Alzheimer’s disease in 2021 & beyond – Where we are now

Dr Atri kicked off the symposium by recalling how it has been over 100 years since Dr Alois Alzheimer and Prof Emil Kraepelin first described the symptoms and neuropathology that now define Alzheimer’s disease (AD).¹ Building on findings of the past century, three ‘streams’ of AD research have developed: neurotransmitter biology, encompassing glutamatergic changes and cell loss; lesion pathology; and positional cloning and genetics, both of which include amyloid and tau pathology.¹

Alzheimer’s disease research focusses on neurotransmitter biology, lesion pathology and positional cloning and genetics

The importance of timely diagnosis of AD

Professor Kivipelto highlighted how with around 52 million people currently living with dementia,² the knowledge that AD prevalence doubles approximately every 6.3 years beyond age 60 and a rapidly increasing elderly population,³ it is currently estimated that there will be around 82 million people living with dementia by 2030.² However, stressed Professor Kivipelto, it is essential to understand that while brain disease and damage leading to cognitive and behavioral changes are common in older adults, these should not be viewed, by healthcare professionals especially, as a ‘normal’ part of aging and they should always be investigated.⁴

Timely, accurate and appropriate diagnosis, disclosure and treatment are medical, ethical, social, and economic imperatives, stressed Dr Atri.⁵ Timely detection of level of impairment is both a patient’s right⁶ and necessary for care, housing, community and financial planning; patient, family and caregiver education; and implementation of multimodal treatment interventions to help slow dementia progression.^5,7,8 Undetected cognitive impairment and dementia can be costly to both the patient and society^5,8,9 and lead to potentially dangerous activities that can impact the patient and others such as driving risks, poor financial planning and medication non-adherence.¹⁰

Timely, accurate and appropriate diagnosis, disclosure and treatment of dementia are medical, ethical, social, and economic imperatives

Accurate diagnosis is important in dementia as it can inform not only treatment but also long-term, evolving care needs.⁷ Dr Atri discussed how initial assessment should involve taking a careful social and medical history from the patient (and caregiver if appropriate); assessment of cognitive, functional and neuropsychiatric domains using standardized instruments; a laboratory panel, including blood count, thyroid function and vitamin B₁₂ status; and brain imaging when dementia is suspected.^5,7

Understanding and addressing risk factors for dementia

Professor Kivipelto discussed how the 2020 Lancet Commission report defined 12 risk factors for dementia including medical conditions, such as hypertension, hearing impairment, obesity, depression, diabetes and head injury; lifestyle factors, such as smoking, physical inactivity, excessive alcohol consumption and infrequent social contact; and more general issues, including less childhood education and air pollution. Modifying these risk factors, the Lancet Commission stated, “might prevent or delay up to 40% of dementias” and hence they called for everything from individuals to governmental policy to “be ambitious about prevention.”¹¹

Modifying risk factors on an individual level should include control of hypertension and diabetes; addressing lifestyle factors with interventions for obesity reduction, smoking cessation and excessive alcohol use; encouraging the use of hearing aids and hearing protection; and preventing head injuries. At the governmental level, policies that provide all children with education up to adulthood and limit air pollution need to be put in place globally.¹¹

Lifestyle management is a key factor in staving off the onset of dementia and may help slow dementia progression

How lifestyle interventions can affect cognitive function has been investigated by The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), of which Professor Kivipelto is a part. This proof-of-concept randomized controlled trial assessed a multidomain approach to prevent cognitive decline in at-risk elderly people (n=1260; 60−77 years old) assigned to either the intervention group or a control group who received regular health advice. The intervention consisted of an individually tailored diet low in saturated and trans fatty acids, sugar and salt; physical exercise training; cognitive training; and social activities.¹²

FINGER results showed that after 2 years, the Control group (n=565) had an odds ratio of 1.31 (95% confidence interval 1.01−1.71) for overall cognitive decline (p=0.04) compared to the Intervention group (n=554), with significant differences in decline in individual components including executive functioning scores (p=0.04) and processing speed (p=0.01).¹²

Following FINGER’s successful outcomes, Professor Kivipelto discussed how the initiative was launched worldwide in 2017 as the WW-FINGERS Network and now includes over 40 participating countries.¹³ The clinical trial model has been adapted to individual populations with regard to dementia risk factors, language, culture, ethnicity and environment, for instance as PENSA in Spain, SUPERBRAIN in Korea, AU-ARROW in Australia and Can Thumbs Up in Canada.^13,14 With learnings gained from these studies, Professor Kivipelto revealed how an updated FINGER 2.0 model will include lifestyle and disease-modifying drugs.

