Alzheimer's disease

Abstract

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Imaging findings of a case similar to patient B’s case in panel 1

(A) Amyloid Pittsburgh compound B-PET scan showing amyloid deposition predominantly in the posterior cingulate region. (B) T1-weighted MRI images showing generalised cortical atrophy, left to right. (C) Tau-PET image using AV1451 tracer, showing left-sided inferotemporal lobe, parietal, and mild posterior cingulate deposition of tau. Image courtesy of Rik Ossenkoppele and Gil Rabinovici.

Figure 2:. Alzheimer’s disease is a continuum

The arrow points to the continuum of Alzheimer’s disease, stretching over a period of 15–25 years, in which Alzheimer’s disease pathology can be present without any symptoms via a stage of mild cognitive impairment leading up to overt dementia, illustrating that dementia is the end result of a long-time presence of Alzheimer’s disease pathology. Not every patient will necessarily follow this path by definition. Note: between normal and mild cognitive impairment, patients can experience subjective complaints, but not all complaints are early signs of dementia and the predictive value of having complaints for dementia is unknown.

Figure 3:. The genetic landscape of Alzheimer’s disease

MAF (x-axis) is the frequency at which a non-reference (variant) allele occurs in the population. Variant carriers with OR=1 and non-carriers have the same odds of developing Alzheimer’s disease, variants with OR >1 are associated with an increased risk of Alzheimer’s disease, and variants with OR PSEN1, PSEN2, and APP cause autosomal dominant Alzheimer’s disease, in some cases with age at onsets as early as 40 years old. Note that not all variants in these three genes give rise to autosomal dominant Alzheimer’s disease; some might be risk-modifiers or non-pathogenic. Further, evidence is accumulating that certain variants in the SORL1 gene are causative of Alzheimer’s disease before the age of 70 years. The Alzheimer’s disease-association of variants in the SORL1, ABCA7, and TREM2 genes was found in gene-based tests; carriers may come from small pedigrees with inheritance patterns of Alzheimer’s disease suggestive of autosomal dominant inheritance. (B) GWAS hits are common (by convention, MAF >1%) variants that represent risk alleles that occur with significantly different frequency in patients with Alzheimer’s disease and controls. Each variant is represented by the gene in which it occurs, or when the variant is non-coding, by the gene that maps closest to the variant (depicted in dark grey). (C) Protective variants are (very) rare variants suggested to confer resistance against age-associated or disease-associated risk factors of cognitive decline. GWAS=genome-wide association studies. MAF=minor allele frequency. OR=odds ratio. PRS=polygenic risk scores.

Figure 4:. The cellular phase of Alzheimer’s disease

Although amyloid plaques (red, middle of the figure) and tau phosphorylation and tangles (neurons, top right corner) are still considered the defining features of Alzheimer’s disease, the focus of research has been widened from neurons to the response of other cell populations in the disease. The microglia-mediated inflammation, known for decades to be present in Alzheimer’s disease, has finally taken centre-stage in functional research on the pathogenesis of the disease. Many of the risk-genes protein products (bold and capitals) identified in Alzheimer’s disease (figure 3) are expressed and have functions in microglia. These genes become upregulated when microglia are exposed to amyloid plaques and many of the Alzheimer’s disease risk genes are enriched in the disease-associated microglia response that characterises this cell state.– Other genes involved in this response and moderately positive in genome-wide association studies are indicated as well. Adapted from Sierksma et al, by permission of EMBO Molecular Medicine.