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Can an Alzheimer's brain be cognitively healthy ? News on amyloid resilience

Some people retain their higher mental functions in old age, although pronounced Alzheimer-typical changes become visible in the brain. Several laboratories are currently on the trail of this phenomenon and are trying to understand the biology behind this so-called Alzheimer's resilience with the intention to use these findings therapeutically. In today's blog post, I would like to focus in particular on human genetic and animal studies that have helped us in our search for such resilience factors.

Dementia is always preceded by neurodegeneration, which in the case of Alzheimer's disease is associated with typical deposits of extracellular beta-amyloid, the so-called Aβ-plaques, and an intracellular accumulation of so-called neurofibrillary tangles (see chapter 2.3 in my book on neurodegeneration). Despite the genetic link between amyloid and Alzheimer's disease, however, a substantial proportion of individuals with amyloid deposits in the brain remain cognitively healthy throughout life: up to one-third of all older people are considered resilient to Alzheimer's pathology.

Recent data now indicate that the number of neurons in the cortex, various synaptic markers, and also axonal morphology are remarkably well preserved in these individuals compared to demented patients. In addition, resilient individuals show a special cytokine profile characterized by higher levels of anti-inflammatory substances (cytokines) and lower concentrations of so-called chemokines. Neurotrophic factors are also increasingly detectable in them.

It is particularly striking that resilient individuals have significantly lower levels of hyper-phosphorylated tau (pTau) in the neocortex compared to demented individuals (with similar amyloid concentrations). It is possible, therefore, that these individuals have a greater cognitive reserve, allowing a higher number of neurons and synaptic contacts to compensate for the loss of function due to a slowly progressive neuropathology.

This hypothesis is supported by the so-called CERAD score (Consortium to Establish a Registry for Alzheimer's Disease) for neuritic plaques and by the Braak scale for neurofibrillary tangles in combination with data from standardized cognitive tests collected before death. In addition, Alzheimer's disease biomarkers in cerebrospinal fluid and the binding of amyloid- and tau-specific ligands in positron emission tomography (PET), but also quantitative analyses of brain structure (volume, cortex thickness, etc.) by magnetic resonance imaging (MRI) point in this direction.

Such data nowadays feed complicated machine learning algorithms that are trained to accurately predict whether a given person is at high or low risk for the onset or progression of AD. In particular, this also involves genetic factors that promote resilience to Alzheimer's pathology.

A recent case study reported on a carrier of a presenilin (PSEN1) mutation (E280A) who, despite high amyloid levels, had no cognitive impairment until she was seventy years old (in carriers of the E280A mutation, dementia otherwise begins at about 49 years of age). It is possible that the resilience in this case is due to the presence of a homozygous APOE variant that leads to a reduction in the low-density lipoprotein (LDL) receptor. Although APOE-ε4 has indeed been identified as the most significant genetic risk factor for AD, some ε4-homozygous individuals do not develop AD.

Other resilience factors are thought to be neurotrophic factors, as, for example, brain derived neurotrophic factor (BDNF) in its mutant form (single nucleotide polymorphism at the 66th amino acid, Val66Met) leads to early neurodegeneration and cognitive decline associated with amyloid pathology. In addition, NRN1, another neurotrophic factor related to resilience, appears to play an important role as it is required for synaptic transmission and maintenance of axonal morphology.

At the level of intra- and intercellular signal transduction, associations were found with sugar and amino acid metabolism, prolactin receptor signaling, and the dehydrogenase pathway, as well as integrin-dependent cell adhesion. Furthermore, an interesting protein associated with resistance to aging and dementia is the transmembrane protein Klotho.

In humans, two variants in the Klotho gene, F352V and C370S, form a so-called functional haplotype. In this case, one but not two copies of the so-called KL-VS haplotype (referred to as KL-VS heterozygosity) are found in the genome and an elevated level of Klotho is found in the blood. Klotho prolongs the lifespan of mice by 20-30% and Klotho mutations lead to accelerated aging as well as a shortened lifespan of the animals. The effects of Klotho can be explained by binding to receptors of the fibroblast growth factor (FGF) family.

KL-VS heterozygosity occurs in 20-25% of the population and is associated with higher cognitive performance, larger brain volume in the frontotemporal region, and lower mortality. In addition to the apparent protective role of Klotho in aging, a lower risk for Alzheimer's disease is also found, as a recent meta-analysis reported that KL-VS heterozygosity is less often associated with dementia in older people carrying the Alzheimer's-associated ApoE-ε4 allele. Neitzel and colleagues further found that the KL-VS variant is associated with reduced tau levels, suggesting that KL-VS heterozygosity potentially protects against tau deposition, i.e., neurofibrillary tangles.

Resilience is also found in animal models of Alzheimer's disease with some mice showing higher levels of learning-related intrinsic neuronal plasticity. In the differential analyses of gene expression in these mice, potential resilience factors can be found in comparison to susceptible siblings. For example, the PLA2G4E gene, which encodes a phospholipase A2, is discussed in this context. Indeed, overexpression of PLA2G4E in hippocampal neurons of Alzheimer's disease mice is already sufficient to restore cognitive functions and increase the number of synaptic contacts without affecting amyloid or tau pathology. PLA2G4E has also been found to be reduced in the brains of late-stage human Alzheimer's patients, so this may be a relevant therapeutic target.

To facilitate the identification of resilience factors, we need to understand which brain regions are involved and at what point in the disease course the resilience mechanisms become effective. Indeed, it is not yet clear exactly where in the brain (or body) resilience originates, when in the disease process it emerges, and how it develops with age. To systematically address such questions, we need comprehensive human data and innovative mouse models that, in the best case scenario, can show us new therapeutic strategies to prevent or treat AD.


Lin, L. et al. (2021) Resilience to plasma and cerebrospinal fluid amyloid-beta in cognitively normal individuals: findings from two cohort studies. Front. Aging Neurosci. 13:610755

Franzmeier, N. et al. (2021) The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease. Mol. Psychiatry 26:614

Neitzel, J. et al. (2021) KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat. Commun. 12:3825

Neuner SM, et al. (2022) Translational approaches to understanding resilience to Alzheimer's disease. Trends. Neurosci. 45:369

Image credit: iStock/Sewcream



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