodo‐ logical issues of the RCTs carried out thus far suggest that a valid evaluation of the efficacy of preventive measures has yet to be undertaken.

#### **3.2. Ongoing multidomain intervention studies**

The disappointing results of previous trials, testing the effects of mono-intervention strategies in cognitively normal elderly or already cognitively impaired persons, have pointed out some key issues: i) timing – starting earlier may lead to better effects; ii) target group – a healthy, young population would require long follow-up times, large sample sizes and considerable financial resources; iii) lack of consistent and uniformly applied definitions of MCI has lead to enrolment of heterogeneous groups underpowering the studies; iv) outcome measures – cognitive impairment may be a better endpoint than conversion to dementia; v) ethical issues are also important, as placebo-controlled trials for high blood pressure and cholesterol are not possible due to their known protective effects regarding cardio- and cerebrovascular disease. Furthermore, a critical aspect that needs to be taken into account when planning preventive measures for dementia and AD, is the multifactorial nature of these disorders, which require multiple prevention approaches. Intervention studies combining several different approaches have not been conducted for AD so far, and the knowledge derived from the previously described observational and interventional studies has paved the way for some ongoing RCTs on prevention of cognitive decline and dementia. In Europe there are three large ongoing RCTs: FINGER, MAPT and PreDIVA [145, 146] (Table 2). The common denominator of these studies is the multidomain approach, which aims to target simultaneously several risk factors for dementia and AD in older adults, mainly by promoting lifestyle changes and adherence to medical treatments for vascular risk factors and vascular diseases. All RCTs exclude individ‐ uals with dementia or substantial cognitive decline, and use clinical evaluation and neuro‐ psychological tests to detect cognitive changes and dementia incidence as main outcomes. Further, secondary outcomes include functional status, mood disorders, quality of life, adherence to the intervention programs and health resources utilization. These two latter aspects are essential from a public health perspective, since they provide information on feasibility and cost effectiveness of prevention strategies. Additionally, both FINGER and MAPT include ancillary studies on neuroimaging (morphological and functional), CSF and blood markers related to AD pathophysiology in order to investigate the effect of the inter‐ ventions on brain morphology and metabolism, clarify mechanisms underlying preventive measures and identify biomarkers that can be used to monitor effects of interventions.

cognition [141]. Overall these results suggest that the role of the HRT in age-related cognition and dementia needs to be further investigated, taking into account the time-

**2.** Short treatment and follow-up: many studies were of relatively short length. Thus, interventions have been implemented for a period that is not long enough to determine a neuroprotective effect, and the limited follow-up duration of many RCTs would not allow

**3.** The statistical power was inadequate, since some RCTs had small samples and dementia has been considered a secondary endpoint in most clinical trials (e.g., antihypertensive therapy), in which clear benefits for primary endpoints (e.g., coronary heart disease and

**4.** The choice of compounds tested in RCTs using nutraceuticals was not optimal: although several products have been tested, supplements composition is still a debated issue. For instance, whereas observational studies suggested that a balanced intake of different forms of vitamin E can be important for reducing dementia/AD risk, only one form (αtocopherol) has been tested in RCTs, with conflicting findings [84, 85, 107, 108, 143]. Moreover, intake of high doses of α-tocopherol supplements has been associated with increased hemorrhagic stroke and mortality risk [144]. Regarding the studies on vitamins B, while the majority of RCTs done so far did not find evidence of benefit [120, 121], a recent RCT reported favourable effects in subjects with MCI, especially individuals with elevated homocysteine levels. In this latter RCT supplementation was done using a combination of vitamins B (B6, B12, folate) at high doses, suggesting that refining the type of supplements (i.e. composition, concentration) might increases the possibility to achieve

**5.** Despite the multifactorial nature of dementia and the importance of combined risk exposures, most studies were based on a mono-intervention approach, almost always testing single agents or lifestyle interventions. In multifactorial conditions, a small

In conclusion, despite the discrepancies between findings of observational and interventional studies and the disappointing results of intervention studies on dementia and AD, methodo‐ logical issues of the RCTs carried out thus far suggest that a valid evaluation of the efficacy of