Professor Kivipelto also discussed how progress is also being made in development and use of blood-based biomarkers of dementia and dementia prevention,¹⁵ for instance, for the latter, with the LipiDiDiet.¹⁶ There have also been advances in e-health tools, particularly targeted at caregivers, which can help with coping skills, education and emotional self-regulation. These include the web-based program CareHeroes and the smartphone application Virtual Hope Box.¹⁷

The National Institute on Aging and the Alzheimer’s Association (NIA-AA) framework to aid AD research

Dr Atri highlighted in his presentation how the NIA-AA have provided a research framework outlining six stages of AD. These stages apply to people with defined evidence of amyloid pathology; however, other changes can also be mapped to them. At Stage 1, while there is no objective cognitive impairment, subtle changes can be detected in cerebrospinal (CSF) beta-amyloid (Ab₄₂), positron emission tomography (PET)-detected amyloid and CSF tau. Moving from Stage 1 to Stage 2, when cognitive decline may be subtly noticed, further biomarker evidence may be accompanied by evidence of neurodegeneration using magnetic resonance imaging or fluorodeoxyglucose PET. It is not until Stage 3 that objective cognitive decline can be more easily detected using these biomarkers and imaging modalities. By Stage 6, frank neurodegeneration and biomarker evidence, is accompanied by severe objective cognitive impairment.^18-20

To stratify research participants, Alzheimer’s disease can be classified through a combination of aggregated Ab, aggregated tau and neurofibrillary tangles

To help with classification of research participants, the NIA-AA framework defines AD biologically, not symptomatically, as a combination of the presence or absence of ‘A’ (aggregated Ab or the associated pathological state), ‘T’ (aggregated tau, as neurofibrillary tangles, or the associated pathological state) and ‘N’ (neurodegeneration or neuronal injury). Of note, pathological change is only defined by amyloid pathology not by neurodegeneration as this does not necessarily correspond with clinical manifestations.¹⁸

How the Covid-19 pandemic is impacting dementia

According to Professor Kivipelto, the Covid-19 pandemic brought great restrictions on people with dementia, especially those in long-term care. There were also increasing burdens on caregivers for patients who live in the community.²¹ While such restrictions helped shield this population from SARS-CoV-2 infection, a survey involving 613 FINGER study participants found negative impacts of the Covid-19 pandemic on contact with friends and relatives, attendance at cultural events and leisure time physical activity. Respondents also reported increased feelings of loneliness.²² In both the short- and long-term, the World Alzheimer Report 2020 postulated that the restrictions may contribute to accelerated physical and cognitive decline in people with dementia.²³

It is not only the social aspects of Covid-19 that are of concern, stressed Professor Kivipelto, findings from a large health database analysis (n=236,379) suggested that having Covid-19 was associated with an increased incidence of dementia in the 6 months following infection. This was greater in people aged above 65 years, patients who needed hospitalization due to Covid-19 and as compared to patients who had influenza (n=105,579) or a respiratory tract infection (n=236,038).²⁴

The Covid-19 pandemic impacted people with dementia and their caregivers and SARS-CoV-2 infection may increase incidence of dementia

Conclusion

The presentations by Professor Kivipelto and Dr Atri highlighted the importance of timely, accurate and appropriate diagnosis and management of dementia. Lifestyle control is a key factor in staving off the onset of dementia and may help slow dementia progression.

Educational financial support for this webinar was provided by H. Lundbeck A/S.