The disappointing results of previous trials, testing the effects of mono-intervention strategies in cognitively normal elderly or already cognitively impaired persons, have pointed out some key issues: i) timing – starting earlier may lead to better effects; ii) target group – a healthy, young population would require long follow-up times, large sample sizes and considerable financial resources; iii) lack of consistent and uniformly applied definitions of MCI has lead to enrolment of heterogeneous groups underpowering the studies; iv) outcome measures – cognitive impairment may be a better endpoint than conversion to dementia; v) ethical issues

reduction in multiple risk factors can substantially decrease overall risk.

window when the treatment is administered.

462 Understanding Alzheimer's Disease

detection of differences in dementia incidence.

stroke) are shown usually in a short period of observation.

beneficial effects in selected populations [122, 123].

preventive measures has yet to be undertaken.

**3.2. Ongoing multidomain intervention studies**

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER, NCT01041989) is a multicenter RCT aiming to prevent cognitive impairment, dementia and disability in 60-77 year-old people. The study population is represented by 1282 individuals at increased risk of dementia, selected according to the CAIDE Dementia Risk Score and the CERAD neuropsychological test battery [128, 145]. The 2-year multidomain intervention includes nutritional guidance, physical activity, cognitive training, increased social activity and intensive monitoring and management of metabolic and vascular risk factors (hypertension, dyslipidemia, obesity, impaired glucose tolerance). Individuals in the reference group are given general public health advice on lifestyle and vascular risk factors. FINGER participants are recruited from previous population-based observational surveys (i.e., FINRISK, FIN-D2D) with detailed retrospective information on lifestyle and vascular factors [145]. Thus, differences in these variables can be taken into account, which is normally not possible in RCTs. The primary outcome is cognitive decline measured by a sensitive Neuro‐ psychological Test Battery (NTB) and the Stroop and Trail Making tests, which can depict early cognitive impairment typical for AD and VaD. The planned 7-year extended follow-up will allow detection of differences in dementia/AD incidence. Two earlier intervention trials in Finland were important sources of inspiration for the FINGER study. The Diabetes Prevention Study (now completed) is a landmark RCT showing the effectiveness and feasibility of physical exercise and dietary interventions as preventive measures in people with impaired glucose tolerance. In this RCT lifestyle intervention in people at high risk for type 2 diabetes resulted in sustained lifestyle changes and a reduction in diabetes incidence, which remained after the individual lifestyle counselling was stopped [147, 148]. The four-year exercise and dietary intervention study Dose-Responses to Exercise Training (DRs EXTRA) had a drop-out rate of only 8% after two years, and preliminary results suggested a potential benefit of higher physical fitness on cognition [149].

domain intervention, or their combination in the prevention of cognitive decline in frail individuals aged ≥70 years. 1680 community-dwelling participants have been enrolled, using a definition of frailty that includes three components: presence of memory complaints, limitation in one instrumental activity of daily living (IADL) and slow walking speed. The 3 year multidomain intervention consists of group training sessions (physical exercise, cognitive training and nutritional advice) and yearly personalized preventive consultations that aim to identify dementia and frailty risk factors (vascular risk factors, nutritional problems, sensory deficits, mood disorders, walking difficulties) and promote their management in collaboration with the general practitioner. Follow-up is 5 years, and the main outcome measure is the 3 year change in cognitive function assessed with a neuropsychological test (Grober and

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The Prevention of Dementia by Intensive Vascular Care (PreDIVA) study is a Dutch multi‐ center, open, cluster-RCT comparing standard and intensive care of cardiovascular risk factors in preventing dementia and disability in elderly people. The study includes 3534 communitydwellers aged 70-78 years, recruited from primary care practices. The standard care is based on guidelines for Dutch general practice, while the multi-component intensive vascular care addresses hypertension, hypercholesterolemia, smoking habits, overweight, physical inactiv‐ ity and diabetes mellitus, which are strictly controlled with medication and lifestyle interven‐ tions. Study duration is 6 years, and primary outcomes are incident dementia assessed according to standard criteria and disability as measured with the AMC Linear Disability Scale

Researchers involved in these large European trials (FINGER, MAPT and PreDIVA) recently started the European Dementia Prevention Initiative (EDPI), an international collaboration to improve preventive strategies against dementia [151]. Collaboration and data sharing within the EDPI will allow refining methodological aspects of prevention trials, including identifica‐ tion of target populations; improvement of intervention methods (i.e., type, intensity, dura‐ tion); and development and standardization of relevant outcome measures and prognostic and monitoring tools that can be easily implemented in large populations. This will help planning larger and international prevention trials able to provide robust evidence on dementia/AD

Presymptomatic (or preclinical) AD treatments have been defined as "those interventions that are initiated before apparent cognitive decline and are intended to reduce the chance of developing AD-related symptoms" [152]. The proposed term refers to an intervention whether it is started before or after biological evidence of the underlying disease, and whether it postpones the onset, partially reduces the risk of, or completely prevents symptomatic AD [153]. The progress on the knowledge about the AD phenotype, particularly on the biomarkers which have been incorporated in the new diagnostic criteria for dementia and MCI due AD, as well preclinical AD, has provided the basis for intervention studies evaluating pharmaco‐ logical interventions in asymptomatic subjects who are at risk of AD, because of an established biomarker burden or a specific genetic profile. Three RCTs are planned to start in 2013 to verify

**3.3. Presymptomatic Alzheimer's disease treatment: Anti-amyloid drugs**

Buschke) [145, 150].

(ALDS) [146].

prevention.


**Table 2.** Ongoing multi-domain prevention RCTs on dementia

The Multidomain Alzheimer Preventive Trial (MAPT, NCT00672685) is a French multicenter RCT evaluating the efficacy of isolated supplementation with ω-3 fatty acid, isolated multi‐ domain intervention, or their combination in the prevention of cognitive decline in frail individuals aged ≥70 years. 1680 community-dwelling participants have been enrolled, using a definition of frailty that includes three components: presence of memory complaints, limitation in one instrumental activity of daily living (IADL) and slow walking speed. The 3 year multidomain intervention consists of group training sessions (physical exercise, cognitive training and nutritional advice) and yearly personalized preventive consultations that aim to identify dementia and frailty risk factors (vascular risk factors, nutritional problems, sensory deficits, mood disorders, walking difficulties) and promote their management in collaboration with the general practitioner. Follow-up is 5 years, and the main outcome measure is the 3 year change in cognitive function assessed with a neuropsychological test (Grober and Buschke) [145, 150].

individual lifestyle counselling was stopped [147, 148]. The four-year exercise and dietary intervention study Dose-Responses to Exercise Training (DRs EXTRA) had a drop-out rate of only 8% after two years, and preliminary results suggested a potential benefit of higher

> **MAPT France**

Frail elderly people (subjective memory complaint, slow walking speed, limitation in IADL)

Multi-center, randomized,

Vascular care, nutritional advice, exercise advice, cognitive training, and/or DHA 800 mg/day

Change in cognitive function (Grober and Buschke memory test)

controlled trial

**Pre-DIVA Netherlands**

All elderly within GP practices, non demented

Multi-site, open, clusterrandomized parallel

Nurse-led vascular care including medical treatment of risk factors, diet advice, exercise

Dementia, Disability

(MMSE >23)

group

advice

physical fitness on cognition [149].

464 Understanding Alzheimer's Disease

**FINGER Finland**

and mild degree of cognitive impairment

Main inclusion criteria Dementia Risk Score >6

Study design Multi-center, randomized,

Multi-domain intervention Nutritional guidance,

Primary outcome Neuropsychological test

**Table 2.** Ongoing multi-domain prevention RCTs on dementia

Sample size 1282 1680 3534

Age at enrolment, yrs 60 -77 ≥ 70 70-78

single-blind, parallel-group

physical activity, cognitive training, increased social activity and intensive monitoring and

management of metabolic and vascular risk factors

battery, Trail Making test, Stroop test, Dementia

Intervention period 2 yrs 3 yrs 6 yrs

Follow-up period 7 yrs 5 ysr 6 yrs

Study Completion 2013 2013 2016

DHA: docosahexaenoic acid acid. IADL: Instrumental Activities of Daily Living. MMSE: Mini Mental State Examination

The Multidomain Alzheimer Preventive Trial (MAPT, NCT00672685) is a French multicenter RCT evaluating the efficacy of isolated supplementation with ω-3 fatty acid, isolated multi‐

**RCT Country**

> The Prevention of Dementia by Intensive Vascular Care (PreDIVA) study is a Dutch multi‐ center, open, cluster-RCT comparing standard and intensive care of cardiovascular risk factors in preventing dementia and disability in elderly people. The study includes 3534 communitydwellers aged 70-78 years, recruited from primary care practices. The standard care is based on guidelines for Dutch general practice, while the multi-component intensive vascular care addresses hypertension, hypercholesterolemia, smoking habits, overweight, physical inactiv‐ ity and diabetes mellitus, which are strictly controlled with medication and lifestyle interven‐ tions. Study duration is 6 years, and primary outcomes are incident dementia assessed according to standard criteria and disability as measured with the AMC Linear Disability Scale (ALDS) [146].

> Researchers involved in these large European trials (FINGER, MAPT and PreDIVA) recently started the European Dementia Prevention Initiative (EDPI), an international collaboration to improve preventive strategies against dementia [151]. Collaboration and data sharing within the EDPI will allow refining methodological aspects of prevention trials, including identifica‐ tion of target populations; improvement of intervention methods (i.e., type, intensity, dura‐ tion); and development and standardization of relevant outcome measures and prognostic and monitoring tools that can be easily implemented in large populations. This will help planning larger and international prevention trials able to provide robust evidence on dementia/AD prevention.

#### **3.3. Presymptomatic Alzheimer's disease treatment: Anti-amyloid drugs**

Presymptomatic (or preclinical) AD treatments have been defined as "those interventions that are initiated before apparent cognitive decline and are intended to reduce the chance of developing AD-related symptoms" [152]. The proposed term refers to an intervention whether it is started before or after biological evidence of the underlying disease, and whether it postpones the onset, partially reduces the risk of, or completely prevents symptomatic AD [153]. The progress on the knowledge about the AD phenotype, particularly on the biomarkers which have been incorporated in the new diagnostic criteria for dementia and MCI due AD, as well preclinical AD, has provided the basis for intervention studies evaluating pharmaco‐ logical interventions in asymptomatic subjects who are at risk of AD, because of an established biomarker burden or a specific genetic profile. Three RCTs are planned to start in 2013 to verify safety and efficacy of anti-amyloid drugs as preventive measure in AD (Table 3). The Alz‐ heimer's Prevention Initiative (API) and the Dominantly Inherited Alzheimer's Network (DIAN) studies will enrol subjects who carry genetic mutations for dominantly inherited AD: mutations in the *APP*, presenilin-1 (*PSEN1*), and presenilin-2 (*PSEN2*) genes can cause earlyonset familial AD that accounts for no more than 5 percent of all cases [154].

they have been provided too late. The preventive RCTs on anti-amyloid drugs are based on the assumption that an earlier interference on amyloid accumulation, before irreversible brain damage occurs, would exert a significant disease-modifying effect. These prevention studies will also allow determining the ability of different biomarkers to predict a clinical benefit, information needed to help qualify biomarker endpoints for use in prevention trials. These studies offer great hope, but also safety concerns, since anti-amyloid compounds will be tested in subjects with no cognitive problems and the long-term risk associated with the use of anti-

> **DIAN Dominantly Inherited Alzheimer**

**A4**

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**AD**

**Anti-Amyloid**

**Treatment of Asymptomatic**

1500 older adults with no cognitive impairment

Evidence of brain amyloid accumulation. Subject with no evidence of amyloid burden will also be included

Randomized, double blind, placebo controlled trial

therapy (to be determined)

Primary: cognitive function Secondary: biomarkers

One anti-amyloid

**Network**

early-onset AD

genetic status

240 members of families with

Carriers of mutation in *PSEN1,* or *PSEN2,* or *APP*. Non-carriers will also be included, to ensure double-blinding about the

Randomized, double blind, placebo controlled trial

Three anti-amyloid therapies: the beta-secretase inhibitor LY2886721 (Lilly), and the anti-

Initial phase (2 yrs): biomarkers analysis, to identify the most promising drug candidate Follow-up phase (3 yrs): cognitive function

amyloid antibodies Gantenerumab (Roche) and Solanezumab (Lilly)

Duration 5 yrs, (interim analysis at 2 yrs) 2 yrs + 3 yrs extension 3 yrs + 2 yrs extension

amyloid drugs is yet unknown.

**Alzheimer's Prevention**

A small number of individuals from USA (collaboration with the DIAN network) will also be

gene. Non-carriers will also be included, to ensure doubleblinding about the genetic

placebo controlled trial

Crenezumab (Genentech)

Secondary: biomarkers, including brain amyloid load

and brain atrophy

*APP*: amyloid precursor protein. *PSEN1*: presenilin 1. *PSEN2*: presenilin 1

**Table 3.** Alzheimer's prevention trials based on anti-amyloid treatments

Age at enrolment, yrs ≥ 30 NA ≥ 70

**Initiative**

included

Main inclusion criteria Carriers of a mutated *PSEN1*

status

Study design Randomized, double blind,

Outcomes Primary: cognitive function

Intervention Anti-amyloid antibody

Sample size 300 members of Colombian families.

**RCT API**

Data from the DIAN study have shown that different phenotypic changes can be detected several years before the onset of cognitive symptoms in individual with autosomal dominant AD: it has been shown that CSF levels of Aβ42 decline 25 years before expected symptom onset, and brain deposition of Aβ can be detected 15 years before. Further, increased concentrations of tau protein in the CSF and brain atrophy are visible 15 years before expected symptom onset, while cerebral hypometabolism can be observed 10 years before [155]. The API RCT will focus on the world largest early-onset AD kindred in Antioquia, Columbia. Of about 5000 individ‐ uals in this kindred, approximately 1500 carry a mutation in the *PSEN1* gene (E280A) causing early onset AD (mean age of onset: 45 years) [156, 157]. The trial will also include a small number of individuals in the United States, recruited in collaboration with researchers from the DIAN study [158]. The drug used in the API study is the anti-amyloid antibody crenezu‐ mab, which has been chosen based on the evidence of its ability to remove from the brain different forms of Aβ and its safety profile (low risk of cerebral vasogenic oedema and microhaemorrhages) [157]. The trial within the DIAN cohort will include people with muta‐ tions in any of the three genes linked to early-onset AD: *PSEN1*, *PSEN2*, and *APP*. Three different anti-amyloid compounds will be evaluated in the first phase of the study (2 years): the beta-secretase inhibitor LY2886721, which limits the production of Aβ; and two antiamyloid antibodies (Gantenerumab, Solanezumab) which promote Aβ removal from the brain. The more effective drug(s) will be further tested in a 3 years extension phase of the study. A third trial, the Anti-Amyloid Treatment of Asymptomatic Alzheimer's (A4) RTC, aims to prevent sporadic AD and will evaluate the effect of an anti-amyloid compound in older adults with evidence of brain amyloid accumulation at neuroimaging evaluation. The study is sponsored by the Alzheimer's Disease Cooperative Study, and also in this case the drug candidate still needs to be identified among anti-amyloid compounds. The study is expected to detect differences in the rate of cogntive decline, while it has not enough statistical power to detect a difference in dementia incidence. The A4 study will also include an ethics arm examining the psychological impact of disclosing information to individuals about their risk of developing AD [157].

Overall, these studies provide the opportunity to test the efficacy of AD-modifying treatments in an earlier stage of AD compared to the pharmacological RCTs done so far. While testing these compounds in young, healthy individuals would require enormous financial resources and too long follow up, the recruitment strategies implemented in these studies allow testing the benefit of anti-amyloid drugs earlier than otherwise possible. This approach provides also the opportunity to further verify the amyloid hypothesis, which has been reconsidered many times over the past decades and criticized in light of the recent failures of RCTs testing antiamyloid drugs in subjects with mild-to-moderate AD. A possible interpretation of these failures is that the anti-amyloid therapies have missed their "window of opportunity", since they have been provided too late. The preventive RCTs on anti-amyloid drugs are based on the assumption that an earlier interference on amyloid accumulation, before irreversible brain damage occurs, would exert a significant disease-modifying effect. These prevention studies will also allow determining the ability of different biomarkers to predict a clinical benefit, information needed to help qualify biomarker endpoints for use in prevention trials. These studies offer great hope, but also safety concerns, since anti-amyloid compounds will be tested in subjects with no cognitive problems and the long-term risk associated with the use of antiamyloid drugs is yet unknown.

safety and efficacy of anti-amyloid drugs as preventive measure in AD (Table 3). The Alz‐ heimer's Prevention Initiative (API) and the Dominantly Inherited Alzheimer's Network (DIAN) studies will enrol subjects who carry genetic mutations for dominantly inherited AD: mutations in the *APP*, presenilin-1 (*PSEN1*), and presenilin-2 (*PSEN2*) genes can cause early-

Data from the DIAN study have shown that different phenotypic changes can be detected several years before the onset of cognitive symptoms in individual with autosomal dominant AD: it has been shown that CSF levels of Aβ42 decline 25 years before expected symptom onset, and brain deposition of Aβ can be detected 15 years before. Further, increased concentrations of tau protein in the CSF and brain atrophy are visible 15 years before expected symptom onset, while cerebral hypometabolism can be observed 10 years before [155]. The API RCT will focus on the world largest early-onset AD kindred in Antioquia, Columbia. Of about 5000 individ‐ uals in this kindred, approximately 1500 carry a mutation in the *PSEN1* gene (E280A) causing early onset AD (mean age of onset: 45 years) [156, 157]. The trial will also include a small number of individuals in the United States, recruited in collaboration with researchers from the DIAN study [158]. The drug used in the API study is the anti-amyloid antibody crenezu‐ mab, which has been chosen based on the evidence of its ability to remove from the brain different forms of Aβ and its safety profile (low risk of cerebral vasogenic oedema and microhaemorrhages) [157]. The trial within the DIAN cohort will include people with muta‐ tions in any of the three genes linked to early-onset AD: *PSEN1*, *PSEN2*, and *APP*. Three different anti-amyloid compounds will be evaluated in the first phase of the study (2 years): the beta-secretase inhibitor LY2886721, which limits the production of Aβ; and two antiamyloid antibodies (Gantenerumab, Solanezumab) which promote Aβ removal from the brain. The more effective drug(s) will be further tested in a 3 years extension phase of the study. A third trial, the Anti-Amyloid Treatment of Asymptomatic Alzheimer's (A4) RTC, aims to prevent sporadic AD and will evaluate the effect of an anti-amyloid compound in older adults with evidence of brain amyloid accumulation at neuroimaging evaluation. The study is sponsored by the Alzheimer's Disease Cooperative Study, and also in this case the drug candidate still needs to be identified among anti-amyloid compounds. The study is expected to detect differences in the rate of cogntive decline, while it has not enough statistical power to detect a difference in dementia incidence. The A4 study will also include an ethics arm examining the psychological impact of disclosing information to individuals about their risk

Overall, these studies provide the opportunity to test the efficacy of AD-modifying treatments in an earlier stage of AD compared to the pharmacological RCTs done so far. While testing these compounds in young, healthy individuals would require enormous financial resources and too long follow up, the recruitment strategies implemented in these studies allow testing the benefit of anti-amyloid drugs earlier than otherwise possible. This approach provides also the opportunity to further verify the amyloid hypothesis, which has been reconsidered many times over the past decades and criticized in light of the recent failures of RCTs testing antiamyloid drugs in subjects with mild-to-moderate AD. A possible interpretation of these failures is that the anti-amyloid therapies have missed their "window of opportunity", since

onset familial AD that accounts for no more than 5 percent of all cases [154].

of developing AD [157].

466 Understanding Alzheimer's Disease


**Table 3.** Alzheimer's prevention trials based on anti-amyloid treatments
